AU2023201100A1 - Therapeutic compositions and uses thereof - Google Patents
Therapeutic compositions and uses thereof Download PDFInfo
- Publication number
- AU2023201100A1 AU2023201100A1 AU2023201100A AU2023201100A AU2023201100A1 AU 2023201100 A1 AU2023201100 A1 AU 2023201100A1 AU 2023201100 A AU2023201100 A AU 2023201100A AU 2023201100 A AU2023201100 A AU 2023201100A AU 2023201100 A1 AU2023201100 A1 AU 2023201100A1
- Authority
- AU
- Australia
- Prior art keywords
- dihydroxy
- propolis
- glycerol
- compounds
- diacetoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 348
- 230000001225 therapeutic effect Effects 0.000 title description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 307
- 201000009030 Carcinoma Diseases 0.000 claims abstract description 165
- 238000000034 method Methods 0.000 claims abstract description 131
- 238000011282 treatment Methods 0.000 claims abstract description 63
- 230000002265 prevention Effects 0.000 claims abstract description 23
- 241000241413 Propolis Species 0.000 claims description 634
- 229940069949 propolis Drugs 0.000 claims description 633
- 239000000284 extract Substances 0.000 claims description 201
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 174
- 210000004027 cell Anatomy 0.000 claims description 129
- 241000219000 Populus Species 0.000 claims description 118
- 125000001124 arachidoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 113
- 150000003839 salts Chemical class 0.000 claims description 110
- 239000012453 solvate Substances 0.000 claims description 108
- 206010028980 Neoplasm Diseases 0.000 claims description 105
- ZBTRYHWJYGJLJU-UHFFFAOYSA-N (2-acetylperoxy-3-hydroxypropyl) ethaneperoxoate Chemical compound C(C)(=O)OOC(CO)COOC(C)=O ZBTRYHWJYGJLJU-UHFFFAOYSA-N 0.000 claims description 88
- 238000011275 oncology therapy Methods 0.000 claims description 63
- DLZWOVIPEOSYEX-UHFFFAOYSA-N 2,3-dihydroxypropyl ethaneperoxoate Chemical compound CC(=O)OOCC(O)CO DLZWOVIPEOSYEX-UHFFFAOYSA-N 0.000 claims description 49
- KAVDTXTXFWEIAW-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl ethaneperoxoate Chemical compound CC(=O)OOC(CO)CO KAVDTXTXFWEIAW-UHFFFAOYSA-N 0.000 claims description 44
- CKDDRHZIAZRDBW-UHFFFAOYSA-N henicosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCC(O)=O CKDDRHZIAZRDBW-UHFFFAOYSA-N 0.000 claims description 44
- 239000003814 drug Substances 0.000 claims description 35
- 230000001613 neoplastic effect Effects 0.000 claims description 28
- 230000002401 inhibitory effect Effects 0.000 claims description 27
- 230000001965 increasing effect Effects 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 24
- FFMOUIYKDWSMFT-UHFFFAOYSA-N (3-acetylperoxy-2-hydroxypropyl) 3,8-dihydroxydocosanoate Chemical compound CCCCCCCCCCCCCCC(O)CCCCC(O)CC(=O)OCC(O)COOC(C)=O FFMOUIYKDWSMFT-UHFFFAOYSA-N 0.000 claims description 23
- ZSDGQKTYLGPRGC-UHFFFAOYSA-N 5-(chloromethyl)-3-[(4-nitrophenoxy)methyl]-1,2,4-oxadiazole Chemical compound C1=CC([N+](=O)[O-])=CC=C1OCC1=NOC(CCl)=N1 ZSDGQKTYLGPRGC-UHFFFAOYSA-N 0.000 claims description 22
- AJRICDSAJQHDSD-UHFFFAOYSA-N n-heneicosanoic acid methyl ester Natural products CCCCCCCCCCCCCCCCCCCCC(=O)OC AJRICDSAJQHDSD-UHFFFAOYSA-N 0.000 claims description 22
- 229940124597 therapeutic agent Drugs 0.000 claims description 22
- XSCKDRYKRJVECP-UHFFFAOYSA-N (2-acetylperoxy-3-hydroxypropyl) 3,8-dihydroxydocosanoate Chemical compound CCCCCCCCCCCCCCC(O)CCCCC(O)CC(=O)OCC(CO)OOC(C)=O XSCKDRYKRJVECP-UHFFFAOYSA-N 0.000 claims description 21
- QLZPKKRWNXVGOM-UHFFFAOYSA-N 2,3-bis(acetylperoxy)propyl 3,8-dihydroxydocosanoate Chemical compound CCCCCCCCCCCCCCC(O)CCCCC(O)CC(=O)OCC(COOC(C)=O)OOC(C)=O QLZPKKRWNXVGOM-UHFFFAOYSA-N 0.000 claims description 21
- ROVOAWDGUWDCCR-UHFFFAOYSA-N 2,3-dihydroxypropyl 3,8-dihydroxydocosanoate Chemical compound CCCCCCCCCCCCCCC(O)CCCCC(O)CC(=O)OCC(O)CO ROVOAWDGUWDCCR-UHFFFAOYSA-N 0.000 claims description 21
- RKFKXODIZQFGIE-UHFFFAOYSA-N 3,8-dihydroxydocosanoic acid Chemical compound OC(CC(=O)O)CCCCC(CCCCCCCCCCCCCC)O RKFKXODIZQFGIE-UHFFFAOYSA-N 0.000 claims description 21
- 238000004587 chromatography analysis Methods 0.000 claims description 21
- 210000000416 exudates and transudate Anatomy 0.000 claims description 21
- QGBRLVONZXHAKJ-UHFFFAOYSA-N n-eicosanoic acid methyl ester Natural products CCCCCCCCCCCCCCCCCCCC(=O)OC QGBRLVONZXHAKJ-UHFFFAOYSA-N 0.000 claims description 21
- MNKBAZOGKRROFZ-UHFFFAOYSA-N methyl 3,8-dihydroxydocosanoate Chemical compound COC(CC(CCCCC(CCCCCCCCCCCCCC)O)O)=O MNKBAZOGKRROFZ-UHFFFAOYSA-N 0.000 claims description 20
- WKIUVAMRRUBHNN-UHFFFAOYSA-N 2,3-bis(acetylperoxy)propyl 3,8-diacetyloxydocosanoate Chemical compound C(C)(=O)OC(CC(=O)OCC(OOC(C)=O)COOC(C)=O)CCCCC(CCCCCCCCCCCCCC)OC(C)=O WKIUVAMRRUBHNN-UHFFFAOYSA-N 0.000 claims description 18
- 230000006907 apoptotic process Effects 0.000 claims description 17
- 206010027476 Metastases Diseases 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 230000009401 metastasis Effects 0.000 claims description 13
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 230000001939 inductive effect Effects 0.000 claims description 10
- 210000005170 neoplastic cell Anatomy 0.000 claims description 10
- 238000002953 preparative HPLC Methods 0.000 claims description 10
- 210000002919 epithelial cell Anatomy 0.000 claims description 9
- 230000004043 responsiveness Effects 0.000 claims description 9
- 230000004614 tumor growth Effects 0.000 claims description 9
- 238000005194 fractionation Methods 0.000 claims description 8
- 230000035945 sensitivity Effects 0.000 claims description 7
- 238000004440 column chromatography Methods 0.000 claims description 5
- 238000004366 reverse phase liquid chromatography Methods 0.000 claims description 4
- 238000000638 solvent extraction Methods 0.000 claims description 4
- 238000004808 supercritical fluid chromatography Methods 0.000 claims description 4
- 238000000194 supercritical-fluid extraction Methods 0.000 claims description 4
- 239000002952 polymeric resin Substances 0.000 claims description 2
- 229920003002 synthetic resin Polymers 0.000 claims description 2
- 241000218978 Populus deltoides Species 0.000 claims 2
- 241000218981 Populus x canadensis Species 0.000 claims 2
- 238000004279 X-ray Guinier Methods 0.000 claims 2
- 208000000453 Skin Neoplasms Diseases 0.000 abstract description 82
- 125000005456 glyceride group Chemical group 0.000 abstract description 28
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 abstract description 12
- 239000002537 cosmetic Substances 0.000 abstract description 7
- 208000017520 skin disease Diseases 0.000 abstract description 2
- 239000011347 resin Substances 0.000 description 333
- 229920005989 resin Polymers 0.000 description 333
- 235000013350 formula milk Nutrition 0.000 description 186
- 229920000858 Cyclodextrin Polymers 0.000 description 143
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 97
- 201000000849 skin cancer Diseases 0.000 description 74
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
- 235000011187 glycerol Nutrition 0.000 description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 56
- 230000000694 effects Effects 0.000 description 45
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- 239000000047 product Substances 0.000 description 41
- 239000000523 sample Substances 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 235000014113 dietary fatty acids Nutrition 0.000 description 31
- 239000000194 fatty acid Substances 0.000 description 31
- 229930195729 fatty acid Natural products 0.000 description 31
- 230000035755 proliferation Effects 0.000 description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- -1 fatty acid compounds Chemical class 0.000 description 30
- 201000001441 melanoma Diseases 0.000 description 27
- 201000011510 cancer Diseases 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 206010029098 Neoplasm skin Diseases 0.000 description 23
- 239000003795 chemical substances by application Substances 0.000 description 23
- 229940098465 tincture Drugs 0.000 description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 22
- 150000004665 fatty acids Chemical class 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 206010041823 squamous cell carcinoma Diseases 0.000 description 21
- RTIXKCRFFJGDFG-UHFFFAOYSA-N Chrysin Natural products C=1C(O)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=CC=C1 RTIXKCRFFJGDFG-UHFFFAOYSA-N 0.000 description 20
- 235000013305 food Nutrition 0.000 description 20
- 229940097362 cyclodextrins Drugs 0.000 description 19
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 19
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 19
- 239000000463 material Substances 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 16
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 16
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 16
- 239000000306 component Substances 0.000 description 16
- 208000035475 disorder Diseases 0.000 description 16
- 229960002949 fluorouracil Drugs 0.000 description 16
- 206010004146 Basal cell carcinoma Diseases 0.000 description 15
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 15
- 230000037396 body weight Effects 0.000 description 15
- 206010017758 gastric cancer Diseases 0.000 description 15
- 239000002609 medium Substances 0.000 description 15
- VCCRNZQBSJXYJD-UHFFFAOYSA-N galangin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=CC=C1 VCCRNZQBSJXYJD-UHFFFAOYSA-N 0.000 description 14
- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 description 14
- 208000005718 Stomach Neoplasms Diseases 0.000 description 13
- 239000003183 carcinogenic agent Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 206010009944 Colon cancer Diseases 0.000 description 12
- WWVKQTNONPWVEL-UHFFFAOYSA-N caffeic acid phenethyl ester Natural products C1=C(O)C(O)=CC=C1C=CC(=O)OCC1=CC=CC=C1 WWVKQTNONPWVEL-UHFFFAOYSA-N 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 210000003491 skin Anatomy 0.000 description 12
- 208000024891 symptom Diseases 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- SUYJZKRQHBQNCA-UHFFFAOYSA-N pinobanksin Natural products O1C2=CC(O)=CC(O)=C2C(=O)C(O)C1C1=CC=CC=C1 SUYJZKRQHBQNCA-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 239000002552 dosage form Substances 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 239000002417 nutraceutical Substances 0.000 description 10
- 235000021436 nutraceutical agent Nutrition 0.000 description 10
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 238000002560 therapeutic procedure Methods 0.000 description 10
- 206010043515 Throat cancer Diseases 0.000 description 9
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 9
- 229960004853 betadex Drugs 0.000 description 9
- 230000002496 gastric effect Effects 0.000 description 9
- 201000011549 stomach cancer Diseases 0.000 description 9
- 230000002195 synergetic effect Effects 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- CUGDOWNTXKLQMD-BQYQJAHWSA-N Pinostrobin chalcone Chemical compound OC1=CC(OC)=CC(O)=C1C(=O)\C=C\C1=CC=CC=C1 CUGDOWNTXKLQMD-BQYQJAHWSA-N 0.000 description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 8
- 208000009956 adenocarcinoma Diseases 0.000 description 8
- 239000003963 antioxidant agent Substances 0.000 description 8
- 235000006708 antioxidants Nutrition 0.000 description 8
- 235000015872 dietary supplement Nutrition 0.000 description 8
- 238000000105 evaporative light scattering detection Methods 0.000 description 8
- 235000013336 milk Nutrition 0.000 description 8
- 239000008267 milk Substances 0.000 description 8
- 210000004080 milk Anatomy 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 230000036559 skin health Effects 0.000 description 8
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 8
- 238000001356 surgical procedure Methods 0.000 description 8
- 230000000699 topical effect Effects 0.000 description 8
- NYCXYKOXLNBYID-UHFFFAOYSA-N 5,7-Dihydroxychromone Natural products O1C=CC(=O)C=2C1=CC(O)=CC=2O NYCXYKOXLNBYID-UHFFFAOYSA-N 0.000 description 7
- 239000001116 FEMA 4028 Substances 0.000 description 7
- 239000012981 Hank's balanced salt solution Substances 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 7
- 235000015838 chrysin Nutrition 0.000 description 7
- 229940043370 chrysin Drugs 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- CIPSYTVGZURWPT-UHFFFAOYSA-N galangin Natural products OC1=C(Oc2cc(O)c(O)cc2C1=O)c3ccccc3 CIPSYTVGZURWPT-UHFFFAOYSA-N 0.000 description 7
- 230000036541 health Effects 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 230000001976 improved effect Effects 0.000 description 7
- 238000004949 mass spectrometry Methods 0.000 description 7
- 210000003800 pharynx Anatomy 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 210000004927 skin cell Anatomy 0.000 description 7
- ACEAELOMUCBPJP-UHFFFAOYSA-N (E)-3,4,5-trihydroxycinnamic acid Natural products OC(=O)C=CC1=CC(O)=C(O)C(O)=C1 ACEAELOMUCBPJP-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 229930182555 Penicillin Natural products 0.000 description 6
- FGUBFGWYEYFGRK-HNNXBMFYSA-N Pinocembrin Natural products Cc1cc(C)c2C(=O)C[C@H](Oc2c1)c3ccccc3 FGUBFGWYEYFGRK-HNNXBMFYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 230000000996 additive effect Effects 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- WWVKQTNONPWVEL-VQHVLOKHSA-N benzyl (e)-3-(3,4-dihydroxyphenyl)prop-2-enoate Chemical compound C1=C(O)C(O)=CC=C1\C=C\C(=O)OCC1=CC=CC=C1 WWVKQTNONPWVEL-VQHVLOKHSA-N 0.000 description 6
- DZAPHTCUSDTZAT-CSKARUKUSA-N benzyl (e)-3-(4-hydroxy-3-methoxyphenyl)prop-2-enoate Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)OCC=2C=CC=CC=2)=C1 DZAPHTCUSDTZAT-CSKARUKUSA-N 0.000 description 6
- DZAPHTCUSDTZAT-UHFFFAOYSA-N benzyl ferulate Natural products C1=C(O)C(OC)=CC(C=CC(=O)OCC=2C=CC=CC=2)=C1 DZAPHTCUSDTZAT-UHFFFAOYSA-N 0.000 description 6
- 235000004883 caffeic acid Nutrition 0.000 description 6
- 229940074360 caffeic acid Drugs 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 description 6
- 208000029742 colonic neoplasm Diseases 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- KCFYHBSOLOXZIF-UHFFFAOYSA-N dihydrochrysin Natural products COC1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 KCFYHBSOLOXZIF-UHFFFAOYSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 239000012909 foetal bovine serum Substances 0.000 description 6
- 235000013373 food additive Nutrition 0.000 description 6
- 239000002778 food additive Substances 0.000 description 6
- 235000021588 free fatty acids Nutrition 0.000 description 6
- 208000010749 gastric carcinoma Diseases 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 239000013642 negative control Substances 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- SWUARLUWKZWEBQ-UHFFFAOYSA-N phenylethyl ester of caffeic acid Natural products C1=C(O)C(O)=CC=C1C=CC(=O)OCCC1=CC=CC=C1 SWUARLUWKZWEBQ-UHFFFAOYSA-N 0.000 description 6
- URFCJEUYXNAHFI-ZDUSSCGKSA-N pinocembrin Chemical compound C1([C@@H]2CC(=O)C3=C(O)C=C(C=C3O2)O)=CC=CC=C1 URFCJEUYXNAHFI-ZDUSSCGKSA-N 0.000 description 6
- 239000013641 positive control Substances 0.000 description 6
- 201000000498 stomach carcinoma Diseases 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 5
- 229930186147 Cephalosporin Natural products 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- 101000617830 Homo sapiens Sterol O-acyltransferase 1 Proteins 0.000 description 5
- 238000000134 MTT assay Methods 0.000 description 5
- 231100000002 MTT assay Toxicity 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 5
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 5
- 102100021993 Sterol O-acyltransferase 1 Human genes 0.000 description 5
- 101000697584 Streptomyces lavendulae Streptothricin acetyltransferase Proteins 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 230000001093 anti-cancer Effects 0.000 description 5
- 210000000270 basal cell Anatomy 0.000 description 5
- 235000013361 beverage Nutrition 0.000 description 5
- 238000004166 bioassay Methods 0.000 description 5
- 229940124587 cephalosporin Drugs 0.000 description 5
- 150000001780 cephalosporins Chemical class 0.000 description 5
- 239000006071 cream Substances 0.000 description 5
- 235000013365 dairy product Nutrition 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 229940049954 penicillin Drugs 0.000 description 5
- 235000013824 polyphenols Nutrition 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000001959 radiotherapy Methods 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 238000011200 topical administration Methods 0.000 description 5
- 239000012049 topical pharmaceutical composition Substances 0.000 description 5
- 239000012224 working solution Substances 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical group OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- CUGDOWNTXKLQMD-UHFFFAOYSA-N Pinostrobinchalkon Natural products OC1=CC(OC)=CC(O)=C1C(=O)C=CC1=CC=CC=C1 CUGDOWNTXKLQMD-UHFFFAOYSA-N 0.000 description 4
- 208000006994 Precancerous Conditions Diseases 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- GRZQNEYQRVPNRY-WUZDHUPESA-N [(e)-3-phenylprop-2-enyl] (e)-3-(3,4-dihydroxyphenyl)prop-2-enoate Chemical compound C1=C(O)C(O)=CC=C1\C=C\C(=O)OC\C=C\C1=CC=CC=C1 GRZQNEYQRVPNRY-WUZDHUPESA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 230000001028 anti-proliverative effect Effects 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 125000003910 behenoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- GRZQNEYQRVPNRY-UHFFFAOYSA-N cinnamyl caffeate Natural products C1=C(O)C(O)=CC=C1C=CC(=O)OCC=CC1=CC=CC=C1 GRZQNEYQRVPNRY-UHFFFAOYSA-N 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 229930003935 flavonoid Natural products 0.000 description 4
- 150000002215 flavonoids Chemical class 0.000 description 4
- 235000017173 flavonoids Nutrition 0.000 description 4
- 239000003349 gelling agent Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 210000001165 lymph node Anatomy 0.000 description 4
- 238000012423 maintenance Methods 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 235000016709 nutrition Nutrition 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- SUYJZKRQHBQNCA-LSDHHAIUSA-N pinobanksin Chemical compound C1([C@@H]2[C@H](C(C3=C(O)C=C(O)C=C3O2)=O)O)=CC=CC=C1 SUYJZKRQHBQNCA-LSDHHAIUSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 229930195734 saturated hydrocarbon Natural products 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 229960005322 streptomycin Drugs 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000007755 survival signaling Effects 0.000 description 4
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 4
- 239000001993 wax Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 description 3
- 201000004624 Dermatitis Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 description 3
- 206010034811 Pharyngeal cancer Diseases 0.000 description 3
- 229940127395 Ribonucleotide Reductase Inhibitors Drugs 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- URLDLSRJTIJNGH-CSKARUKUSA-N benzyl (E)-3-(3-hydroxy-4-methoxyphenyl)prop-2-enoate Chemical compound C1=C(O)C(OC)=CC=C1\C=C\C(=O)OCC1=CC=CC=C1 URLDLSRJTIJNGH-CSKARUKUSA-N 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 238000010260 bioassay-guided fractionation Methods 0.000 description 3
- 238000001516 cell proliferation assay Methods 0.000 description 3
- 239000007957 coemulsifier Substances 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000000378 dietary effect Effects 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 239000002702 enteric coating Substances 0.000 description 3
- 238000009505 enteric coating Methods 0.000 description 3
- 210000000981 epithelium Anatomy 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000007717 exclusion Effects 0.000 description 3
- 229940114123 ferulate Drugs 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000012139 lysis buffer Substances 0.000 description 3
- 230000011987 methylation Effects 0.000 description 3
- 238000007069 methylation reaction Methods 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 239000004570 mortar (masonry) Substances 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000001694 spray drying Methods 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 230000002459 sustained effect Effects 0.000 description 3
- 230000035899 viability Effects 0.000 description 3
- 238000012800 visualization Methods 0.000 description 3
- XFRVVPUIAFSTFO-UHFFFAOYSA-N 1-Tridecanol Chemical compound CCCCCCCCCCCCCO XFRVVPUIAFSTFO-UHFFFAOYSA-N 0.000 description 2
- WZRJTRPJURQBRM-UHFFFAOYSA-N 4-amino-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 WZRJTRPJURQBRM-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000219429 Betula Species 0.000 description 2
- 235000003932 Betula Nutrition 0.000 description 2
- 238000006027 Birch reduction reaction Methods 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 239000004150 EU approved colour Substances 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- 229930182566 Gentamicin Natural products 0.000 description 2
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- 241000218652 Larix Species 0.000 description 2
- 235000005590 Larix decidua Nutrition 0.000 description 2
- 206010023825 Laryngeal cancer Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 102000014171 Milk Proteins Human genes 0.000 description 2
- 108010011756 Milk Proteins Proteins 0.000 description 2
- 239000004909 Moisturizer Substances 0.000 description 2
- 206010061534 Oesophageal squamous cell carcinoma Diseases 0.000 description 2
- 240000007817 Olea europaea Species 0.000 description 2
- 240000007594 Oryza sativa Species 0.000 description 2
- BJYHZSNSMVEQEH-SJORKVTESA-N Pinobanksin 3-O-acetate Chemical compound C1([C@@H]2[C@H](C(C3=C(O)C=C(O)C=C3O2)=O)OC(=O)C)=CC=CC=C1 BJYHZSNSMVEQEH-SJORKVTESA-N 0.000 description 2
- BJYHZSNSMVEQEH-UHFFFAOYSA-N Pinobanksin-3-O-acetat Natural products O1C2=CC(O)=CC(O)=C2C(=O)C(OC(=O)C)C1C1=CC=CC=C1 BJYHZSNSMVEQEH-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 241000218998 Salicaceae Species 0.000 description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- 241001122767 Theaceae Species 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 229930003427 Vitamin E Natural products 0.000 description 2
- 102000007544 Whey Proteins Human genes 0.000 description 2
- 108010046377 Whey Proteins Proteins 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 239000006096 absorbing agent Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- JVFGXECLSQXABC-UHFFFAOYSA-N ac1l3obq Chemical compound O1C(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(O)C2O)C(COCC(O)C)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC2C(O)C(O)C1OC2COCC(C)O JVFGXECLSQXABC-UHFFFAOYSA-N 0.000 description 2
- 230000004308 accommodation Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229960001220 amsacrine Drugs 0.000 description 2
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 230000003127 anti-melanomic effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 2
- 235000012216 bentonite Nutrition 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- QRYRORQUOLYVBU-VBKZILBWSA-N carnosic acid Chemical compound CC([C@@H]1CC2)(C)CCC[C@]1(C(O)=O)C1=C2C=C(C(C)C)C(O)=C1O QRYRORQUOLYVBU-VBKZILBWSA-N 0.000 description 2
- XIURVHNZVLADCM-IUODEOHRSA-N cefalotin Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)CC1=CC=CS1 XIURVHNZVLADCM-IUODEOHRSA-N 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 229940047766 co-trimoxazole Drugs 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 201000010897 colon adenocarcinoma Diseases 0.000 description 2
- 210000003022 colostrum Anatomy 0.000 description 2
- 235000021277 colostrum Nutrition 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 208000030381 cutaneous melanoma Diseases 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 2
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 239000008157 edible vegetable oil Substances 0.000 description 2
- 230000002500 effect on skin Effects 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- 208000007276 esophageal squamous cell carcinoma Diseases 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 description 2
- 239000002038 ethyl acetate fraction Substances 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 150000002191 fatty alcohols Chemical class 0.000 description 2
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 2
- 229960004413 flucytosine Drugs 0.000 description 2
- 238000013467 fragmentation Methods 0.000 description 2
- 238000006062 fragmentation reaction Methods 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 235000015203 fruit juice Nutrition 0.000 description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 229960002518 gentamicin Drugs 0.000 description 2
- 230000000762 glandular Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 150000002314 glycerols Chemical class 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 210000003026 hypopharynx Anatomy 0.000 description 2
- VKOBVWXKNCXXDE-UHFFFAOYSA-N icosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 230000000415 inactivating effect Effects 0.000 description 2
- 230000006882 induction of apoptosis Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000004898 kneading Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 206010023841 laryngeal neoplasm Diseases 0.000 description 2
- 210000000867 larynx Anatomy 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- RGLRXNKKBLIBQS-XNHQSDQCSA-N leuprolide acetate Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 RGLRXNKKBLIBQS-XNHQSDQCSA-N 0.000 description 2
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 2
- 229960003907 linezolid Drugs 0.000 description 2
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000011177 media preparation Methods 0.000 description 2
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 235000021243 milk fat Nutrition 0.000 description 2
- 235000021239 milk protein Nutrition 0.000 description 2
- 230000001333 moisturizer Effects 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N n-hexadecanoic acid Natural products CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 210000001989 nasopharynx Anatomy 0.000 description 2
- 235000014571 nuts Nutrition 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 2
- 210000003300 oropharynx Anatomy 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 210000002741 palatine tonsil Anatomy 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 229960005079 pemetrexed Drugs 0.000 description 2
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000004237 preparative chromatography Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- MQSZRBPYXNEFHF-UHFFFAOYSA-N rhamnocitrin Chemical compound C=1C(OC)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C=C1 MQSZRBPYXNEFHF-UHFFFAOYSA-N 0.000 description 2
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 2
- 229960001225 rifampicin Drugs 0.000 description 2
- 239000011669 selenium Substances 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 235000011649 selenium Nutrition 0.000 description 2
- 239000002884 skin cream Substances 0.000 description 2
- 201000003708 skin melanoma Diseases 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 235000013616 tea Nutrition 0.000 description 2
- IRZVHDLBAYNPCT-UHFFFAOYSA-N tectochrysin Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=CC=C1 IRZVHDLBAYNPCT-UHFFFAOYSA-N 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- 239000003734 thymidylate synthase inhibitor Substances 0.000 description 2
- 229960004089 tigecycline Drugs 0.000 description 2
- FPZLLRFZJZRHSY-HJYUBDRYSA-N tigecycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=C(NC(=O)CNC(C)(C)C)C(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O FPZLLRFZJZRHSY-HJYUBDRYSA-N 0.000 description 2
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 2
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 235000019165 vitamin E Nutrition 0.000 description 2
- 229940046009 vitamin E Drugs 0.000 description 2
- 239000011709 vitamin E Substances 0.000 description 2
- 235000021119 whey protein Nutrition 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 235000016804 zinc Nutrition 0.000 description 2
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- TZZQZCIACNYHBG-OLPCVCRBSA-N (1r,3e,5s,7s)-3-[(3,4-dihydroxyphenyl)-hydroxymethylidene]-6,6-dimethyl-5,7-bis(3-methylbut-2-enyl)-1-[(2r)-5-methyl-2-prop-1-en-2-ylhex-5-enyl]bicyclo[3.3.1]nonane-2,4,9-trione Chemical compound O=C([C@]1(C[C@@H](CCC(C)=C)C(C)=C)C[C@@H](C([C@@](CC=C(C)C)(C1=O)C1=O)(C)C)CC=C(C)C)\C1=C(/O)C1=CC=C(O)C(O)=C1 TZZQZCIACNYHBG-OLPCVCRBSA-N 0.000 description 1
- SYKFHCWMZKYPEA-RFQWPUQQSA-N (1r,5r,7s)-5-benzoyl-2-hydroxy-6,6-dimethyl-1,3,7-tris(3-methylbut-2-enyl)bicyclo[3.3.1]non-2-ene-4,9-dione Chemical compound O=C([C@@]12C(=O)C(CC=C(C)C)=C(O)[C@@](C2=O)(CC=C(C)C)C[C@@H](C1(C)C)CC=C(C)C)C1=CC=CC=C1 SYKFHCWMZKYPEA-RFQWPUQQSA-N 0.000 description 1
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 description 1
- MQHLMHIZUIDKOO-OKZBNKHCSA-N (2R,6S)-2,6-dimethyl-4-[(2S)-2-methyl-3-[4-(2-methylbutan-2-yl)phenyl]propyl]morpholine Chemical compound C1=CC(C(C)(C)CC)=CC=C1C[C@H](C)CN1C[C@@H](C)O[C@@H](C)C1 MQHLMHIZUIDKOO-OKZBNKHCSA-N 0.000 description 1
- ORJDDOBAOGKRJV-CQSZACIVSA-N (2S)-Pinocembrin Natural products C1([C@H]2CC(=O)C3=C(O)C=C(C=C3O2)OC)=CC=CC=C1 ORJDDOBAOGKRJV-CQSZACIVSA-N 0.000 description 1
- DSEKYWAQQVUQTP-XEWMWGOFSA-N (2r,4r,4as,6as,6as,6br,8ar,12ar,14as,14bs)-2-hydroxy-4,4a,6a,6b,8a,11,11,14a-octamethyl-2,4,5,6,6a,7,8,9,10,12,12a,13,14,14b-tetradecahydro-1h-picen-3-one Chemical compound C([C@H]1[C@]2(C)CC[C@@]34C)C(C)(C)CC[C@]1(C)CC[C@]2(C)[C@H]4CC[C@@]1(C)[C@H]3C[C@@H](O)C(=O)[C@@H]1C DSEKYWAQQVUQTP-XEWMWGOFSA-N 0.000 description 1
- XMQUEQJCYRFIQS-YFKPBYRVSA-N (2s)-2-amino-5-ethoxy-5-oxopentanoic acid Chemical compound CCOC(=O)CC[C@H](N)C(O)=O XMQUEQJCYRFIQS-YFKPBYRVSA-N 0.000 description 1
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 1
- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 description 1
- WDLWHQDACQUCJR-ZAMMOSSLSA-N (6r,7r)-7-[[(2r)-2-azaniumyl-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 WDLWHQDACQUCJR-ZAMMOSSLSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- MINDHVHHQZYEEK-UHFFFAOYSA-N (E)-(2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-epoxy-5-hydroxy-4-methylhexyl]tetrahydro-3,4-dihydroxy-(beta)-methyl-2H-pyran-2-crotonic acid ester with 9-hydroxynonanoic acid Natural products CC(O)C(C)C1OC1CC1C(O)C(O)C(CC(C)=CC(=O)OCCCCCCCCC(O)=O)OC1 MINDHVHHQZYEEK-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 description 1
- MPIPASJGOJYODL-SFHVURJKSA-N (R)-isoconazole Chemical compound ClC1=CC(Cl)=CC=C1[C@@H](OCC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 MPIPASJGOJYODL-SFHVURJKSA-N 0.000 description 1
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 1
- NCCJWSXETVVUHK-ZYSAIPPVSA-N (z)-7-[(2r)-2-amino-2-carboxyethyl]sulfanyl-2-[[(1s)-2,2-dimethylcyclopropanecarbonyl]amino]hept-2-enoic acid;(5r,6s)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6-[(1r)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1C(SCC\N=C/N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21.CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O NCCJWSXETVVUHK-ZYSAIPPVSA-N 0.000 description 1
- KGOISFRDFAYUTJ-UHFFFAOYSA-N 1,2,3-trihydroxypropyl acetate Chemical compound CC(=O)OC(O)C(O)CO KGOISFRDFAYUTJ-UHFFFAOYSA-N 0.000 description 1
- QPCIUXWQCCFLCI-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl acetate Chemical compound CC(=O)OC(CO)CO QPCIUXWQCCFLCI-UHFFFAOYSA-N 0.000 description 1
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 1
- AFNXATANNDIXLG-SFHVURJKSA-N 1-[(2r)-2-[(4-chlorophenyl)methylsulfanyl]-2-(2,4-dichlorophenyl)ethyl]imidazole Chemical compound C1=CC(Cl)=CC=C1CS[C@H](C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 AFNXATANNDIXLG-SFHVURJKSA-N 0.000 description 1
- ZCJYUTQZBAIHBS-UHFFFAOYSA-N 1-[2-(2,4-dichlorophenyl)-2-{[4-(phenylsulfanyl)benzyl]oxy}ethyl]imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C=CC(SC=2C=CC=CC=2)=CC=1)CN1C=NC=C1 ZCJYUTQZBAIHBS-UHFFFAOYSA-N 0.000 description 1
- OCAPBUJLXMYKEJ-UHFFFAOYSA-N 1-[biphenyl-4-yl(phenyl)methyl]imidazole Chemical compound C1=NC=CN1C(C=1C=CC(=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 OCAPBUJLXMYKEJ-UHFFFAOYSA-N 0.000 description 1
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 description 1
- QXHHHPZILQDDPS-UHFFFAOYSA-N 1-{2-[(2-chloro-3-thienyl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound S1C=CC(COC(CN2C=NC=C2)C=2C(=CC(Cl)=CC=2)Cl)=C1Cl QXHHHPZILQDDPS-UHFFFAOYSA-N 0.000 description 1
- JLGKQTAYUIMGRK-UHFFFAOYSA-N 1-{2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C2=CC=CC(Cl)=C2SC=1)CN1C=NC=C1 JLGKQTAYUIMGRK-UHFFFAOYSA-N 0.000 description 1
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- UBFHQBMHQCYCKN-UHFFFAOYSA-N 2,2-dihydroxydocosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCC(O)(O)C(O)=O UBFHQBMHQCYCKN-UHFFFAOYSA-N 0.000 description 1
- DKHMRZWLJPBWSX-UHFFFAOYSA-N 2,2-dihydroxyicosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCC(O)(O)C(O)=O DKHMRZWLJPBWSX-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- QXLQZLBNPTZMRK-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-1-(2,4-dimethylphenyl)prop-2-en-1-one Chemical compound CN(C)CC(=C)C(=O)C1=CC=C(C)C=C1C QXLQZLBNPTZMRK-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- CXNXZUZCPHKUPN-UHFFFAOYSA-N 3,8-dihydroxyoctanoic acid Chemical compound OCCCCCC(O)CC(O)=O CXNXZUZCPHKUPN-UHFFFAOYSA-N 0.000 description 1
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- FJNCXZZQNBKEJT-UHFFFAOYSA-N 8beta-hydroxymarrubiin Natural products O1C(=O)C2(C)CCCC3(C)C2C1CC(C)(O)C3(O)CCC=1C=COC=1 FJNCXZZQNBKEJT-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- 240000004507 Abelmoschus esculentus Species 0.000 description 1
- 241001133760 Acoelorraphe Species 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- JDLKFOPOAOFWQN-VIFPVBQESA-N Allicin Natural products C=CCS[S@](=O)CC=C JDLKFOPOAOFWQN-VIFPVBQESA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 235000009328 Amaranthus caudatus Nutrition 0.000 description 1
- 240000001592 Amaranthus caudatus Species 0.000 description 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 235000011437 Amygdalus communis Nutrition 0.000 description 1
- 244000226021 Anacardium occidentale Species 0.000 description 1
- 108010064760 Anidulafungin Proteins 0.000 description 1
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 244000125300 Argania sideroxylon Species 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 240000005343 Azadirachta indica Species 0.000 description 1
- 108010001478 Bacitracin Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 235000021357 Behenic acid Nutrition 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 235000018185 Betula X alpestris Nutrition 0.000 description 1
- 235000018212 Betula X uliginosa Nutrition 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 235000007689 Borago officinalis Nutrition 0.000 description 1
- 240000004355 Borago officinalis Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 244000056139 Brassica cretica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000014698 Brassica juncea var multisecta Nutrition 0.000 description 1
- 235000006008 Brassica napus var napus Nutrition 0.000 description 1
- 240000000385 Brassica napus var. napus Species 0.000 description 1
- 235000006618 Brassica rapa subsp oleifera Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 235000004977 Brassica sinapistrum Nutrition 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- VSEIDZLLWQQJGK-CHOZPQDDSA-N CCC1=C(C)C2=N\C\1=C/C1=C(C)C(C(O)=O)=C(N1)\C(CC(=O)N[C@@H](CC(O)=O)C(O)=O)=C1/N=C(/C=C3\N/C(=C\2)C(C=C)=C3C)[C@@H](C)[C@@H]1CCC(O)=O Chemical compound CCC1=C(C)C2=N\C\1=C/C1=C(C)C(C(O)=O)=C(N1)\C(CC(=O)N[C@@H](CC(O)=O)C(O)=O)=C1/N=C(/C=C3\N/C(=C\2)C(C=C)=C3C)[C@@H](C)[C@@H]1CCC(O)=O VSEIDZLLWQQJGK-CHOZPQDDSA-N 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 235000014595 Camelina sativa Nutrition 0.000 description 1
- 244000197813 Camelina sativa Species 0.000 description 1
- 240000001548 Camellia japonica Species 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 235000012766 Cannabis sativa ssp. sativa var. sativa Nutrition 0.000 description 1
- 235000012765 Cannabis sativa ssp. sativa var. spontanea Nutrition 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- SHHKQEUPHAENFK-UHFFFAOYSA-N Carboquone Chemical compound O=C1C(C)=C(N2CC2)C(=O)C(C(COC(N)=O)OC)=C1N1CC1 SHHKQEUPHAENFK-UHFFFAOYSA-N 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 235000003255 Carthamus tinctorius Nutrition 0.000 description 1
- 244000020518 Carthamus tinctorius Species 0.000 description 1
- 235000009025 Carya illinoensis Nutrition 0.000 description 1
- 244000068645 Carya illinoensis Species 0.000 description 1
- 235000017165 Caryocar brasiliense Nutrition 0.000 description 1
- 241000176785 Caryocar brasiliense Species 0.000 description 1
- 108010020326 Caspofungin Proteins 0.000 description 1
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 description 1
- 235000003301 Ceiba pentandra Nutrition 0.000 description 1
- 244000146553 Ceiba pentandra Species 0.000 description 1
- 240000008886 Ceratonia siliqua Species 0.000 description 1
- 235000013912 Ceratonia siliqua Nutrition 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 1
- 240000006162 Chenopodium quinoa Species 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 1
- 241000132536 Cirsium Species 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- 208000030808 Clear cell renal carcinoma Diseases 0.000 description 1
- 241001249666 Clusia <angiosperm> Species 0.000 description 1
- 108010078777 Colistin Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 241000218631 Coniferophyta Species 0.000 description 1
- 240000009226 Corylus americana Species 0.000 description 1
- 235000001543 Corylus americana Nutrition 0.000 description 1
- 235000007466 Corylus avellana Nutrition 0.000 description 1
- 240000001980 Cucurbita pepo Species 0.000 description 1
- 235000009852 Cucurbita pepo Nutrition 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 240000004784 Cymbopogon citratus Species 0.000 description 1
- 235000017897 Cymbopogon citratus Nutrition 0.000 description 1
- 244000019459 Cynara cardunculus Species 0.000 description 1
- 235000019106 Cynara scolymus Nutrition 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 229940127399 DNA Polymerase Inhibitors Drugs 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- MQJKPEGWNLWLTK-UHFFFAOYSA-N Dapsone Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=C1 MQJKPEGWNLWLTK-UHFFFAOYSA-N 0.000 description 1
- 108010013198 Daptomycin Proteins 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- XMSXQFUHVRWGNA-UHFFFAOYSA-N Decamethylcyclopentasiloxane Chemical compound C[Si]1(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O1 XMSXQFUHVRWGNA-UHFFFAOYSA-N 0.000 description 1
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 description 1
- FMTDIUIBLCQGJB-UHFFFAOYSA-N Demethylchlortetracyclin Natural products C1C2C(O)C3=C(Cl)C=CC(O)=C3C(=O)C2=C(O)C2(O)C1C(N(C)C)C(O)=C(C(N)=O)C2=O FMTDIUIBLCQGJB-UHFFFAOYSA-N 0.000 description 1
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 1
- ORJDDOBAOGKRJV-UHFFFAOYSA-N Dihydrotectochrysin Natural products O1C2=CC(OC)=CC(O)=C2C(=O)CC1C1=CC=CC=C1 ORJDDOBAOGKRJV-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 239000005697 Dodecan-1-ol Substances 0.000 description 1
- 101100186820 Drosophila melanogaster sicily gene Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108010049047 Echinocandins Proteins 0.000 description 1
- XXPXYPLPSDPERN-UHFFFAOYSA-N Ecteinascidin 743 Natural products COc1cc2C(NCCc2cc1O)C(=O)OCC3N4C(O)C5Cc6cc(C)c(OC)c(O)c6C(C4C(S)c7c(OC(=O)C)c(C)c8OCOc8c37)N5C XXPXYPLPSDPERN-UHFFFAOYSA-N 0.000 description 1
- 208000005431 Endometrioid Carcinoma Diseases 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- 244000207620 Euterpe oleracea Species 0.000 description 1
- 235000012601 Euterpe oleracea Nutrition 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 229930183931 Filipin Natural products 0.000 description 1
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- IECPWNUMDGFDKC-UHFFFAOYSA-N Fusicsaeure Natural products C12C(O)CC3C(=C(CCC=C(C)C)C(O)=O)C(OC(C)=O)CC3(C)C1(C)CCC1C2(C)CCC(O)C1C IECPWNUMDGFDKC-UHFFFAOYSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 241001643722 Gomesa radicans Species 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 1
- 235000003239 Guizotia abyssinica Nutrition 0.000 description 1
- 240000002795 Guizotia abyssinica Species 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- CTETYYAZBPJBHE-UHFFFAOYSA-N Haloprogin Chemical compound ClC1=CC(Cl)=C(OCC#CI)C=C1Cl CTETYYAZBPJBHE-UHFFFAOYSA-N 0.000 description 1
- 244000020551 Helianthus annuus Species 0.000 description 1
- 235000003222 Helianthus annuus Nutrition 0.000 description 1
- 235000005206 Hibiscus Nutrition 0.000 description 1
- 235000007185 Hibiscus lunariifolius Nutrition 0.000 description 1
- 244000284380 Hibiscus rosa sinensis Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 241000257303 Hymenoptera Species 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 description 1
- OWYWGLHRNBIFJP-UHFFFAOYSA-N Ipazine Chemical compound CCN(CC)C1=NC(Cl)=NC(NC(C)C)=N1 OWYWGLHRNBIFJP-UHFFFAOYSA-N 0.000 description 1
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 1
- 240000007049 Juglans regia Species 0.000 description 1
- 235000009496 Juglans regia Nutrition 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 244000303847 Lagenaria vulgaris Species 0.000 description 1
- 235000009797 Lagenaria vulgaris Nutrition 0.000 description 1
- 241001050682 Lallemantia Species 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 241000408747 Lepomis gibbosus Species 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- 241001072282 Limnanthes Species 0.000 description 1
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 1
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 108010028921 Lipopeptides Proteins 0.000 description 1
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000208467 Macadamia Species 0.000 description 1
- TYMRLRRVMHJFTF-UHFFFAOYSA-N Mafenide Chemical compound NCC1=CC=C(S(N)(=O)=O)C=C1 TYMRLRRVMHJFTF-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 240000002129 Malva sylvestris Species 0.000 description 1
- 235000006770 Malva sylvestris Nutrition 0.000 description 1
- 235000013500 Melia azadirachta Nutrition 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 108010021062 Micafungin Proteins 0.000 description 1
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 1
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 240000005125 Myrtus communis Species 0.000 description 1
- 235000013418 Myrtus communis Nutrition 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- XCOBLONWWXQEBS-KPKJPENVSA-N N,O-bis(trimethylsilyl)trifluoroacetamide Chemical compound C[Si](C)(C)O\C(C(F)(F)F)=N\[Si](C)(C)C XCOBLONWWXQEBS-KPKJPENVSA-N 0.000 description 1
- ZBJNZFQKYZCUJU-PAHFEQBRSA-N N-[(2S)-4-amino-1-[[(2S,3R)-1-[[(2S)-4-amino-1-oxo-1-[[(3S,6S,9S,12S,15R,18R,21S)-6,9,18-tris(2-aminoethyl)-15-benzyl-3-[(1R)-1-hydroxyethyl]-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methylheptanamide (6S)-N-[(2S)-4-amino-1-[[(2S,3R)-1-[[(2S)-4-amino-1-oxo-1-[[(3S,6S,9S,12S,15R,18R,21S)-6,9,18-tris(2-aminoethyl)-15-benzyl-3-[(1R)-1-hydroxyethyl]-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methyloctanamide Polymers CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@@H](NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](CCN)NC1=O)[C@@H](C)O.CC[C@H](C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@@H](NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](CCN)NC1=O)[C@@H](C)O ZBJNZFQKYZCUJU-PAHFEQBRSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- LYPFDBRUNKHDGX-SOGSVHMOSA-N N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 Chemical compound N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 LYPFDBRUNKHDGX-SOGSVHMOSA-N 0.000 description 1
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 241000219925 Oenothera Species 0.000 description 1
- 235000004496 Oenothera biennis Nutrition 0.000 description 1
- 235000002725 Olea europaea Nutrition 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 235000014643 Orbignya martiana Nutrition 0.000 description 1
- 244000021150 Orbignya martiana Species 0.000 description 1
- 241000233855 Orchidaceae Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- 239000012661 PARP inhibitor Substances 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 235000008753 Papaver somniferum Nutrition 0.000 description 1
- UOZODPSAJZTQNH-UHFFFAOYSA-N Paromomycin II Natural products NC1C(O)C(O)C(CN)OC1OC1C(O)C(OC2C(C(N)CC(N)C2O)OC2C(C(O)C(O)C(CO)O2)N)OC1CO UOZODPSAJZTQNH-UHFFFAOYSA-N 0.000 description 1
- 240000002834 Paulownia tomentosa Species 0.000 description 1
- 235000010678 Paulownia tomentosa Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 235000004347 Perilla Nutrition 0.000 description 1
- 244000124853 Perilla frutescens Species 0.000 description 1
- 244000025272 Persea americana Species 0.000 description 1
- 235000008673 Persea americana Nutrition 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 235000003447 Pistacia vera Nutrition 0.000 description 1
- 240000006711 Pistacia vera Species 0.000 description 1
- 235000011751 Pogostemon cablin Nutrition 0.000 description 1
- 240000002505 Pogostemon cablin Species 0.000 description 1
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- 235000001560 Prosopis chilensis Nutrition 0.000 description 1
- 240000007909 Prosopis juliflora Species 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 235000009827 Prunus armeniaca Nutrition 0.000 description 1
- 244000018633 Prunus armeniaca Species 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- AHHFEZNOXOZZQA-ZEBDFXRSSA-N Ranimustine Chemical compound CO[C@H]1O[C@H](CNC(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O AHHFEZNOXOZZQA-ZEBDFXRSSA-N 0.000 description 1
- 102000034527 Retinoid X Receptors Human genes 0.000 description 1
- 108010038912 Retinoid X Receptors Proteins 0.000 description 1
- 240000001890 Ribes hudsonianum Species 0.000 description 1
- 235000016954 Ribes hudsonianum Nutrition 0.000 description 1
- 235000001466 Ribes nigrum Nutrition 0.000 description 1
- AWGBZRVEGDNLDZ-UHFFFAOYSA-N Rimocidin Natural products C1C(C(C(O)C2)C(O)=O)OC2(O)CC(O)CCCC(=O)CC(O)C(CC)C(=O)OC(CCC)CC=CC=CC=CC=CC1OC1OC(C)C(O)C(N)C1O AWGBZRVEGDNLDZ-UHFFFAOYSA-N 0.000 description 1
- AWGBZRVEGDNLDZ-JCUCCFEFSA-N Rimocidine Chemical compound O([C@H]1/C=C/C=C/C=C/C=C/C[C@H](OC(=O)[C@@H](CC)[C@H](O)CC(=O)CCC[C@H](O)C[C@@]2(O)O[C@H]([C@@H]([C@@H](O)C2)C(O)=O)C1)CCC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N)[C@@H]1O AWGBZRVEGDNLDZ-JCUCCFEFSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- 244000040738 Sesamum orientale Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241000862969 Stella Species 0.000 description 1
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 1
- 206010042496 Sunburn Diseases 0.000 description 1
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 108010053950 Teicoplanin Proteins 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- YCPOZVAOBBQLRI-WDSKDSINSA-N Treosulfan Chemical compound CS(=O)(=O)OC[C@H](O)[C@@H](O)COS(C)(=O)=O YCPOZVAOBBQLRI-WDSKDSINSA-N 0.000 description 1
- UMILHIMHKXVDGH-UHFFFAOYSA-N Triethylene glycol diglycidyl ether Chemical compound C1OC1COCCOCCOCCOCC1CO1 UMILHIMHKXVDGH-UHFFFAOYSA-N 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- PFRQBZFETXBLTP-UHFFFAOYSA-N Vitamin K2 Natural products C1=CC=C2C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C(=O)C2=C1 PFRQBZFETXBLTP-UHFFFAOYSA-N 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- BYJHKVPTXGTNJE-DUOXSESHSA-N Xanthochymol Natural products CC(=CC[C@@H]1C[C@@]2(C[C@@H](CCC(=C)C)C(=C)C)[C@@H](O)[C@@H](C(=O)c3ccc(O)c(O)c3)C(=O)[C@](CC=C(C)C)(C2=O)C1(C)C)C BYJHKVPTXGTNJE-DUOXSESHSA-N 0.000 description 1
- 235000006801 Ximenia americana Nutrition 0.000 description 1
- 244000112726 Ximenia americana Species 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- MSAQSJXMDMTPBO-UHFFFAOYSA-M [Br-].CCCCCCCCCCCCCC[Mg+] Chemical compound [Br-].CCCCCCCCCCCCCC[Mg+] MSAQSJXMDMTPBO-UHFFFAOYSA-M 0.000 description 1
- ZZPTUMYVHJFPGB-UHFFFAOYSA-M [Br-].CCCCCCCCCCCCC[Mg+] Chemical compound [Br-].CCCCCCCCCCCCC[Mg+] ZZPTUMYVHJFPGB-UHFFFAOYSA-M 0.000 description 1
- TYBHXIFFPVFXQW-UHFFFAOYSA-N abafungin Chemical compound CC1=CC(C)=CC=C1OC1=CC=CC=C1C1=CSC(NC=2NCCCN=2)=N1 TYBHXIFFPVFXQW-UHFFFAOYSA-N 0.000 description 1
- 229950006373 abafungin Drugs 0.000 description 1
- 235000003650 acai Nutrition 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 229920006243 acrylic copolymer Polymers 0.000 description 1
- 229920000800 acrylic rubber Polymers 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- 239000002487 adenosine deaminase inhibitor Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229960001445 alitretinoin Drugs 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 235000010081 allicin Nutrition 0.000 description 1
- JDLKFOPOAOFWQN-UHFFFAOYSA-N allicin Chemical compound C=CCSS(=O)CC=C JDLKFOPOAOFWQN-UHFFFAOYSA-N 0.000 description 1
- 235000020224 almond Nutrition 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 229950010817 alvocidib Drugs 0.000 description 1
- BIIVYFLTOXDAOV-YVEFUNNKSA-N alvocidib Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O BIIVYFLTOXDAOV-YVEFUNNKSA-N 0.000 description 1
- 239000004178 amaranth Substances 0.000 description 1
- 235000012735 amaranth Nutrition 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 229960003204 amorolfine Drugs 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229960003942 amphotericin b Drugs 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960002550 amrubicin Drugs 0.000 description 1
- VJZITPJGSQKZMX-XDPRQOKASA-N amrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C(O)=C21)(N)C(=O)C)[C@H]1C[C@H](O)[C@H](O)CO1 VJZITPJGSQKZMX-XDPRQOKASA-N 0.000 description 1
- 229960001694 anagrelide Drugs 0.000 description 1
- OTBXOEAOVRKTNQ-UHFFFAOYSA-N anagrelide Chemical compound N1=C2NC(=O)CN2CC2=C(Cl)C(Cl)=CC=C21 OTBXOEAOVRKTNQ-UHFFFAOYSA-N 0.000 description 1
- JHVAMHSQVVQIOT-MFAJLEFUSA-N anidulafungin Chemical compound C1=CC(OCCCCC)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@@H](C)O)[C@H](O)[C@@H](O)C=2C=CC(O)=CC=2)[C@@H](C)O)=O)C=C1 JHVAMHSQVVQIOT-MFAJLEFUSA-N 0.000 description 1
- 229960003348 anidulafungin Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- RGHILYZRVFRRNK-UHFFFAOYSA-N anthracene-1,2-dione Chemical class C1=CC=C2C=C(C(C(=O)C=C3)=O)C3=CC2=C1 RGHILYZRVFRRNK-UHFFFAOYSA-N 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- KZNIFHPLKGYRTM-UHFFFAOYSA-N apigenin Chemical compound C1=CC(O)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C=C2O1 KZNIFHPLKGYRTM-UHFFFAOYSA-N 0.000 description 1
- XADJWCRESPGUTB-UHFFFAOYSA-N apigenin Natural products C1=CC(O)=CC=C1C1=CC(=O)C2=CC(O)=C(O)C=C2O1 XADJWCRESPGUTB-UHFFFAOYSA-N 0.000 description 1
- 235000008714 apigenin Nutrition 0.000 description 1
- 229940117893 apigenin Drugs 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 1
- 229960002594 arsenic trioxide Drugs 0.000 description 1
- VLAXZGHHBIJLAD-UHFFFAOYSA-N arsphenamine Chemical compound [Cl-].[Cl-].C1=C(O)C([NH3+])=CC([As]=[As]C=2C=C([NH3+])C(O)=CC=2)=C1 VLAXZGHHBIJLAD-UHFFFAOYSA-N 0.000 description 1
- 229940003446 arsphenamine Drugs 0.000 description 1
- 235000016520 artichoke thistle Nutrition 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 229950010993 atrasentan Drugs 0.000 description 1
- MOTJMGVDPWRKOC-QPVYNBJUSA-N atrasentan Chemical compound C1([C@H]2[C@@H]([C@H](CN2CC(=O)N(CCCC)CCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1 MOTJMGVDPWRKOC-QPVYNBJUSA-N 0.000 description 1
- 235000021302 avocado oil Nutrition 0.000 description 1
- 239000008163 avocado oil Substances 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 229960003623 azlocillin Drugs 0.000 description 1
- JTWOMNBEOCYFNV-NFFDBFGFSA-N azlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCNC1=O JTWOMNBEOCYFNV-NFFDBFGFSA-N 0.000 description 1
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 1
- 229960003644 aztreonam Drugs 0.000 description 1
- 229960003071 bacitracin Drugs 0.000 description 1
- 229930184125 bacitracin Natural products 0.000 description 1
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 1
- 235000015173 baked goods and baking mixes Nutrition 0.000 description 1
- 208000003373 basosquamous carcinoma Diseases 0.000 description 1
- 229940116226 behenic acid Drugs 0.000 description 1
- LNHWXBUNXOXMRL-VWLOTQADSA-N belotecan Chemical compound C1=CC=C2C(CCNC(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 LNHWXBUNXOXMRL-VWLOTQADSA-N 0.000 description 1
- 229950011276 belotecan Drugs 0.000 description 1
- 229960002707 bendamustine Drugs 0.000 description 1
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 150000008366 benzophenones Chemical class 0.000 description 1
- 229960002938 bexarotene Drugs 0.000 description 1
- 229960002206 bifonazole Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 235000015895 biscuits Nutrition 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 229960002962 butenafine Drugs 0.000 description 1
- ABJKWBDEJIDSJZ-UHFFFAOYSA-N butenafine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)CC1=CC=C(C(C)(C)C)C=C1 ABJKWBDEJIDSJZ-UHFFFAOYSA-N 0.000 description 1
- 229960005074 butoconazole Drugs 0.000 description 1
- SWLMUYACZKCSHZ-UHFFFAOYSA-N butoconazole Chemical compound C1=CC(Cl)=CC=C1CCC(SC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 SWLMUYACZKCSHZ-UHFFFAOYSA-N 0.000 description 1
- PPKJUHVNTMYXOD-PZGPJMECSA-N c49ws9n75l Chemical compound O=C([C@@H]1N(C2=O)CC[C@H]1S(=O)(=O)CCN(CC)CC)O[C@H](C(C)C)[C@H](C)\C=C\C(=O)NC\C=C\C(\C)=C\[C@@H](O)CC(=O)CC1=NC2=CO1.N([C@@H]1C(=O)N[C@@H](C(N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(=CC=2)N(C)C)C(=O)N2C[C@@H](CS[C@H]3C4CCN(CC4)C3)C(=O)C[C@H]2C(=O)N[C@H](C(=O)O[C@@H]1C)C=1C=CC=CC=1)=O)CC)C(=O)C1=NC=CC=C1O PPKJUHVNTMYXOD-PZGPJMECSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000009120 camo Nutrition 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 230000005773 cancer-related death Effects 0.000 description 1
- PTOJXIKSKSASRB-UHFFFAOYSA-O candicine Chemical compound C[N+](C)(C)CCC1=CC=C(O)C=C1 PTOJXIKSKSASRB-UHFFFAOYSA-O 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- KHAVLLBUVKBTBG-UHFFFAOYSA-N caproleic acid Natural products OC(=O)CCCCCCCC=C KHAVLLBUVKBTBG-UHFFFAOYSA-N 0.000 description 1
- JSVCEVCSANKFDY-SFYZADRCSA-N carbacephem Chemical compound C1CC(C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)C)[C@H]21 JSVCEVCSANKFDY-SFYZADRCSA-N 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 229960003669 carbenicillin Drugs 0.000 description 1
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 229960002115 carboquone Drugs 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 208000002458 carcinoid tumor Diseases 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 235000020226 cashew nut Nutrition 0.000 description 1
- JYIKNQVWKBUSNH-WVDDFWQHSA-N caspofungin Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 JYIKNQVWKBUSNH-WVDDFWQHSA-N 0.000 description 1
- 229960003034 caspofungin Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229960005361 cefaclor Drugs 0.000 description 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 1
- 229960004841 cefadroxil Drugs 0.000 description 1
- NBFNMSULHIODTC-CYJZLJNKSA-N cefadroxil monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=C(O)C=C1 NBFNMSULHIODTC-CYJZLJNKSA-N 0.000 description 1
- 229960000603 cefalotin Drugs 0.000 description 1
- 229960003012 cefamandole Drugs 0.000 description 1
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- 229960003719 cefdinir Drugs 0.000 description 1
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 description 1
- 229960004069 cefditoren Drugs 0.000 description 1
- KMIPKYQIOVAHOP-YLGJWRNMSA-N cefditoren Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C/C=1SC=NC=1C KMIPKYQIOVAHOP-YLGJWRNMSA-N 0.000 description 1
- HVFLCNVBZFFHBT-ZKDACBOMSA-N cefepime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 HVFLCNVBZFFHBT-ZKDACBOMSA-N 0.000 description 1
- 229960002100 cefepime Drugs 0.000 description 1
- 229960002129 cefixime Drugs 0.000 description 1
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 1
- 229960004682 cefoperazone Drugs 0.000 description 1
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 1
- 229960004261 cefotaxime Drugs 0.000 description 1
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 1
- 229960002682 cefoxitin Drugs 0.000 description 1
- 229960005090 cefpodoxime Drugs 0.000 description 1
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 description 1
- 229960002580 cefprozil Drugs 0.000 description 1
- 229960000484 ceftazidime Drugs 0.000 description 1
- ORFOPKXBNMVMKC-DWVKKRMSSA-N ceftazidime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 ORFOPKXBNMVMKC-DWVKKRMSSA-N 0.000 description 1
- 229960004086 ceftibuten Drugs 0.000 description 1
- UNJFKXSSGBWRBZ-BJCIPQKHSA-N ceftibuten Chemical compound S1C(N)=NC(C(=C\CC(O)=O)\C(=O)N[C@@H]2C(N3C(=CCS[C@@H]32)C(O)=O)=O)=C1 UNJFKXSSGBWRBZ-BJCIPQKHSA-N 0.000 description 1
- 229960001991 ceftizoxime Drugs 0.000 description 1
- NNULBSISHYWZJU-LLKWHZGFSA-N ceftizoxime Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 NNULBSISHYWZJU-LLKWHZGFSA-N 0.000 description 1
- VOAZJEPQLGBXGO-SDAWRPRTSA-N ceftobiprole Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(\C=C/4C(N([C@H]5CNCC5)CC\4)=O)CS[C@@H]32)C(O)=O)=O)=N1 VOAZJEPQLGBXGO-SDAWRPRTSA-N 0.000 description 1
- 229950004259 ceftobiprole Drugs 0.000 description 1
- 229960004755 ceftriaxone Drugs 0.000 description 1
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 1
- 229960001668 cefuroxime Drugs 0.000 description 1
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229940106164 cephalexin Drugs 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 235000005513 chalcones Nutrition 0.000 description 1
- 235000005607 chanvre indien Nutrition 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 235000013351 cheese Nutrition 0.000 description 1
- DDTDNCYHLGRFBM-YZEKDTGTSA-N chembl2367892 Chemical compound CC(=O)N[C@H]1[C@@H](O)[C@H](O)[C@H](CO)O[C@H]1O[C@@H]([C@H]1C(N[C@@H](C2=CC(O)=CC(O[C@@H]3[C@H]([C@H](O)[C@H](O)[C@@H](CO)O3)O)=C2C=2C(O)=CC=C(C=2)[C@@H](NC(=O)[C@@H]2NC(=O)[C@@H]3C=4C=C(O)C=C(C=4)OC=4C(O)=CC=C(C=4)[C@@H](N)C(=O)N[C@H](CC=4C=C(Cl)C(O5)=CC=4)C(=O)N3)C(=O)N1)C(O)=O)=O)C(C=C1Cl)=CC=C1OC1=C(O[C@H]3[C@H]([C@@H](O)[C@H](O)[C@H](CO)O3)NC(C)=O)C5=CC2=C1 DDTDNCYHLGRFBM-YZEKDTGTSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940112822 chewing gum Drugs 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 229960003749 ciclopirox Drugs 0.000 description 1
- SCKYRAXSEDYPSA-UHFFFAOYSA-N ciclopirox Chemical compound ON1C(=O)C=C(C)C=C1C1CCCCC1 SCKYRAXSEDYPSA-UHFFFAOYSA-N 0.000 description 1
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000010632 citronella oil Substances 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 1
- 229960000928 clofarabine Drugs 0.000 description 1
- 229960004287 clofazimine Drugs 0.000 description 1
- WDQPAMHFFCXSNU-BGABXYSRSA-N clofazimine Chemical compound C12=CC=CC=C2N=C2C=C(NC=3C=CC(Cl)=CC=3)C(=N/C(C)C)/C=C2N1C1=CC=C(Cl)C=C1 WDQPAMHFFCXSNU-BGABXYSRSA-N 0.000 description 1
- 229960004022 clotrimazole Drugs 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 229960003326 cloxacillin Drugs 0.000 description 1
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 235000016213 coffee Nutrition 0.000 description 1
- 235000013353 coffee beverage Nutrition 0.000 description 1
- 229960003346 colistin Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 239000000549 coloured material Substances 0.000 description 1
- 235000018597 common camellia Nutrition 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 229920002770 condensed tannin Polymers 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000008162 cooking oil Substances 0.000 description 1
- 235000014510 cooky Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000001359 coriandrum sativum l. oleoresin Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 description 1
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 description 1
- 229940086555 cyclomethicone Drugs 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 239000001939 cymbopogon martini roxb. stapf. oil Substances 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000860 dapsone Drugs 0.000 description 1
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 description 1
- 229960005484 daptomycin Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 229960002398 demeclocycline Drugs 0.000 description 1
- 229960005052 demecolcine Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 150000001982 diacylglycerols Chemical class 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229960001585 dicloxacillin Drugs 0.000 description 1
- YFAGHNZHGGCZAX-JKIFEVAISA-N dicloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl YFAGHNZHGGCZAX-JKIFEVAISA-N 0.000 description 1
- 239000003166 dihydrofolate reductase inhibitor Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 235000014505 dips Nutrition 0.000 description 1
- 229960004100 dirithromycin Drugs 0.000 description 1
- WLOHNSSYAXHWNR-NXPDYKKBSA-N dirithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H]2O[C@H](COCCOC)N[C@H]([C@@H]2C)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 WLOHNSSYAXHWNR-NXPDYKKBSA-N 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 125000000567 diterpene group Chemical group 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- KFEVDPWXEVUUMW-UHFFFAOYSA-N docosanoic acid Natural products CCCCCCCCCCCCCCCCCCCCCC(=O)OCCC1=CC=C(O)C=C1 KFEVDPWXEVUUMW-UHFFFAOYSA-N 0.000 description 1
- 229960000895 doripenem Drugs 0.000 description 1
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- 229960003913 econazole Drugs 0.000 description 1
- BNFRJXLZYUTIII-UHFFFAOYSA-N efaproxiral Chemical compound CC1=CC(C)=CC(NC(=O)CC=2C=CC(OC(C)(C)C(O)=O)=CC=2)=C1 BNFRJXLZYUTIII-UHFFFAOYSA-N 0.000 description 1
- 229960000925 efaproxiral Drugs 0.000 description 1
- 229950003247 elesclomol Drugs 0.000 description 1
- BKJIXTWSNXCKJH-UHFFFAOYSA-N elesclomol Chemical compound C=1C=CC=CC=1C(=S)N(C)NC(=O)CC(=O)NN(C)C(=S)C1=CC=CC=C1 BKJIXTWSNXCKJH-UHFFFAOYSA-N 0.000 description 1
- 229950002339 elsamitrucin Drugs 0.000 description 1
- MGQRRMONVLMKJL-KWJIQSIXSA-N elsamitrucin Chemical compound O1[C@H](C)[C@H](O)[C@H](OC)[C@@H](N)[C@H]1O[C@@H]1[C@](O)(C)[C@@H](O)[C@@H](C)O[C@H]1OC1=CC=CC2=C(O)C(C(O3)=O)=C4C5=C3C=CC(C)=C5C(=O)OC4=C12 MGQRRMONVLMKJL-KWJIQSIXSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 208000028730 endometrioid adenocarcinoma Diseases 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 229960002549 enoxacin Drugs 0.000 description 1
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 1
- 229960002770 ertapenem Drugs 0.000 description 1
- HCZKYJDFEPMADG-UHFFFAOYSA-N erythro-nordihydroguaiaretic acid Natural products C=1C=C(O)C(O)=CC=1CC(C)C(C)CC1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-UHFFFAOYSA-N 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 201000005619 esophageal carcinoma Diseases 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229960000285 ethambutol Drugs 0.000 description 1
- 239000002031 ethanolic fraction Substances 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 229960005237 etoglucid Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 235000019387 fatty acid methyl ester Nutrition 0.000 description 1
- 229960001274 fenticonazole Drugs 0.000 description 1
- KSEBMYQBYZTDHS-HWKANZROSA-N ferulic acid Chemical class COC1=CC(\C=C\C(O)=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-N 0.000 description 1
- 235000001785 ferulic acid Nutrition 0.000 description 1
- 229950000152 filipin Drugs 0.000 description 1
- IMQSIXYSKPIGPD-NKYUYKLDSA-N filipin Chemical compound CCCCC[C@H](O)[C@@H]1[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@H](O)\C(C)=C\C=C\C=C\C=C\C=C\[C@H](O)[C@@H](C)OC1=O IMQSIXYSKPIGPD-NKYUYKLDSA-N 0.000 description 1
- IMQSIXYSKPIGPD-UHFFFAOYSA-N filipin III Natural products CCCCCC(O)C1C(O)CC(O)CC(O)CC(O)CC(O)CC(O)CC(O)C(C)=CC=CC=CC=CC=CC(O)C(C)OC1=O IMQSIXYSKPIGPD-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229960004273 floxacillin Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000012041 food component Nutrition 0.000 description 1
- 239000005428 food component Substances 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 229960000308 fosfomycin Drugs 0.000 description 1
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 235000013569 fruit product Nutrition 0.000 description 1
- 229960001625 furazolidone Drugs 0.000 description 1
- PLHJDBGFXBMTGZ-WEVVVXLNSA-N furazolidone Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)OCC1 PLHJDBGFXBMTGZ-WEVVVXLNSA-N 0.000 description 1
- 229960004675 fusidic acid Drugs 0.000 description 1
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical compound O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000013110 gastrectomy Methods 0.000 description 1
- 201000011587 gastric lymphoma Diseases 0.000 description 1
- 229960003923 gatifloxacin Drugs 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- 230000036449 good health Effects 0.000 description 1
- 235000014168 granola/muesli bars Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940087559 grape seed Drugs 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229960002867 griseofulvin Drugs 0.000 description 1
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 1
- GRBCIRZXESZBGJ-UHFFFAOYSA-N guttiferone F Natural products CC(=CCCC(C(=C)C)C12CC(CC=C(C)C)C(C)(C)C(CC=C(C)C)(C(=O)C(=C1O)C(=O)c3ccc(O)c(O)c3)C2=O)C GRBCIRZXESZBGJ-UHFFFAOYSA-N 0.000 description 1
- 229960001906 haloprogin Drugs 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000007407 health benefit Effects 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000011487 hemp Substances 0.000 description 1
- MCAHMSDENAOJFZ-BVXDHVRPSA-N herbimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](OC)[C@@H](OC)C[C@H](C)[C@@H](OC)C2=CC(=O)C=C1C2=O MCAHMSDENAOJFZ-BVXDHVRPSA-N 0.000 description 1
- 229930193320 herbimycin Natural products 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 235000020278 hot chocolate Nutrition 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 229940075628 hypomethylating agent Drugs 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
- 206010021198 ichthyosis Diseases 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000005470 impregnation Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000002348 inosinate dehydrogenase inhibitor Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 208000030776 invasive breast carcinoma Diseases 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- DDFOUSQFMYRUQK-RCDICMHDSA-N isavuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC=C(F)C=2)F)=NC=1C1=CC=C(C#N)C=C1 DDFOUSQFMYRUQK-RCDICMHDSA-N 0.000 description 1
- 229960000788 isavuconazole Drugs 0.000 description 1
- 229960004849 isoconazole Drugs 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 description 1
- 229960002014 ixabepilone Drugs 0.000 description 1
- SQFSKOYWJBQGKQ-UHFFFAOYSA-N kaempferide Chemical compound C1=CC(OC)=CC=C1C1=C(O)C(=O)C2=C(O)C=C(O)C=C2O1 SQFSKOYWJBQGKQ-UHFFFAOYSA-N 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 229950005692 larotaxel Drugs 0.000 description 1
- SEFGUGYLLVNFIJ-QDRLFVHASA-N larotaxel dihydrate Chemical compound O.O.O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@@]23[C@H]1[C@@]1(CO[C@@H]1C[C@@H]2C3)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 SEFGUGYLLVNFIJ-QDRLFVHASA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229960005287 lincomycin Drugs 0.000 description 1
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229960002422 lomefloxacin Drugs 0.000 description 1
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 1
- 229960001977 loracarbef Drugs 0.000 description 1
- JAPHQRWPEGVNBT-UTUOFQBUSA-N loracarbef Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CC[C@@H]32)C([O-])=O)=O)[NH3+])=CC=CC=C1 JAPHQRWPEGVNBT-UTUOFQBUSA-N 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 229960003640 mafenide Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000001055 magnesium Nutrition 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- UUVIQYKKKBJYJT-ZYUZMQFOSA-N mannosulfan Chemical compound CS(=O)(=O)OC[C@@H](OS(C)(=O)=O)[C@@H](O)[C@H](O)[C@H](OS(C)(=O)=O)COS(C)(=O)=O UUVIQYKKKBJYJT-ZYUZMQFOSA-N 0.000 description 1
- 229960000733 mannosulfan Drugs 0.000 description 1
- 229960003951 masoprocol Drugs 0.000 description 1
- HCZKYJDFEPMADG-TXEJJXNPSA-N masoprocol Chemical compound C([C@H](C)[C@H](C)CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-TXEJJXNPSA-N 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 210000002752 melanocyte Anatomy 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- DKHGMERMDICWDU-GHDNBGIDSA-N menaquinone-4 Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)=C(C)C(=O)C2=C1 DKHGMERMDICWDU-GHDNBGIDSA-N 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 229960002260 meropenem Drugs 0.000 description 1
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 208000011645 metastatic carcinoma Diseases 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- YUUAYBAIHCDHHD-UHFFFAOYSA-N methyl 5-aminolevulinate Chemical compound COC(=O)CCC(=O)CN YUUAYBAIHCDHHD-UHFFFAOYSA-N 0.000 description 1
- 229960005033 methyl aminolevulinate Drugs 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N methyl undecanoic acid Natural products CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- 229960000198 mezlocillin Drugs 0.000 description 1
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 1
- 229960002159 micafungin Drugs 0.000 description 1
- PIEUQSKUWLMALL-YABMTYFHSA-N micafungin Chemical compound C1=CC(OCCCCC)=CC=C1C1=CC(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@H](O)CC(N)=O)[C@H](O)[C@@H](O)C=2C=C(OS(O)(=O)=O)C(O)=CC=2)[C@@H](C)O)=O)=NO1 PIEUQSKUWLMALL-YABMTYFHSA-N 0.000 description 1
- 229960002509 miconazole Drugs 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 235000020124 milk-based beverage Nutrition 0.000 description 1
- 235000020166 milkshake Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 229960005485 mitobronitol Drugs 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 229940041009 monobactams Drugs 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 229960003702 moxifloxacin Drugs 0.000 description 1
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 229960003128 mupirocin Drugs 0.000 description 1
- 229930187697 mupirocin Natural products 0.000 description 1
- DDHVILIIHBIMQU-YJGQQKNPSA-L mupirocin calcium hydrate Chemical compound O.O.[Ca+2].C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1.C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1 DDHVILIIHBIMQU-YJGQQKNPSA-L 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- JORAUNFTUVJTNG-BSTBCYLQSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Chemical compound CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O.CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O JORAUNFTUVJTNG-BSTBCYLQSA-N 0.000 description 1
- GPXLMGHLHQJAGZ-JTDSTZFVSA-N nafcillin Chemical compound C1=CC=CC2=C(C(=O)N[C@@H]3C(N4[C@H](C(C)(C)S[C@@H]43)C(O)=O)=O)C(OCC)=CC=C21 GPXLMGHLHQJAGZ-JTDSTZFVSA-N 0.000 description 1
- 229960000515 nafcillin Drugs 0.000 description 1
- 229960004313 naftifine Drugs 0.000 description 1
- OZGNYLLQHRPOBR-DHZHZOJOSA-N naftifine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)C\C=C\C1=CC=CC=C1 OZGNYLLQHRPOBR-DHZHZOJOSA-N 0.000 description 1
- 229960003255 natamycin Drugs 0.000 description 1
- 239000004311 natamycin Substances 0.000 description 1
- NCXMLFZGDNKEPB-FFPOYIOWSA-N natamycin Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C[C@@H](C)OC(=O)/C=C/[C@H]2O[C@@H]2C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 NCXMLFZGDNKEPB-FFPOYIOWSA-N 0.000 description 1
- 235000010298 natamycin Nutrition 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229950007221 nedaplatin Drugs 0.000 description 1
- SYKFHCWMZKYPEA-UHFFFAOYSA-N nemorosone Natural products CC1(C)C(CC=C(C)C)CC(C2=O)(CC=C(C)C)C(O)=C(CC=C(C)C)C(=O)C12C(=O)C1=CC=CC=C1 SYKFHCWMZKYPEA-UHFFFAOYSA-N 0.000 description 1
- NXZAENPZCAUREW-UHFFFAOYSA-N nemorosone II Natural products CC1(C)C(CC=C(C)C)CC(C2=O)(CC=C(C)C)C(=O)C(CC=C(C)C)=C(O)C12C(=O)C1=CC=CC=C1 NXZAENPZCAUREW-UHFFFAOYSA-N 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 229960000808 netilmicin Drugs 0.000 description 1
- ZBGPYVZLYBDXKO-HILBYHGXSA-N netilmycin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@]([C@H](NC)[C@@H](O)CO1)(C)O)NCC)[C@H]1OC(CN)=CC[C@H]1N ZBGPYVZLYBDXKO-HILBYHGXSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229960001420 nimustine Drugs 0.000 description 1
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 description 1
- 229960000564 nitrofurantoin Drugs 0.000 description 1
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 1
- 229960000572 olaparib Drugs 0.000 description 1
- 150000002888 oleic acid derivatives Chemical class 0.000 description 1
- OJFMDENMLJWYEW-UHFFFAOYSA-N oncidinol Natural products CCCCCCCCCCCCCCC(CCC(CC(=O)OC(CO)COC(=O)C)OC(=O)C)OC(=O)C OJFMDENMLJWYEW-UHFFFAOYSA-N 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- BWKDAMBGCPRVPI-ZQRPHVBESA-N ortataxel Chemical compound O([C@@H]1[C@]23OC(=O)O[C@H]2[C@@H](C(=C([C@@H](OC(C)=O)C(=O)[C@]2(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]21)OC(C)=O)C3(C)C)C)OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)CC(C)C)C(=O)C1=CC=CC=C1 BWKDAMBGCPRVPI-ZQRPHVBESA-N 0.000 description 1
- 229950001094 ortataxel Drugs 0.000 description 1
- 229940026778 other chemotherapeutics in atc Drugs 0.000 description 1
- 229960001019 oxacillin Drugs 0.000 description 1
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960003483 oxiconazole Drugs 0.000 description 1
- QRJJEGAJXVEBNE-MOHJPFBDSA-N oxiconazole Chemical compound ClC1=CC(Cl)=CC=C1CO\N=C(C=1C(=CC(Cl)=CC=1)Cl)\CN1C=NC=C1 QRJJEGAJXVEBNE-MOHJPFBDSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229960001914 paromomycin Drugs 0.000 description 1
- UOZODPSAJZTQNH-LSWIJEOBSA-N paromomycin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO UOZODPSAJZTQNH-LSWIJEOBSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 229960001744 pegaspargase Drugs 0.000 description 1
- 108010001564 pegaspargase Proteins 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 239000010702 perfluoropolyether Substances 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000009048 phenolic acids Nutrition 0.000 description 1
- 150000007965 phenolic acids Chemical class 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000000485 pigmenting effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- ORJDDOBAOGKRJV-AWEZNQCLSA-N pinostrobin Chemical compound C1([C@@H]2CC(=O)C3=C(O)C=C(C=C3O2)OC)=CC=CC=C1 ORJDDOBAOGKRJV-AWEZNQCLSA-N 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- 235000020233 pistachio Nutrition 0.000 description 1
- 229960004403 pixantrone Drugs 0.000 description 1
- PEZPMAYDXJQYRV-UHFFFAOYSA-N pixantrone Chemical compound O=C1C2=CN=CC=C2C(=O)C2=C1C(NCCN)=CC=C2NCCN PEZPMAYDXJQYRV-UHFFFAOYSA-N 0.000 description 1
- CSOMAHTTWTVBFL-OFBLZTNGSA-N platensimycin Chemical compound C([C@]1([C@@H]2[C@@H]3C[C@@H]4C[C@@]2(C=CC1=O)C[C@@]4(O3)C)C)CC(=O)NC1=C(O)C=CC(C(O)=O)=C1O CSOMAHTTWTVBFL-OFBLZTNGSA-N 0.000 description 1
- CSOMAHTTWTVBFL-UHFFFAOYSA-N platensimycin Natural products O1C2(C)CC3(C=CC4=O)CC2CC1C3C4(C)CCC(=O)NC1=C(O)C=CC(C(O)=O)=C1O CSOMAHTTWTVBFL-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 1
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 150000004291 polyenes Chemical class 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 1
- XDJYMJULXQKGMM-UHFFFAOYSA-N polymyxin E1 Natural products CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O XDJYMJULXQKGMM-UHFFFAOYSA-N 0.000 description 1
- KNIWPHSUTGNZST-UHFFFAOYSA-N polymyxin E2 Natural products CC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O KNIWPHSUTGNZST-UHFFFAOYSA-N 0.000 description 1
- 229960005266 polymyxin b Drugs 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229960004293 porfimer sodium Drugs 0.000 description 1
- 150000004033 porphyrin derivatives Chemical class 0.000 description 1
- 229960001589 posaconazole Drugs 0.000 description 1
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- ABBQGOCHXSPKHJ-WUKNDPDISA-N prontosil Chemical compound NC1=CC(N)=CC=C1\N=N\C1=CC=C(S(N)(=O)=O)C=C1 ABBQGOCHXSPKHJ-WUKNDPDISA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 229930191173 propolin Natural products 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 235000020236 pumpkin seed Nutrition 0.000 description 1
- 239000012521 purified sample Substances 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 229940052337 quinupristin/dalfopristin Drugs 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 229960002185 ranimustine Drugs 0.000 description 1
- OPAHEYNNJWPQPX-RCDICMHDSA-N ravuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=1C1=CC=C(C#N)C=C1 OPAHEYNNJWPQPX-RCDICMHDSA-N 0.000 description 1
- 229950004154 ravuconazole Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- ATEBXHFBFRCZMA-VXTBVIBXSA-N rifabutin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC(=C2N3)C(=O)C=4C(O)=C5C)C)OC)C5=C1C=4C2=NC13CCN(CC(C)C)CC1 ATEBXHFBFRCZMA-VXTBVIBXSA-N 0.000 description 1
- 229960000885 rifabutin Drugs 0.000 description 1
- 229960005224 roxithromycin Drugs 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 229950009213 rubitecan Drugs 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229960005399 satraplatin Drugs 0.000 description 1
- 190014017285 satraplatin Chemical compound 0.000 description 1
- 235000015067 sauces Nutrition 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- BTIHMVBBUGXLCJ-OAHLLOKOSA-N seliciclib Chemical compound C=12N=CN(C(C)C)C2=NC(N[C@@H](CO)CC)=NC=1NCC1=CC=CC=C1 BTIHMVBBUGXLCJ-OAHLLOKOSA-N 0.000 description 1
- 229950000055 seliciclib Drugs 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 229960005429 sertaconazole Drugs 0.000 description 1
- 230000009450 sialylation Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 230000009759 skin aging Effects 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 235000009561 snack bars Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229960001407 sodium bicarbonate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 229960000268 spectinomycin Drugs 0.000 description 1
- UNFWWIHTNXNPBV-WXKVUWSESA-N spectinomycin Chemical compound O([C@@H]1[C@@H](NC)[C@@H](O)[C@H]([C@@H]([C@H]1O1)O)NC)[C@]2(O)[C@H]1O[C@H](C)CC2=O UNFWWIHTNXNPBV-WXKVUWSESA-N 0.000 description 1
- 235000011496 sports drink Nutrition 0.000 description 1
- 208000017572 squamous cell neoplasm Diseases 0.000 description 1
- 230000007103 stamina Effects 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940041022 streptomycins Drugs 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229960002607 sulconazole Drugs 0.000 description 1
- 229960002673 sulfacetamide Drugs 0.000 description 1
- SKIVFJLNDNKQPD-UHFFFAOYSA-N sulfacetamide Chemical compound CC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 SKIVFJLNDNKQPD-UHFFFAOYSA-N 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004306 sulfadiazine Drugs 0.000 description 1
- 229960000654 sulfafurazole Drugs 0.000 description 1
- 229960005158 sulfamethizole Drugs 0.000 description 1
- VACCAVUAMIDAGB-UHFFFAOYSA-N sulfamethizole Chemical compound S1C(C)=NN=C1NS(=O)(=O)C1=CC=C(N)C=C1 VACCAVUAMIDAGB-UHFFFAOYSA-N 0.000 description 1
- 229950008188 sulfamidochrysoidine Drugs 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229950010924 talaporfin Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 239000010677 tea tree oil Substances 0.000 description 1
- 229940111630 tea tree oil Drugs 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960001608 teicoplanin Drugs 0.000 description 1
- 229960003250 telithromycin Drugs 0.000 description 1
- LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 description 1
- 229960002197 temoporfin Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960002722 terbinafine Drugs 0.000 description 1
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 1
- 229960000580 terconazole Drugs 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- MODVSQKJJIBWPZ-VLLPJHQWSA-N tesetaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3CC[C@@]2(C)[C@H]2[C@@H](C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C(=CC=CN=4)F)C[C@]1(O)C3(C)C)O[C@H](O2)CN(C)C)C(=O)C1=CC=CC=C1 MODVSQKJJIBWPZ-VLLPJHQWSA-N 0.000 description 1
- 229950009016 tesetaxel Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- OTVAEFIXJLOWRX-NXEZZACHSA-N thiamphenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CO)NC(=O)C(Cl)Cl)C=C1 OTVAEFIXJLOWRX-NXEZZACHSA-N 0.000 description 1
- 229960003053 thiamphenicol Drugs 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 239000010496 thistle oil Substances 0.000 description 1
- 229960003723 tiazofurine Drugs 0.000 description 1
- FVRDYQYEVDDKCR-DBRKOABJSA-N tiazofurine Chemical compound NC(=O)C1=CSC([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=N1 FVRDYQYEVDDKCR-DBRKOABJSA-N 0.000 description 1
- 229960004659 ticarcillin Drugs 0.000 description 1
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 1
- 229960005053 tinidazole Drugs 0.000 description 1
- 229960004214 tioconazole Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 1
- 229950009158 tipifarnib Drugs 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- FUSNMLFNXJSCDI-UHFFFAOYSA-N tolnaftate Chemical compound C=1C=C2C=CC=CC2=CC=1OC(=S)N(C)C1=CC=CC(C)=C1 FUSNMLFNXJSCDI-UHFFFAOYSA-N 0.000 description 1
- 229960004880 tolnaftate Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229960000977 trabectedin Drugs 0.000 description 1
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 description 1
- NGSWKAQJJWESNS-ZZXKWVIFSA-N trans-4-coumaric acid Chemical class OC(=O)\C=C\C1=CC=C(O)C=C1 NGSWKAQJJWESNS-ZZXKWVIFSA-N 0.000 description 1
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 229960003181 treosulfan Drugs 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 150000004654 triazenes Chemical class 0.000 description 1
- 229960004560 triaziquone Drugs 0.000 description 1
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 190014017283 triplatin tetranitrate Chemical compound 0.000 description 1
- 229950002860 triplatin tetranitrate Drugs 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 229960005041 troleandomycin Drugs 0.000 description 1
- LQCLVBQBTUVCEQ-QTFUVMRISA-N troleandomycin Chemical compound O1[C@@H](C)[C@H](OC(C)=O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](C)C(=O)O[C@H](C)[C@H](C)[C@H](OC(C)=O)[C@@H](C)C(=O)[C@@]2(OC2)C[C@H](C)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)OC(C)=O)[C@H]1C LQCLVBQBTUVCEQ-QTFUVMRISA-N 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 229960003895 verteporfin Drugs 0.000 description 1
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 229960000922 vinflunine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 235000019143 vitamin K2 Nutrition 0.000 description 1
- 239000011728 vitamin K2 Substances 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 235000020234 walnut Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000010508 watermelon seed oil Substances 0.000 description 1
- 239000010497 wheat germ oil Substances 0.000 description 1
- 239000003357 wound healing promoting agent Substances 0.000 description 1
- 235000008924 yoghurt drink Nutrition 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/76—Salicaceae (Willow family), e.g. poplar
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Biotechnology (AREA)
- General Chemical & Material Sciences (AREA)
- Alternative & Traditional Medicine (AREA)
- Emergency Medicine (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Jellies, Jams, And Syrups (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
This invention provides pharmaceutical and cosmeceutical compositions, including
anti-epithelial cancer compositions, containing glyceride compounds, and compositions
comprising one or more of these compounds. Methods of preparing and using such
compositions, in particular in the treatment or prevention of epithelial cancers, such as skin
cancers, gastrointestinal cancers, and skin disorders, are also provided.
Description
This invention relates to compositions for use in skin and gut care and in the
treatment and prevention of epithelial cancers, including skin cancers and gastrointestinal
cancers. In particular, this invention relates to anti-epithelial cancer compositions
comprising one or more glycerides containing dihydroxy fatty acids. Particularly
contemplated are skin and gut care and anti-epithelial cancer compositions comprising one
or more dihydroxy fatty acid compounds, and the use of such compositions in the treatment
or prevention of skin disorders, disorders of the alimentary canal, disorders of mucosal
surfaces, and epithelial cancers, including gastrointestinal cancers, such as colorectal,
throat, buccal, and gastric cancers, and skin cancers, such as basal cell carcinomas,
squamous cell carcinomas, and melanomas.
Epithelial cancers include some of the most prevalent cancers in the world. Colorectal
cancer is reportedly the second and third most common cancer in women and men,
respectively, from developed countries. Colorectal cancer is more prevalent in developed
countries - the US, Australia, Europe, and New Zealand having the highest rates - with
incidence being as much as 10 times greater than in developing countries. While surgery
can be effective, early detection is critical to positive surgical outcomes. Other therapies
are largely directed at life extension and palliative care, as the efficacy of current
chemotherapies and radiotherapies in treating primary tumours, or metastases outside the
lymph nodes is debated.
Throat cancer, also referred to as esophageal cancer, pharyngeal cancer, or laryngeal
cancer, encompasses tumours that develop in the tissues of the pharynx, nasopharynx,
oropharynx, hypopharynx, larynx (voice box) or tonsils. Therapies for throat cancer include surgery, radiotherapy or chemotherapy. Treatment for throat cancer can damage the throat and may cause changes to the way a patient eats, breathes and sleeps. Existing treatments for buccal cancer have similar issues.
Gastric or stomach cancer is the second most common cause of cancer-related death
in the world. Diagnosis is often delayed because symptoms may not occur in the early
stages of the disease. Surgery to remove the stomach (gastrectomy) is the only treatment
that can cure gastric cancers. Chemotherapy and radiation therapy after surgery may
improve the chance of a cure.
Skin cancers are also highly prevalent, with more than 3 million diagnosed cases
annually in the USA alone. Skin cancer rates are particularly high in Australia and New
Zealand, with incidence being as much as 4 times greater than in the USA. While surgery
can be effective, early detection is critical to positive surgical outcomes. Other therapies
are largely directed at low risk disease, as the efficacy of current chemotherapies and
radiotherapies in treating primary tumours, particularly of malignant melanomas, or
metastases outside the lymph nodes, is debated.
Accordingly, there is a need for anti-epithelial cancer compositions, including those
suitable for use in the treatment or prevention of skin cancers and/or gastrointestinal
cancers, and those which are able to support the maintenance of anti-epithelial cancer
activity or augment anti-epithelial cancer activity.
It is an object of the present invention to provide anti-epithelial cancer compositions
for use in the treatment or prevention of epithelial cancers, such as skin cancers, including
basal cell carcinoma, squamous cell carcinoma, and melanoma, and/or gastrointestinal
cancers, such as colorectal, throat, buccal, and gastric cancers, or to at least provide the
public with a useful choice.
Accordingly, in a first aspect the invention relates to a method of treating or
preventing an epithelial cancer in a subject, the method comprising administering to a
subject in need thereof an effective amount of a compound of formula (I): R1 (CH (CH R6
0 OR 4 OR5
R 1 =OH, OR 7 or0 OR3
OR2 (I)
or a pharmaceutically acceptable salt or solvate thereof, wherein R2, R3, R4 and Rs are
each independently H or acetyl (CH3CO-),
R6 is H or CH3, R7 is CH3 or C2 to C6 saturated or unsaturated hydrocarbon, and
x and y are each independently an integer from 3 to 14,
provided that when R6is H, x+ y is greater than 10 and less than or equal to 18, and
when R6 is CH3, x+y is greater than 9 and less than or equal to 17.In one embodiment, the
invention relates to a method of treating or preventing an epithelial cancer in a subject, the
method comprising administering to a subject in need thereof an effective amount of a
compound selected from any one or more of the group consisting of
a) 3,8-dihydroxy eicosanoic acid,
b) 1-(3,8-dihydroxy eicosanoyl) glycerol,
c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol,
d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol,
e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol,
f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol,
g) 3,8-dihydroxy eicosanoic acid methyl ester
h) 3,8-dihydroxy heneicosanoic acid, i) 1-(3,8-dihydroxy heneicosanoyl) glycerol, j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol, k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
1) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,
n) 3,8-dihydroxy heneicosanoic acid methyl ester
o) 3,8-dihydroxy docosanoic acid,
p) 1-(3,8-dihydroxy docosanoyl) glycerol,
q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol,
r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol,
s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol,
t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and
u) 3,8-dihydroxy docosanoic acid methyl ester,
or a pharmaceutically acceptable salt or solvate of any one of a) to u),
to a subject in need thereof.
In one embodiment, the method comprises administering a composition comprising,
consisting essentially or, or consisting of an effective amount of at least one compound of
formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a compound
selected from any one or more of the group consisting of
a) 3,8-dihydroxy eicosanoic acid,
b) 1-(3,8-dihydroxy eicosanoyl) glycerol,
c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol,
d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol,
e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol,
f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol,
g) 3,8-dihydroxy eicosanoic acid methyl ester
h) 3,8-dihydroxy heneicosanoic acid,
i) 1-(3,8-dihydroxy heneicosanoyl) glycerol,
j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol,
k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
I) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,
n) 3,8-dihydroxy heneicosanoic acid methyl ester
o) 3,8-dihydroxy docosanoic acid,
p) 1-(3,8-dihydroxy docosanoyl) glycerol,
q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol,
r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol,
s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol,
t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and
u) 3,8-dihydroxy docosanoic acid methyl ester,
or a pharmaceutically acceptable salt or solvate of any one of a) to u),
to a subject in need thereof.
In one embodiment, the invention relates to a method of treating or preventing a skin
cancer in a subject, the method comprising administering an effective amount of a
composition comprising, consisting essentially or, or consisting of at least one compound of
formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a compound
selected from any one or more of the group consisting of
a) 3,8-dihydroxy eicosanoic acid,
b) 1-(3,8-dihydroxy eicosanoyl) glycerol,
c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol,
d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol,
e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol,
f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol,
g) 3,8-dihydroxy eicosanoic acid methyl ester
h) 3,8-dihydroxy heneicosanoic acid,
i) 1-(3,8-dihydroxy heneicosanoyl) glycerol,
j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol,
k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
1) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol, n) 3,8-dihydroxy heneicosanoic acid methyl ester o) 3,8-dihydroxy docosanoic acid, p) 1-(3,8-dihydroxy docosanoyl) glycerol, q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol, r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol, s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol, t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and u) 3,8-dihydroxy docosanoic acid methyl ester, or a pharmaceutically acceptable salt or solvate of any one of a) to u), to a subject in need thereof.
In another aspect the invention relates to a method of inhibiting epithelial tumour
formation, inhibiting epithelial tumour growth, or inhibiting epithelial tumour metastasis in a
subject, the method comprising administration of an effective amount of a compound of
formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a compound
selected from any one or more of the group consisting of
a) 3,8-dihydroxy eicosanoic acid,
b) 1-(3,8-dihydroxy eicosanoyl) glycerol,
c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol,
d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol,
e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol,
f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol,
g) 3,8-dihydroxy eicosanoic acid methyl ester
h) 3,8-dihydroxy heneicosanoic acid,
i) 1-(3,8-dihydroxy heneicosanoyl) glycerol,
j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol, k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
1) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,
n) 3,8-dihydroxy heneicosanoic acid methyl ester
o) 3,8-dihydroxy docosanoic acid, p) 1-(3,8-dihydroxy docosanoyl) glycerol, q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol, r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol, s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol, t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and u) 3,8-dihydroxy docosanoic acid methyl ester, or a pharmaceutically acceptable salt or solvate of any one of a) to u), to a subject in need thereof.
In one embodiment the invention relates to a method of inhibiting skin tumour
formation, inhibiting skin tumour growth, or inhibiting skin tumour metastasis in a subject,
the method comprising administration of an effective amount of a compound of formula (I)
or a pharmaceutically acceptable salt or solvate thereof, or a compound selected from any
one or more of the group consisting of
a) 3,8-dihydroxy eicosanoic acid,
b) 1-(3,8-dihydroxy eicosanoyl) glycerol,
c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol,
d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol,
e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol,
f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol,
g) 3,8-dihydroxy eicosanoic acid methyl ester
h) 3,8-dihydroxy heneicosanoic acid,
i) 1-(3,8-dihydroxy heneicosanoyl) glycerol,
j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol,
k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
I) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,
n) 3,8-dihydroxy heneicosanoic acid methyl ester
o) 3,8-dihydroxy docosanoic acid,
p) 1-(3,8-dihydroxy docosanoyl) glycerol,
q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol, r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol, s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol, t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and u) 3,8-dihydroxy docosanoic acid methyl ester, or a pharmaceutically acceptable salt or solvate of any one of a) to u), to a subject in need thereof.
Another aspect relates to a method of inducing apoptosis of one or more neoplastic
epithelial cells in a subject, the method comprising administration of an effective amount of
a composition comprising a therapeutically effective amount of a compound of formula (I)
or a pharmaceutically acceptable salt or solvate thereof, or a therapeutically effective
amount of at least one compound selected from any one or more of the group consisting of
a) 3,8-dihydroxy eicosanoic acid,
b) 1-(3,8-dihydroxy eicosanoyl) glycerol,
c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol,
d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol,
e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol,
f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol,
g) 3,8-dihydroxy eicosanoic acid methyl ester
h) 3,8-dihydroxy heneicosanoic acid,
i) 1-(3,8-dihydroxy heneicosanoyl) glycerol,
j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol,
k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
1) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,
n) 3,8-dihydroxy heneicosanoic acid methyl ester
o) 3,8-dihydroxy docosanoic acid,
p) 1-(3,8-dihydroxy docosanoyl) glycerol,
q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol,
r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol,
s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol, t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and u) 3,8-dihydroxy docosanoic acid methyl ester, or a pharmaceutically acceptable salt or solvate of any one of a) to u), to a subject in need thereof.
In one embodiment, the method is a method of inducing apoptosis of one or more
neoplastic skin cells in a subject, the method comprising administration of an effective
amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate
thereof, or a compound selected from any one or more of the group consisting of
a) 3,8-dihydroxy eicosanoic acid,
b) 1-(3,8-dihydroxy eicosanoyl) glycerol,
c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol,
d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol,
e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol,
f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol,
g) 3,8-dihydroxy eicosanoic acid methyl ester
h) 3,8-dihydroxy heneicosanoic acid,
i) 1-(3,8-dihydroxy heneicosanoyl) glycerol,
j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol,
k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
I) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,
n) 3,8-dihydroxy heneicosanoic acid methyl ester
o) 3,8-dihydroxy docosanoic acid,
p) 1-(3,8-dihydroxy docosanoyl) glycerol,
q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol,
r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol,
s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol,
t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and
u) 3,8-dihydroxy docosanoic acid methyl ester,
or a pharmaceutically acceptable salt or solvate of any one of a) to u), to a subject in need thereof.
In one embodiment, the apoptosis is of basal carcinoma cells. In another embodiment
the apoptosis is of squamous carcinoma cells. In a further embodiment the apoptosis is of
melanoma cells.
In another embodiment, the method is a method of inducing apoptosis of one or more
neoplastic gastrointestinal cancer cells in a subject.
For example, the apoptosis is of colorectal cancer cells, throat cancer cells, buccal
cancer cells, or gastric cancer cells.
Another aspect relates to a method of modulating proliferation of one or more
neoplastic epithelial cells in a subject, the method comprising administration of an effective
amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate
thereof, or a compound selected from any one or more of the group consisting of
a) 3,8-dihydroxy eicosanoic acid,
b) 1-(3,8-dihydroxy eicosanoyl) glycerol,
c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol,
d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol,
e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol,
f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol,
g) 3,8-dihydroxy eicosanoic acid methyl ester
h) 3,8-dihydroxy heneicosanoic acid,
i) 1-(3,8-dihydroxy heneicosanoyl) glycerol,
j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol,
k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
1) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,
n) 3,8-dihydroxy heneicosanoic acid methyl ester
o) 3,8-dihydroxy docosanoic acid,
p) 1-(3,8-dihydroxy docosanoyl) glycerol,
q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol,
r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol, s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol, t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and u) 3,8-dihydroxy docosanoic acid methyl ester, or a pharmaceutically acceptable salt or solvate of any one of a) to u), to a subject in need thereof.
In one embodiment, the invention relates to a method of modulating proliferation of
one or more neoplastic skin cells in a subject.
For example in one embodiment the modulation is reduction. Accordingly the
invention relates to a method of reducing proliferation of one or more neoplastic skin cells in
a subject, the method comprising administration of an effective amount of a compound
selected from the group consisting of 3,8-dihydroxy eicosanoic acid, 1-(3,8-dihydroxy
eicosanoyl) glycerol, 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol, 1-(3,8-dihydroxy
eicosanoyl) 3-acetoxy glycerol, 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol, 1-(3,8
diacetoxy eicosanoyl) 2,3-diacetoxy glycerol, 3,8-dihydroxy eicosanoic acid methyl ester,
3,8-dihydroxy heneicosanoic acid, 1-(3,8-dihydroxy heneicosanoyl) glycerol, 1-(3,8
dihydroxy heneicosanoyl) 2-acetoxy glycerol, 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy
glycerol, 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol, 1-(3,8-diacetoxy
heneicosanoyl) 2,3-diacetoxy glycerol, 3,8-dihydroxy heneicosanoic acid methyl ester, 3,8
dihydroxy docosanoic acid, 1-(3,8-dihydroxy docosanoyl) glycerol, 1-(3,8-dihydroxy
docosanoyl) 2-acetoxy glycerol, 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol, 1-(3,8
dihydroxy docosanoyl) 2,3-diacetoxy glycerol, 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy
glycerol, and 3,8-dihydroxy docosanoic acid methyl ester, to a subject in need thereof.
In one embodiment, the proliferation is of basal carcinoma cells. In another
embodiment the proliferation is of squamous carcinoma cells. In a further embodiment the
proliferation is of melanoma cells.
In one embodiment, the method is a method of modulating proliferation of one or
more neoplastic gastrointestinal cancer cells in a subject. For example, the proliferation is
of colorectal cancer cells, of throat cancer cells, of buccal cancer cells, or of gastric cancer
cells.
Accordingly the invention relates to a method of reducing proliferation of one or more
neoplastic gastrointestinal cancer cells in a subject, the method comprising administration
of an effective amount of a compound selected from the group consisting of 3,8-dihydroxy
eicosanoic acid, 1-(3,8-dihydroxy eicosanoyl) glycerol, 1-(3,8-dihydroxy eicosanoyl) 2
acetoxy glycerol, 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol, 1-(3,8-dihydroxy
eicosanoyl) 2,3-diacetoxy glycerol, 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol, 3,8
dihydroxy eicosanoic acid methyl ester, 3,8-dihydroxy heneicosanoic acid, 1-(3,8-dihydroxy
heneicosanoyl) glycerol, 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol, 1-(3,8
dihydroxy heneicosanoyl) 3-acetoxy glycerol, 1-(3,8-dihydroxy heneicosanoyl) 2,3
diacetoxy glycerol, 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol, 3,8-dihydroxy
heneicosanoic acid methyl ester, 3,8-dihydroxy docosanoic acid, 1-(3,8-dihydroxy
docosanoyl) glycerol, 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol, 1-(3,8-dihydroxy
docosanoyl) 3-acetoxy glycerol, 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol, 1
(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and 3,8-dihydroxy docosanoic acid
methyl ester, to a subject in need thereof.
Another aspect relates to a method of inducing apoptosis of one or more neoplastic
epithelial cells, or of modulating proliferation of one or more neoplastic epithelial cells, for
example of one or more neoplastic epithelial cells in vitro or ex vivo, the method comprising
contacting the one or more cells with an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt or solvate thereof, or a compound selected from any one
or more of the group consisting of
a) 3,8-dihydroxy eicosanoic acid,
b) 1-(3,8-dihydroxy eicosanoyl) glycerol,
c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol,
d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol,
e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol,
f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol,
g) 3,8-dihydroxy eicosanoic acid methyl ester
h) 3,8-dihydroxy heneicosanoic acid,
i) 1-(3,8-dihydroxy heneicosanoyl) glycerol, j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol, k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
1) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,
n) 3,8-dihydroxy heneicosanoic acid methyl ester
o) 3,8-dihydroxy docosanoic acid,
p) 1-(3,8-dihydroxy docosanoyl) glycerol,
q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol,
r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol,
s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol,
t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and
u) 3,8-dihydroxy docosanoic acid methyl ester,
or a pharmaceutically acceptable salt or solvate of any one of a) to u).
In a further aspect, the invention relates to a composition for use in the treatment or
prevention of an epithelial cancer in a subject, the composition comprising, consisting
essentially of, or consisting of, a therapeutically effective amount of a compound of formula
(I): R1 (CH (CH y R6
0 OR4 OR5
R 1 =OH, OR 7or0 OR 3
OR 2
(1)
or a pharmaceutically acceptable salt or solvate thereof, wherein R2, R3, R4 and Rs are
each independently H or acetyl (CH3CO-),
R6 is H or CH3, R7 is CH3 or C2 to C6 saturated or unsaturated hydrocarbon and
x and y are each independently an integer from 3 to 14, provided that when R6is H, x+ y is greater than 10 and less than or equal to 18, and when R6 is CH3, x+y is greater than 9 and less than or equal to 17.
In one embodiment, x = 4, R6 = H and y = 9, 10, 11, 12, or 13.
For example, x = 4, R4, Rs, and R6 = H and y = 10, 11 or 12.
Accordingly, in another aspect the invention relates to an anti-epithelial cancer
composition comprising, consisting essentially of, or consisting of at least one compound as
defined herein, including a compound of formula (I) or a pharmaceutically acceptable salt
or solvate thereof, or a compound selected from any one or more of the group consisting of
a) 3,8-dihydroxy eicosanoic acid,
b) 1-(3,8-dihydroxy eicosanoyl) glycerol,
c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol,
d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol,
e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol,
f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol,
g) 3,8-dihydroxy eicosanoic acid methyl ester
h) 3,8-dihydroxy heneicosanoic acid,
i) 1-(3,8-dihydroxy heneicosanoyl) glycerol,
j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol,
k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
I) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,
n) 3,8-dihydroxy heneicosanoic acid methyl ester
o) 3,8-dihydroxy docosanoic acid,
p) 1-(3,8-dihydroxy docosanoyl) glycerol,
q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol,
r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol,
s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol,
t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and
u) 3,8-dihydroxy docosanoic acid methyl ester,
or a pharmaceutically acceptable salt or solvate of any one of a) to u),
In another aspect, the present invention relates to a pharmaceutical composition
comprising, consisting essentially of, or consisting of at least one compound as defined
herein, including a compound of formula (I) or a pharmaceutically acceptable salt or solvate
thereof, or a compound selected from any one or more of the group consisting of
a) 3,8-dihydroxy eicosanoic acid,
b) 1-(3,8-dihydroxy eicosanoyl) glycerol,
c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol,
d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol,
e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol,
f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol,
g) 3,8-dihydroxy eicosanoic acid methyl ester
h) 3,8-dihydroxy heneicosanoic acid,
i) 1-(3,8-dihydroxy heneicosanoyl) glycerol,
j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol,
k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
1) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,
n) 3,8-dihydroxy heneicosanoic acid methyl ester
o) 3,8-dihydroxy docosanoic acid,
p) 1-(3,8-dihydroxy docosanoyl) glycerol,
q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol,
r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol,
s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol,
t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and
u) 3,8-dihydroxy docosanoic acid methyl ester,
or a pharmaceutically acceptable salt or solvate of any one of a) to u).
In one embodiment, the composition is for use in the treatment or prevention of an
epithelial cancer.
In one embodiment, the composition is for maintaining or improving skin health.
In one embodiment, the composition is for maintaining or improving gut health.
In another aspect the invention relates to a method of inhibiting epithelial tumour
formation, preferably skin tumour formation, inhibiting epithelial tumour growth, preferably
skin tumour growth, inhibiting epithelial tumour metastasis, preferably skin tumour
metastasis or treating or preventing epithelial cancer, preferably skin cancer, in a subject,
the method comprising separate, simultaneous or sequential administration of an effective
amount of a composition comprising, consisting essentially of, or consisting of a
therapeutically effective amount of at least one compound as defined herein, including a
compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a
therapeutically effective amount of at least one compound selected from any one or more of
the group consisting of
a) 3,8-dihydroxy eicosanoic acid,
b) 1-(3,8-dihydroxy eicosanoyl) glycerol,
c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol,
d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol,
e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol,
f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol,
g) 3,8-dihydroxy eicosanoic acid methyl ester
h) 3,8-dihydroxy heneicosanoic acid,
i) 1-(3,8-dihydroxy heneicosanoyl) glycerol,
j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol,
k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
1) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,
n) 3,8-dihydroxy heneicosanoic acid methyl ester
o) 3,8-dihydroxy docosanoic acid,
p) 1-(3,8-dihydroxy docosanoyl) glycerol,
q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol,
r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol,
s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol,
t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and u) 3,8-dihydroxy docosanoic acid methyl ester, or a pharmaceutically acceptable salt or solvate of any one of a) to u), to a subject in need thereof.
Another aspect relates to a method of increasing the responsiveness of a subject to an
epithelial cancer therapy comprising administration to the subject of an effective amount of
a composition comprising a therapeutically effective amount of a compound of formula (I),
or a therapeutically effective amount of at least one compound selected from any one or
more of compounds a) to u) described herein or a pharmaceutically acceptable salt or
solvate thereof or of a composition as described herein.
In one embodiment the epithelial cancer therapy is a gastrointestinal cancer therapy.
For example, the gastrointestinal cancer therapy is a colorectal cancer therapy, a throat
cancer therapy, a buccal cancer therapy, or a gastric cancer therapy.
In one embodiment, the invention relates to a method of increasing the
responsiveness of a subject to a skin cancer therapy comprising administration to the
subject of a composition as described herein.
In one embodiment the skin cancer therapy is basal cell carcinoma therapy. In
another embodiment the skin cancer therapy is squamous cell carcinoma therapy. In a
further embodiment the skin cancer therapy is melanoma therapy.
Another aspect relates to a method of increasing the sensitivity of an epithelial tumour
in a subject to an epithelial cancer therapy comprising administration to the subject of an
effective amount of a composition comprising a therapeutically effective amount of a
compound of formula (I), or a therapeutically effective amount of at least one compound
selected from any one or more of compounds a) to u) described herein or a
pharmaceutically acceptable salt or solvate thereof or of a composition as described herein.
Another aspect relates to method of resensitising one or more epithelial cancer cells
that are resistant to treatment, the method comprising administering an effective amount of
a composition comprising a therapeutically effective amount of a compound of formula (I),
or a therapeutically effective amount of at least one compound selected from any one or
more of compounds a) to u) described herein or a pharmaceutically acceptable salt or
solvate thereof.
In one embodiment the epithelial tumour is a gastrointestinal tumour. For example,
the the gastrointestinal tumour is a colorectal tumour, a throat tumour, a buccal tumour, or
a gastric tumour.
In one embodiment, the invention relates to a method of increasing the sensitivity of a
skin tumour in a subject to a cancer therapy comprising administration to the subject of a
composition as described herein.
In one embodiment the skin tumour is a basal cell carcinoma. In another embodiment
the skin tumour is a squamous cell carcinoma. In a further embodiment the skin tumour is
a melanoma.
In a further aspect, the invention relates to a method of resensitising to treatment one
or more epithelial cancer cells that are resistant to treatment, the method comprising
administering an effective amount of a compound of formula (I) or a pharmaceutically
acceptable salt or solvate thereof or of a composition as described herein to the one or
more epithelial cancer cells.
In one embodiment, the epithelial cancer cells comprise a tumour present in a subject.
In one embodiment, the invention relates to a method of resensitising one or more
epithelial cancer cells, preferably skin cancer cells that are resistant to treatment, the
method comprising administering an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt or solvate thereof or of a composition as described herein
to the one or more epithelial cancer cells, preferably skin cancer cells.
In one embodiment, the skin cancer cells comprise a tumour present in a subject.
The invention also relates to a method of at least partially reversing the resistance of
a neoplastic cell in a subject suffering from an epithelial cancer to an epithelial cancer
therapy, the method comprising administration to the subject of an effective amount of a a
composition comprising a therapeutically effective amount of a compound of formula (I) or
a pharmaceutically acceptable salt or solvate thereof, or a therapeutically effective amount
of at least one compound selected from any one or more of compounds a) to u) described
herein or a pharmaceutically acceptable salt or solvate thereof or of a composition as
described herein.
In one embodiment, the method is a method of at least partially reversing the
resistance of a neoplastic cell in a subject suffering from skin cancer to a cancer therapy,
the method comprising administration to the subject of an effective amount of a compound
of formula (I) or a pharmaceutically acceptable salt or solvate thereof or of a composition as
described herein.
The present invention further relates to a method of reversing, wholly or in part, the
resistance of an epithelial cancer-burdened, preferably a skin cancer-burdened patient to an
epithelial cancer therapy, preferably a skin cancer therapy, the method comprising the step
of administering to said patient an effective amount of a a composition comprising a a
therapeutically effective amount of a compound of formula (I) or a pharmaceutically
acceptable salt or solvate thereof, or a therapeutically effective amount of at least one
compound selected from any one or more of compounds a) to u) described herein or a
pharmaceutically acceptable salt or solvate thereof, or of a composition as described herein.
In another aspect, the invention provides a method of re-sensitising one or more
tumours of an epithelial cancer-burdened patient which are, or are predicted to either be or
become, resistant to treatment with an epithelial cancer therapy to treatment with an
epithelial cancer therapy, said method comprising the step of administering to said patient
an effective amount of a composition comprising a therapeutically effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a
therapeutically effective amount of at least one compound selected from any one or more
of compounds a) to u) described herein or a pharmaceutically acceptable salt or solvate
thereof, of a composition as described herein.
In one embodiment, the method is a method of re-sensitising one or more tumours of
a skin cancer-burdened patient which are, or are predicted to either be or become, resistant
to treatment with a skin cancer therapy to treatment with a skin cancer therapy, said
method comprising the step of administering to said patient an effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof or of a
composition as described herein.
In one embodiment, the tumours are resistant to treatment with a chemotherapeutic.
In one embodiment the subject is a human.In still a further aspect, the present
invention relates to a method of improving skin health or gut health, the method comprising
administering to a subject in need thereof an effective amount of a compound of formula (I)
or a pharmaceutically acceptable salt or solvate thereof or of a composition as described
herein.
In one embodiment, the composition is a synergistic therapeutic composition. In one
embodiment, the composition provides a synergistic therapeutic effect.
In one embodiment the composition comprises a compound described herein and at
least one additional therapeutic agent that provide a synergistic therapeutic effect that is
greater than the effect of either one alone or greater than the additive effects of either one
alone. For example, there is a greater effect on induction of apoptosis, on epithelial cancer
cell survival or proliferation such as skin cancer cell survival or proliferation, on
resensitisation to therapy, on treatment or prevention of epithelial cancer, such as skin
cancer, or the responsiveness of a subject or a tumour to the treatment method. Without
wishing to be bound by theory the inventors believe that this enhanced effect may be due
to improved bioavailability of the composition, for example through improved water
dispersibility. In one embodiment, the compound and the at least one additional therapeutic
agent allow the administration of a co-administered or sequentially administered epithelial
cancer therapy, such as a skin cancer therapy, to be reduced or increased in dose or in
length of administration, as appropriate.
In one embodiment the composition, for example a synergistic therapeutic
composition, comprises at least one additional compound or extract derived from poplar
derived propolis. For example, the composition additionally comprises at least one
compound selected from the group comprising pinocembrin, CAPE, chrysin, pinostrobin
chalcone, galangin, benzyl caffeate, benzyl ferulate or caffeic acid.
Another aspect relates to use of at least one compound as defined herein, including a
compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a
compound selected from any one or more of the group consisting of
a) 3,8-dihydroxy eicosanoic acid,
b) 1-(3,8-dihydroxy eicosanoyl) glycerol, c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol, d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol, e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol, f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol, g) 3,8-dihydroxy eicosanoic acid methyl ester h) 3,8-dihydroxy heneicosanoic acid, i) 1-(3,8-dihydroxy heneicosanoyl) glycerol, j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol, k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
I) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,
n) 3,8-dihydroxy heneicosanoic acid methyl ester
o) 3,8-dihydroxy docosanoic acid,
p) 1-(3,8-dihydroxy docosanoyl) glycerol,
q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol,
r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol,
s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol,
t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and
u) 3,8-dihydroxy docosanoic acid methyl ester,
or a pharmaceutically acceptable salt or solvate of any one of a) to u),
in the manufacture of a medicament or composition for a purpose as herein described.
In one embodiment, the use is use together with at least one additional therapeutic
agent in the manufacture of a medicament or composition for a purpose as herein
described.
Another aspect relates to use of a composition comprising at least one compound as
defined herein, including a compound of formula (I) or a pharmaceutically acceptable salt
or solvate thereof, or a compound selected from any one or more of the group consisting of
a) 3,8-dihydroxy eicosanoic acid,
b) 1-(3,8-dihydroxy eicosanoyl) glycerol,
c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol, d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol, e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol, f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol, g) 3,8-dihydroxy eicosanoic acid methyl ester h) 3,8-dihydroxy heneicosanoic acid, i) 1-(3,8-dihydroxy heneicosanoyl) glycerol, j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol, k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
1) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,
n) 3,8-dihydroxy heneicosanoic acid methyl ester
o) 3,8-dihydroxy docosanoic acid,
p) 1-(3,8-dihydroxy docosanoyl) glycerol,
q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol,
r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol,
s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol,
t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and
u) 3,8-dihydroxy docosanoic acid methyl ester,
or a pharmaceutically acceptable salt or solvate of any one of a) to u),
with at least one additional therapeutic agent in the manufacture of a medicament or
composition for a purpose as herein described, wherein the medicament or composition is
formulated to provide separate, simultaneous or sequential administration of the at least
one compound and the at least one additional therapeutic agent.
In one embodiment the medicament or composition comprises cyclodextrin. In one
embodiment, the medicament or composition comprises one or more dihydroxy fatty acid
compounds as described herein, such as a compound of formula (I), complexed with
cyclodextrin.
In another embodiment the compound is provided dissolved in a solvent or mixture of
solvents, for example ethanol, ethanol/water, propanol, propanol/water, isopropanol,
isopropanol/water, ethyl acetate, hydrocarbon solvents, edible oils or propylene glycol.
In one embodiment, the medicament or composition is one to which has been added
at least one compound selected from any one or more of the group consisting of
a) 3,8-dihydroxy eicosanoic acid,
b) 1-(3,8-dihydroxy eicosanoyl) glycerol,
c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol,
d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol,
e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol,
f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol,
g) 3,8-dihydroxy eicosanoic acid methyl ester
h) 3,8-dihydroxy heneicosanoic acid,
i) 1-(3,8-dihydroxy heneicosanoyl) glycerol,
j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol,
k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
1) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,
n) 3,8-dihydroxy heneicosanoic acid methyl ester
o) 3,8-dihydroxy docosanoic acid,
p) 1-(3,8-dihydroxy docosanoyl) glycerol,
q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol,
r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol,
s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol,
t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and
u) 3,8-dihydroxy docosanoic acid methyl ester,
or a pharmaceutically acceptable salt or solvate of any one of a) to u).
Another aspect relates to a composition for use in inhibiting epithelial tumour
formation, inhibiting epithelial tumour growth, inhibiting epithelial tumour metastasis or
treating or preventing epithelial cancer in a human subject; inducing apoptosis of one or
more neoplastic epithelial cells in a human subject; increasing the responsiveness of a
human subject to an epithelial cancer therapy; increasing the sensitivity of an epithelial
tumour in a human subject to an epithelial cancer therapy; resensitising one or more epithelial cancer cells in a human subject that are resistant to treatment; at least partially reversing the resistance of a neoplastic cell in a human subject suffering from epithelial cancer to an epithelial cancer therapy; reversing, wholly or in part, the resistance of an epithelial cancer-burdened human patient to an epithelial cancer therapy; or re-sensitising one or more tumours of an epithelial cancer-burdened human patient which are, or are predicted to either be or become, resistant to treatment with an epithelial cancer therapy to treatment with an epithelial cancer therapy.
In one embodiment the composition is for use in inhibiting skin tumour formation,
inhibiting skin tumour growth, inhibiting skin tumour metastasis or treating or preventing
skin cancer in a human subject; inducing apoptosis of one or more neoplastic skin cells in a
human subject; increasing the responsiveness of a human subject to a skin cancer therapy;
increasing the sensitivity of a skin tumour in a human subject to a skin cancer therapy;
resensitising one or more skin cancer cells in a human subject that are resistant to
treatment; at least partially reversing the resistance of a neoplastic cell in a human subject
suffering from skin cancer to a skin cancer therapy; reversing, wholly or in part, the
resistance of a skin cancer-burdened human patient to a skin cancer therapy; or re
sensitising one or more tumours of a skin cancer-burdened human patient which are, or are
predicted to either be or become, resistant to treatment with a skin cancer therapy to
treatment with a skin cancer therapy.
In one example, the invention relates to a composition for use in the treatment or
prevention of skin cancer.
In one embodiment, the composition additionally comprises cyclodextrin.
In one embodiment, the composition additionally comprises propolis, for example,
poplar-derived propolis.
In one embodiment, the composition additionally comprises an extract derived from
poplar, such as a poplar leaf or bud exudate as described herein in the Examples.
In various embodiments, the composition comprises propolis, for example a poplar
derived propolis, including a propolis extract or fraction, propolis resin, propolis resin extract
and/or an extract derived from poplar, wherein the propolis, propolis resin, propolis resin extract and/or extract from poplar is enriched in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof.
In one embodiment, the composition additionally comprises propolis, propolis resin, or
propolis resin extract and cyclodextrin.
In one embodiment, the cyclodextrin is alpha-cyclodextrin.
In one embodiment, the cyclodextrin is beta-cyclodextrin.
In one embodiment, the cyclodextrin is gamma-cyclodextrin.
In one embodiment, the cyclodextrin is hydroxypropyl beta-cyclodextrin.
In one embodiment, the cyclodextrin is hydroxypropyl gamma-cyclodextrin.
In one embodiment, the cyclodextrin is a mixture of cyclodextrins.
In one embodiment the anti-skin cancer composition is an anti-basal cell carcinoma
composition. In another embodiment the anti-skin cancer composition is an anti-squamous
cell carcinoma composition. In a further embodiment the anti-skin cancer composition is an
anti-melanoma composition.
In another aspect, the present invention relates to a pharmaceutical composition
comprising, consisting essentially of, or consisting of propolis, propolis resin, or propolis
resin extract enriched in one or more compounds of formula (I) or one or more
pharmaceutically acceptable salts or solvates thereof.
In one embodiment, the composition comprises propolis, propolis resin, or propolis
resin extract and one or more compounds of formula (I) or one or more pharmaceutically
acceptable salts or solvates thereof, for example, the composition comprises propolis,
propolis resin, or propolis resin extract to which has been added one or more compounds of
formula (I) or one or more pharmaceutically acceptable salts or solvates thereof. In another
embodiment, the composition comprises a fraction from propolis and/or poplar bud or leaf
exudate, propolis resin, or propolis resin extract enriched in one or more compounds of
formula (I) or one or more pharmaceutically acceptable salts or solvates thereof.
In one embodiment, the propolis is poplar-derived propolis.
In one embodiment, the composition additionally comprises cyclodextrin.
In one embodiment, the composition is for maintaining or improving skin health.
Accordingly, in one embodiment the invention relates to a pharmaceutical composition for
maintaining or improving skin health, the composition comprising, consisting essentially of,
or consisting of propolis, propolis resin, or propolis resin extract enriched in one or more
compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates
thereof, and cyclodextrin.
In one embodiment the propolis enriched in one or more compounds of formula (I) or
one or more pharmaceutically acceptable salts or solvates thereof is propolis resin, for
example poplar-derived propolis resin. In one embodiment the resin is propolis resin, for
example, poplar-derived propolis resin and the cyclodextrin is alpha, beta or gamma
cyclodextrin.
In another aspect the invention relates to a method of treating or preventing a skin
cancer in a subject, a method of inhibiting skin tumour formation, inhibiting skin tumour
growth, or inhibiting skin tumour metastasis, a method of inducing apoptosis of one or more
neoplastic skin cells in a subject, a method of modulating proliferation of one or more
neoplastic skin cells in a subject, a method of increasing the responsiveness of a subject to
a skin cancer therapy, a method of increasing the sensitivity of a skin tumour in a subject to
a skin cancer therapy, a method of resensitising one or more skin cancer cells that are
resistant to treatment, the method comprising administering an effective amount of a
composition comprising, consisting essentially of, or consisting of propolis, propolis resin, or
propolis resin extract enriched in one or more compounds of formula (I) or one or more
pharmaceutically acceptable salts or solvates thereof, and cyclodextrin, to a subject in need
thereof or to the one or more cells.
In one embodiment the apoptosis is of skin tumour cells, such as basal carcinoma,
squamous carcinoma, or melanoma cells.
In one embodiment the modulation is reduction. Accordingly the invention relates to a
method of reducing proliferation of one or more neoplastic skin cells in a subject, the
method comprising administration of an effective amount of a composition comprising,
consisting essentially of, or consisting of propolis, propolis resin, or propolis resin extract
enriched in one or more compounds of formula (I) or one or more pharmaceutically
acceptable salts or solvates thereof, and cyclodextrin, to a subject in need thereof.
In one embodiment the proliferation is of skin tumour cells, such as basal carcinoma,
squamous carcinoma, or melanoma cells.
In one embodiment, the skin cancer cells comprise a tumour present in a subject. In
one embodiment the skin cancer cells are basal carcinoma cells. In another embodiment
the skin cancer cells are squamous carcinoma cells. In a further embodiment the skin
cancer cells are melanoma cells.
The invention also relates to a method of at least partially reversing the resistance of
a neoplastic cell in a subject suffering from a skin cancer to a skin cancer therapy, the
method comprising administration to the subject of a composition comprising, consisting
essentially or, or consisting of propolis, propolis resin, or propolis resin extract enriched in
one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or
solvates thereof, and cyclodextrin.
The present invention further relates to a method of reversing, wholly or in part, the
resistance of a skin cancer-burdened patient to a skin cancer therapy, the method
comprising the step of administering to said patient a composition comprising, consisting
essentially of, or consisting of propolis, propolis resin, or propolis resin extract enriched in
one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or
solvates thereof, and cyclodextrin.
In another aspect, the invention provides a method of re-sensitising one or more
tumours of a skin cancer-burdened patient which are, or are predicted to either be or
become, resistant to treatment with a skin cancer therapy, said method comprising the step
of administering to said patient a composition comprising, consisting essentially or, or
consisting of propolis, propolis resin, or propolis resin extract enriched in one or more
compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates
thereof, and cyclodextrin.
In one embodiment, the one or more tumours are or are predicted to be or to become
resistant to a skin cancer therapy due to increased activation of one or more pro-cancer cell
survival signaling pathways within the one or more tumours or within the patient, including
increased activation of one or more of the AKT,JNK or JAK/STAT signaling pathways, for
example within a sample from the patient, such as a tissue sample, a tumour biopsy, or a
blood or plasma sample.
In one embodiment, the invention provides a method of inactivating or suppressing
one or more pro-cancer cell survival signaling pathways within the one or more tumours or
within the patient. For example, the invention relates to a method of inactivating or
suppressing one or more of the AKT, JNK or JAK/STAT signaling pathways within the one or
more tumours.
In one embodiment, the one or more tumours are or are predicted to be or to become
resistant to a skin cancer therapy due to increased activation of one or more of the AKT,
JNK or JAK/STAT signaling pathways within the tumour(s).
In one embodiment, the invention provides a method of preventing tumours becoming
resistant to a primary skin cancer therapy, wherein the resistance is at least in part
mediated by increased activation of one or more of the AKT, JNK or JAK/STAT signaling
pathways, for example within the tumour(s).
In one embodiment, the tumours are resistant to treatment with a chemotherapeutic.
In one embodiment the skin cancer is basal cell carcinoma. In another embodiment
the skin cancer is squamous cell carcinoma. In a further embodiment the skin cancer is
melanoma.
In one embodiment, the composition comprises, consists essentially of, or consists of
propolis, propolis resin, or propolis resin extract enriched in one or more compounds of
formula (I) or one or more pharmaceutically acceptable salts or solvates thereof, and alpha
cyclodextrin, for example poplar-derived propolis, propolis resin, or propolis resin extract
and cyclodextrin, such as poplar-derived propolis and alpha-cyclodextrin.
In one embodiment, the composition comprises, consists essentially of, or consists of
propolis, propolis resin, or propolis resin extract enriched in one or more compounds of
formula (I) or one or more pharmaceutically acceptable salts or solvates thereof, and beta
cyclodextrin, for example poplar-derived propolis, propolis resin, or propolis resin extract
and cyclodextrin, such as poplar-derived propolis, propolis resin, or propolis resin extract
and beta-cyclodextrin.
In one embodiment, the composition comprises, consists essentially of, or consists of
propolis, propolis resin, or propolis resin extract enriched in one or more compounds of
formula (I) or one or more pharmaceutically acceptable salts or solvates thereof, and
gamma-cyclodextrin, for example poplar-derived propolis, propolis resin, or propolis resin
extract and cyclodextrin, such as poplar-derived propolis, propolis resin, or propolis resin
extract and gamma-cyclodextrin.
In a further aspect, the invention provides a synergistic composition comprising
propolis, propolis resin, or propolis resin extract enriched in one or more compounds of
formula (I) or one or more pharmaceutically acceptable salts or solvates thereof, and
cyclodextrin. In one embodiment, the composition is a synergistic therapeutic composition.
In one embodiment, the composition provides a synergistic therapeutic effect.
In one embodiment the propolis, propolis resin, or propolis resin extract enriched in
one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or
solvates thereof and cyclodextrin provide a synergistic therapeutic effect that is greater
than the effect of either one alone or greater than the additive effects of either one alone.
For example, there is a greater effect on induction of apoptosis, on skin cancer cell survival
or proliferation, on resensitisation to therapy, on treatment or prevention of skin cancer, or
the responsiveness of a subject or a tumour to the treatment method. In one embodiment,
the propolis, propolis resin, or propolis resin extract enriched in one or more compounds of
formula (I) or one or more pharmaceutically acceptable salts or solvates thereof and
cyclodextrin allow the administration of a co-administered or sequentially administered skin
cancer therapy to be reduced or increased in dose or in length of administration, as
appropriate.
Another aspect relates to use of propolis, propolis resin, or propolis resin extract
enriched in one or more compounds of formula (I) or one or more pharmaceutically
acceptable salts or solvates thereof and cyclodextrin in the manufacture of a composition for
a purpose as herein described.
Another aspect relates to use of propolis, propolis resin, or propolis resin extract
enriched in one or more compounds of formula (I) or one or more pharmaceutically
acceptable salts or solvates thereof and cyclodextrin with at least one additional therapeutic
agent in the manufacture of a composition for a purpose as herein described. In one
embodiment, the use is of enriched propolis, propolis resin, or propolis resin extract and
alpha-cyclodextrin. In one embodiment, the use is of enriched propolis, propolis resin, or
propolis resin extract and beta-cyclodextrin. In one embodiment, the use is of enriched
propolis and gamma-cyclodextrin.
Another aspect of the invention relates to use of a complex comprising propolis,
propolis resin, or propolis resin extract enriched in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof and cyclodextrin, with at least one additional therapeutic agent in the manufacture of a composition for a purpose as herein described, wherein the composition is formulated to provide separate, simultaneous or sequential administration of the propolis, propolis resin, or propolis resin extract and cyclodextrin complex and the at least one additional therapeutic agent.
Another aspect relates to a composition comprising, consisting essentially of or
consisting of propolis, propolis resin, or propolis resin extract enriched in one or more
compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates
thereof and cyclodextrin for use in improving skin health. In one embodiment, the
composition comprises, consists essentially of, or consists of propolis, propolis resin, or
propolis resin extract enriched in one or more compounds of formula (I) or one or more
pharmaceutically acceptable salts or solvates thereof and alpha-cyclodextrin. In one
embodiment, the composition comprises, consists essentially of, or consists of propolis,
propolis resin, or propolis resin extract enriched in one or more compounds of formula (I) or
one or more pharmaceutically acceptable salts or solvates thereof and gamma-cyclodextrin.
In another aspect, the invention relates to a composition comprising, consisting
essentially of or consisting of propolis, propolis resin, or propolis resin extract enriched in
one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or
solvates thereof and cyclodextrin for use in treating or preventing a skin cancer in a subject.
In one embodiment, the composition comprises, consists essentially of, or consists of
propolis, propolis resin, or propolis resin extract enriched in one or more compounds of
formula (I) or one or more pharmaceutically acceptable salts or solvates thereof and alpha
cyclodextrin. In one embodiment, the composition comprises, consists essentially of, or
consists of propolis, propolis resin, or propolis resin extract enriched in one or more
compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates
thereof and gamma-cyclodextrin.
Another aspect relates to a product comprising, consisting essentially of or consisting
of propolis, propolis resin, or propolis resin extract enriched in one or more compounds of
formula (I) or one or more pharmaceutically acceptable salts or solvates thereof and
cyclodextrin, optionally with one or more, two or more or three or more additional
therapeutic agents as a combined preparation for simultaneous, separate or sequential use
for a purpose as described herein.
Another aspect relates to a composition for use in the treatment or prevention of a
skin cancer.
One aspect relates to a method of isolating or purifying a compound or mixture of
compounds of formula (I) from propolis or poplar, propolis resin or an extract or exudate
thereof comprising the steps of
providing poplar, propolis, propolis resin or an extract or exudate thereof, and
isolating or purifying the compound or mixture of compounds from the poplar,
propolis, propolis resin or an extract or exudate thereof.
In various embodiments the method comprises one or more of the following non
limiting steps:
a) fractionating the poplar, propolis, propolis resin or extract or exudate thereof by
chromatography, for example, column chromatography, reverse phase chromatography,
normal phase chromatography, or supercritical fluid chromatography, and/or solvent
partitioning and/or supercritical extraction to produce one or more fractions comprising one
or more of the compounds of formula (I),
b) fractionating the poplar, propolis, propolis resin or extract or exudate thereof or
one or more fractions, by preparative HPLC and/or polymeric resin fractionation to produce
one or more fractions comprising one or more of the compounds of formula (I), and,
optionally, c) further purifying the compound or compounds of formula (I) from the one or more fractions of step b) and/or step c).
In a further embodiment, the poplar, propolis, propolis resin or extract or exudate
could be subjected to a hydrolysis, methylation or acetylation reaction, and then one or
more of steps a), b) or c) performed to isolate and purify one or more compounds of
formula (I).
A further aspect relates to a marker of anti-epithelial cancer efficacy comprising a
compound of formula (I).
Another aspect relates to a method of evaluating the anti-epithelial cancer efficacy of
a composition or product comprising
a) providing a sample of the composition or product, and
b) either
i) determining the presence of one or more compounds of formula (I) in the
sample, or
ii) measuring the amount and/or concentration of one or more compounds of
formula (I) in the sample and determining whether the amount and/or concentration of one
or more of the one or more compounds in the sample is equal to, or greater than, a
reference amount of that compound known to provide anti-epithelial cancer efficacy, and
optionally,
iii) determining the biological activity of compound(s) and/or fractions containing
the compounds using an in-vitro or in-vivo bioassay.
A further aspect relates to a method of evaluating the anti-epithelial cancer efficacy of
a composition or product comprising
a) receiving information about the presence and/or amount of one or more
compounds of formula (I) in a sample of the composition or product, and b) determining whether the amount of each compound in the sample is equal to, or greater than, a reference amount of that compound known to provide anti-epithelial cancer efficacy.
A further aspect relates to a method of evaluating the anti-epithelial cancer efficacy of
a composition or product comprising
a) confirming the presence and/or amount of one or more compounds of formula (I)
in a sample of the composition or product using gas, liquid or supercritical fluid
chromatography, and
b) determining whether the amount of each compound in the sample is equal to, or
greater than, a reference amount of that compound known to provide anti-epithelial cancer
efficacy.
In various embodiments the method of evaluating the anti-epithelial cancer efficacy of
a composition or product comprises any one or more of the following steps:
a) fractionating the sample by solvent partitioning and/or supercritical extraction
and/or chromatography, for example, reverse phase chromatography to produce one or
more fractions enriched in one or more of the compounds of formula (I),
b) further fractionating the one or more fractions enriched in one or more of the
compounds of formula (I) by one or more of solvent or supercritical extraction or
chromatography to produce one or more fractions highly enriched in one or more of the
compounds of formula (I),
c) analysing the highly enriched fraction(s), for example by one or more of gas, liquid
or supercritical chromatography, to determine the presence and/or amount of one or more
of the compound(s) of formula (I) in the sample.
In various embodiments the method of evaluating the anti-epithelial cancer efficacy of a
composition or product comprises any one or more of the following steps: a. fractionating the sample by chromatography, for example, reverse phase chromatography to produce one or more chromatography fractions, b. fractionating the sample or chromatography fraction by preparative HPLC to produce one or more HPLC fractions, c. analysing the trace produced by preparative HPLC to determine the presence and/or amount of the compound in the sample, and/or d. subjecting the sample, one or more reverse chromatography fractions or one or more HPLC fractions to mass spectrometry to determine the presence and/or amount of the one or more compounds of formula (I) in the sample.
In one embodiment, the determination of the presence and/or amount of one or
more of the compound(s) of formula (I) in the sample is by mass spectrometry, for
example, liquid chromatography mass spectrometry (LC-MS).
In one aspect the invention relates to a composition or product comprising one or
more compounds of formula (I) wherein the amount and/or concentration of one or more
compounds of formula (I) is specified on an indicator, such as but not limited to a product
label, certificate of analysis, website, promotional material associated with the composition
or product.
In various embodiments the compound of formula (I) is selected from the group
consisting of
a) 3,8-dihydroxy eicosanoic acid,
b) 1-(3,8-dihydroxy eicosanoyl) glycerol,
c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol,
d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol,
e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol,
f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol,
g) 3,8-dihydroxy eicosanoic acid methyl ester
h) 3,8-dihydroxy heneicosanoic acid,
i) 1-(3,8-dihydroxy heneicosanoyl) glycerol, j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol, k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
1) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,
n) 3,8-dihydroxy heneicosanoic acid methyl ester
o) 3,8-dihydroxy docosanoic acid,
p) 1-(3,8-dihydroxy docosanoyl) glycerol,
q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol,
r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol,
s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol,
t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and
u) 3,8-dihydroxy docosanoic acid methyl ester.
In one embodiment the composition or product is, or comprises, propolis, propolis
resin, or propolis resin extract, for example, propolis, propolis resin, or propolis resin
extract comprising or enriched in one or more compounds of formula (I).
In one embodiment, the indicator associated with the composition or product is a label
or packaging insert.
In one embodiment, the indicator associated with the composition or product is a
Certificate Of Analysis (COA).
In one embodiment, the indicator associated with the composition or product is a
website promoting the product.
In one embodiment, the indicator associated with the composition or product is a
brochure or pamphlet promoting the product.
The following embodiments may relate to any of the above aspects.
In various embodiments, the epithelial cancer is an epidermal cancer or an epidermoid
cancer.
In various embodiments, the epithelial cancer is a gastrointestinal cancer, such as a
colorectal cancer, throat cancer, oesophageal cancer, buccal cancer, or gastric cancer. For
example, in one embodiment the colorectal cancer is a colon adenocarcinoma. In another
embodiment, the oesophageal cancer is an oesophageal squamous carcinoma. In another
embodiment, the gastric cancer is a gastric carcinoma.
In other embodiments, the epithelial cancer is a skin cancer, such as a basal cell
carcinoma, a squamous cell carcinoma, or a melanoma.
In various embodiments, the composition additionally comprises one or more of caffeic
acid phenylether ester (CAPE), caffeic acid, pinocembrin, benzyl caffeate, benzyl ferulate,
benzyl isoferulate, chrysin, cinnamyl caffeate, pinostrobin chalcone, galangin, and
pinobanksin.
In exemplary embodiments, the composition is one to which has been added one or
more of CAPE, caffeic acid, pinocembrin, benzyl caffeate, benzyl ferulate, benzyl isoferulate,
cinnamyl caffeate, pinostrobin chalcone, chrysin, galangin, and pinobanksin-3-acetate.
In one embodiment, the composition has a CAPE concentration of greater than about
1,2,3,5,10,15,20,25,30,35,40,45,50,60,70,75,80,90,100,125,150,175,200,
250, 300, 350, 400, 450, 500, or 600 mg/g and useful ranges may be selected between any
of these values (for example, about 1 to about 5, about 1 to about 10, about 2 to about 20,
about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to about 40,
about 15 to about 100, or about 20 to about 600 mg/g).
In one embodiment, the composition has a pinocembrin concentration of greater than
about 1,2,3,5,10,15,20,25,30,35,40,45,50,60,70,75,80,90,100,125,150,175,
200, 250, 300, 350, 400, 450, 500, or 600 mg/g and useful ranges may be selected
between any of these values (for example, about 1 to about 5, about 1 to about 10, about 2
to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to
about 40, about 15 to about 100, or about 20 to about 600 mg/g).
In one embodiment, the composition has a galangin concentration of greater than
about 1,2,3,5,10,15,20,25,30,35,40,45,50,60,70,75,80,90,100,125,150,175,
200, 250, 300, 350, 400, 450, 500, or 600 mg/g and useful ranges may be selected
between any of these values (for example, about 1 to about 5, about 1 to about 10, about 2
to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to
about 40, about 15 to about 100, or about 20 to about 600 mg/g).
In one embodiment, the composition has a chrysin concentration of greater than
about 1,2,3,5,10,15,20,25,30,35,40,45,50,60,70,75,80,90,100,125,150,175,
200, 250, 300, 350, 400, 450, 500, or 600 mg/g and useful ranges may be selected
between any of these values (for example, about 1 to about 5, about 1 to about 10, about 2
to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to
about 40, about 15 to about 100, or about 20 to about 600 mg/g).
In one embodiment, the composition has a pinobanksin concentration of greater than
about 1,2,3,5,10,15,20,25,30,35,40,45,50,60,70,75,80,90,100,125,150,175,
200, 250, 300, 350, 400, 450, 500, or 600 mg/g and useful ranges may be selected
between any of these values (for example, about 1 to about 5, about 1 to about 10, about 2
to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to
about 40, about 15 to about 100, or about 20 to about 600 mg/g).
In one embodiment, the composition has a caffeic acid concentration of greater than
about 1,2,3,5,10,15,20,25,30,35,40,45,50,60,70,75,80,90,100,125,150,175,
200, 250, 300, 350, 400, 450, 500, or 600 mg/g and useful ranges may be selected
between any of these values (for example, about 1 to about 5, about 1 to about 10, about 2
to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to
about 40, about 15 to about 100, or about 20 to about 600 mg/g).
In one embodiment, the composition has a benzyl caffeate concentration of greater
than about 1,2,3,5,10,15,20,25,30,35,40,45,50,60,70,75,80,90,100,125,150,
175, 200, 250, 300, 350, 400, 450, 500, or 600 mg/g and useful ranges may be selected
between any of these values (for example, about 1 to about 5, about 1 to about 10, about 2
to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to
about 40, about 15 to about 100, or about 20 to about 600 mg/g).
In one embodiment, the composition has a benzyl ferulate concentration of greater
than about 1,2,3,5,10,15,20,25,30,35,40,45,50,60,70,75,80,90,100,125,150,
175, 200, 250, 300, 350, 400, 450, 500, or 600 mg/g and useful ranges may be selected
between any of these values (for example, about 1 to about 5, about 1 to about 10, about 2
to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to
about 40, about 15 to about 100, or about 20 to about 600 mg/g).
In one embodiment, the composition has a cinnamyl caffeate concentration of greater
than about 1,2,3,5,10,15,20,25,30,35,40,45,50,60,70,75,80,90,100,125,150,
175, 200, 250, 300, 350, 400, 450, 500, or 600 mg/g and useful ranges may be selected
between any of these values (for example, about 1 to about 5, about 1 to about 10, about 2
to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to
about 40, about 15 to about 100, or about 20 to about 600 mg/g).
In one embodiment, the composition has a cinnamyl ferulate concentration of greater
than about 1,2,3,5,10,15,20,25,30,35,40,45,50,60,70,75,80,90,100,125,150,
175, 200, 250, 300, 350, 400, 450, 500, or 600 mg/g and useful ranges may be selected
between any of these values (for example, about 1 to about 5, about 1 to about 10, about 2
to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to
about 40, about 15 to about 100, or about 20 to about 600 mg/g).
In various embodiments, the cyclodextrin is alpha-cyclodextrin, or the cyclodextrin is
present as a combination of cyclodextrins comprising alpha-cyclodextrin.
In various embodiments, the cyclodextrin is beta-cyclodextrin, or the cyclodextrin is
present as a combination of cyclodextrins comprising beta-cyclodextrin.
In various embodiments, the cyclodextrin is gamma-cyclodextrin, or the cyclodextrin
is present as a combination of cyclodextrins comprising gamma-cyclodextrin.
In one embodiment, the cyclodextrin is chemically-modified cyclodextrin, examples of
which are described in Stella and He, Cyclodextrins, Toxicologic Pathology, 36, 2008, 30-42.
In one embodiment, the chemically-modified cyclodextrin is hydroxy propyl beta
cyclodextrin or hydroxy propyl gamma cyclodextrin
In one embodiment, the propolis is present in the anti-epithelial cancer composition as
a propolis extract or fraction.
In one embodiment, the propolis present in the anti-epithelial cancer composition is
free of wax. For example, the propolis has been dewaxed using extraction processes known
in the art. Dewaxed propolis is often known or referred to as 'propolis resin'.
In one embodiment, the propolis is "poplar-derived" or "Poplar" propolis. For
example, the "poplar-derived" propolis is at least in part derived from the bud and leaf
exudates of one or more species of poplars, birches, larches or willows.
In one embodiment, the composition comprises from about 1.0%wt to about 99 %wt
propolis, propolis resin, or propolis resin extract enriched in one or more compounds of
formula (I). In one embodiment the composition comprises from about 1.0%wt to about
99 %wt propolis resin enriched in one or more compounds of formula (I).
In various embodiments, the composition comprises from about 1%wt to about
99 %wt propolis, propolis resin, or propolis resin extract enriched in one or more
compounds of formula (I), from about 1%wt to about 25%wt propolis, propolis resin, or
propolis resin extract enriched in one or more compounds of formula (I), from about 1%wt
to about 30%wt propolis, propolis resin, or propolis resin extract enriched in one or more
compounds of formula (I), from about 1%wt to about 40%wt propolis, propolis resin, or
propolis resin extract enriched in one or more compounds of formula (I), from about 1%wt
to about 50%wt propolis, propolis resin, or propolis resin extract enriched in one or more compounds of formula (I), from about 5%wt to about 25%wt propolis, propolis resin, or propolis resin extract enriched in one or more compounds of formula (I), from about 5%wt to about 30%wt propolis, propolis resin, or propolis resin extract enriched in one or more compounds of formula (I), from about 5%wt to about 40%wt propolis, propolis resin, or propolis resin extract enriched in one or more compounds of formula (I), from about 5%wt to about 50%wt propolis, propolis resin, or propolis resin extract enriched in one or more compounds of formula (I), from about 5%wt to about 99%wt propolis, propolis resin, or propolis resin extract enriched in one or more compounds of formula (I), from about 10%wt to about 25%wt propolis, propolis resin, or propolis resin extract enriched in one or more compounds of formula (I), from about 10%wt to about 30%wt propolis , propolis resin, or propolis resin extract enriched in one or more compounds of formula (I), from about 10%wt to about 40%wt propolis, propolis resin, or propolis resin extract enriched in one or more compounds of formula (I), from about 10%wt to about 50%wt propolis, propolis resin, or propolis resin extract enriched in one or more compounds of formula (I), from about 10%wt to about 99%wt propolis, propolis resin, or propolis resin extract enriched in one or more compounds of formula (I), from about 15%wt to about 25%wt propolis, propolis resin, or propolis resin extract enriched in one or more compounds of formula (I), from about 15%wt to about 30%wt propolis, propolis resin, or propolis resin extract enriched in one or more compounds of formula (I), from about 15%wt to about 40%wt propolis enriched in one or more compounds of formula (I), from about 15%wt to about 50%wt propolis, propolis resin, or propolis resin extract enriched in one or more compounds of formula (I), from about
15%wt to about 99%wt propolis, propolis resin, or propolis resin extract enriched in one or
more compounds of formula (I), from about 20%wt to about 25%wt propolis, propolis resin,
or propolis resin extract enriched in one or more compounds of formula (I), from about
20%wt to about 30%wt propolis, propolis resin, or propolis resin extract enriched in one or
more compounds of formula (I), from about 20%wt to about 40%wt propolis, propolis resin, or propolis resin extract enriched in one or more compounds of formula (I), from about
20%wt to about 50%wt propolis, propolis resin, or propolis resin extract enriched in one or
more compounds of formula (I), from about 20%wt to about 99%wt propolis, propolis resin,
or propolis resin extract enriched in one or more compounds of formula (I), or about 25%wt
propolis, propolis resin, or propolis resin extract enriched in one or more compounds of
formula (I), or about 30%wt propolis, propolis resin, or propolis resin extract enriched in
one or more compounds of formula (I).
In various embodiments, the composition comprises from about 1%wt to about
99 %wt propolis resin enriched in one or more compounds of formula (I), from about 1%wt
to about 25%wt propolis resin enriched in one or more compounds of formula (I), from
about 1%wt to about 30%wt propolis resin enriched in one or more compounds of formula
(I), from about 1%wt to about 40%wt propolis resin enriched in one or more compounds of
formula (I), from about 1%wt to about 50%wt propolis resin enriched in one or more
compounds of formula (I), from about 5%wt to about 25%wt propolis resin enriched in one
or more compounds of formula (I), from about 5%wt to about 30%wt propolis resin
enriched in one or more compounds of formula (I), from about 5%wt to about 40%wt
propolis resin enriched in one or more compounds of formula (I), from about 5%wt to about
50%wt propolis resin enriched in one or more compounds of formula (I), from about 5%wt
to about 99%wt propolis resin enriched in one or more compounds of formula (I), from
about 10%wt to about 25%wt propolis resin enriched in one or more compounds of formula
(I), from about 10%wt to about 30%wt propolis resin enriched in one or more compounds
of formula (I), from about 10%wt to about 40%wt propolis resin enriched in one or more
compounds of formula (I), from about 10%wt to about 50%wt propolis resin enriched in
one or more compounds of formula (I), from about 10%wt to about 99%wt propolis resin
enriched in one or more compounds of formula (I), from about 15%wt to about 25%wt
propolis resin enriched in one or more compounds of formula (I), from about 15%wt to about 30%wt propolis resin enriched in one or more compounds of formula (I), from about
15%wt to about 40%wt propolis resin enriched in one or more compounds of formula (I),
from about 15%wt to about 50%wt propolis resin enriched in one or more compounds of
formula (I), from about 15%wt to about 99%wt propolis resin enriched in one or more
compounds of formula (I), from about 20%wt to about 25%wt propolis resin enriched in
one or more compounds of formula (I), from about 20%wt to about 30%wt propolis resin
enriched in one or more compounds of formula (I), from about 20%wt to about 40%wt
propolis resin enriched in one or more compounds of formula (I), from about 20%wt to
about 50%wt propolis resin enriched in one or more compounds of formula (I), from about
20%wt to about 99%wt propolis resin enriched in one or more compounds of formula (I), or
about 25%wt propolis resin enriched in one or more compounds of formula (I), or about
30%wt propolis resin propolis resin enriched in one or more compounds of formula (I).
In one embodiment the propolis, propolis resin, or propolis resin extract in the
composition is entirely encapsulated within the cyclodextrin.
In one embodiment the molar ratio of propolis, propolis resin, or propolis resin extract
to cyclodextrin in the composition is no greater than about 1:1.
In one embodiment, the propolis, propolis resin, or propolis resin extract is poplar
derived propolis, propolis resin, or propolis resin extract.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract comprises and/or is enriched in 3,8-dihydroxy eicosanoic acid. In one embodiment,
the poplar-derived propolis, propolis resin, or propolis resin extract comprises and/or is
enriched in 1-(3,8-dihydroxy eicosanoyl) glycerol. In one embodiment, the poplar-derived
propolis, propolis resin, or propolis resin extract comprises and/or is enriched in 1-(3,8
dihydroxy eicosanoyl) 2-acetoxy glycerol. In one embodiment, the poplar-derived propolis,
propolis resin, or propolis resin extract comprises and/or is enriched in 1-(3,8-dihydroxy
eicosanoyl) 3-acetoxy glycerol. In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin extract comprises and/or is enriched in 1-(3,8-dihydroxy eicosanoyl)
2,3-diacetoxy glycerol. In one embodiment, the poplar-derived propolis, propolis resin, or
propolis resin extract comprises and/or is enriched in 1-(3,8-diacetoxy eicosanoyl) 2,3
diacetoxy glycerol. In one embodiment, the poplar-derived propolis, propolis resin, or
propolis resin extract comprises and/or is enriched in 3,8-dihydroxy eicosanoic acid methyl
ester. In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract comprises and/or is enriched in 3,8-dihydroxy heneicosanoic acid. In one
embodiment, the poplar-derived propolis, propolis resin, or propolis resin extract comprises
and/or is enriched in 1-(3,8-dihydroxy heneicosanoyl) glycerol. In one embodiment, the
poplar-derived propolis, propolis resin, or propolis resin extract comprises and/or is enriched
in 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol. In one embodiment, the poplar
derived propolis, propolis resin, or propolis resin extract comprises and/or is enriched in 1
(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol. In one embodiment, the poplar-derived
propolis, propolis resin, or propolis resin extract comprises and/or is enriched in 1-(3,8
dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol. In one embodiment, the poplar-derived
propolis, propolis resin, or propolis resin extract comprises and/or is enriched in 1-(3,8
diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol. In one embodiment, the poplar-derived
propolis, propolis resin, or propolis resin extract comprises and/or is enriched in 3,8
dihydroxy heneicosanoic acid methyl ester. In one embodiment, the poplar-derived propolis,
propolis resin, or propolis resin extract comprises and/or is enriched in 3,8-dihydroxy
docosanoic acid. In one embodiment, the poplar-derived propolis, propolis resin, or propolis
resin extract comprises and/or is enriched in 1-(3,8-dihydroxy docosanoyl) glycerol. In one
embodiment, the poplar-derived propolis, propolis resin, or propolis resin extract comprises
and/or is enriched in 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol. In one embodiment,
the poplar-derived propolis, propolis resin, or propolis resin extract comprises and/or is
enriched in 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol. In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin extract comprises and/or is enriched in 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol. In one embodiment, the poplar derived propolis, propolis resin, or propolis resin extract comprises and/or is enriched in 1
(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol. In one embodiment, the poplar-derived
propolis, propolis resin, or propolis resin extract comprises and/or is enriched in and 3,8
dihydroxy docosanoic acid methyl ester.
In one embodiment, the poplar-derived propolis has any one or more of compounds
a) to u) described herein at a concentration of greater than about 1mg/kg, about 1.5mg/kg,
about 2mg/kg, about 2.5mg/kg, about 3mg/kg, about 3.5mg/kg, about 4mg/kg, about
4.5mg/kg, about 5mg/kg, about 5.5mg/kg, about 6mg/kg, about 7.5mg/kg, about
10mg/kg, about 15mg/kg, about 20mg/kgabout 25mg/kg, about 30mg/kg, about 40mg/kg,
about 50mg/kg, about 75mg/kg, about 100mg/kg, about 125mg/kg, about 150mg/kg,
about 175mg/kg, about 200mg/kg, 250mg/kg, about 300mg/kg, about 350mg/kg, about
400mg/kg, about 450mg/kg, about 500 mg/kg, about 550mg/kg, or about 600mg/kg.
In some embodiments the poplar-derived propolis, propolis resin, or propolis resin
extract has fromat least about 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4,4.5, 5, 5.5, 6, 7.5, 10, 15,
20,25,30,40,50,75,100,125,150,175,200,250,300,350,400,450,500,550,600,
650, 700, 750, 800, 850, 900, 950, or 1000mg/g of any two or more, three or more, or
four or more, of compounds a) to u) described herein, and useful ranges may be selected
from any of these values (for example from about 1 to about 400, about 1 to about 100,
about 5 to about 1000, about 5 to about 500, about 5 to about 300, or about 5 to about
100). For example, in some embodiments the poplar-derived propolis has 1-(3,8-dihydroxy
eicosanoyl) 3-acetoxy glycerol and 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol, or 1
(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol, 1-(3,8-dihydroxy docosanoyl) 3-acetoxy
glycerol and 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol, or 1-(3,8-dihydroxy
eicosanoyl) 3-acetoxy glycerol, 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol and 1-
(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol and any one or more of compounds a) to
c), e) to j), or 1) to u) at a concentration of about 1mg/g to 1000mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 3,8-dihydroxy eicosanoic acid concentration of at least about O.1mg/g, about
0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about 2.5mg/g, about 3mg/g, about
3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about 5.5mg/g, about 6mg/g, about
7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout 25mg/g, about 30mg/g, about
40mg/g, about 50mg/g, about 75mg/g, about 100mg/g, about 125mg/g, about 150mg/g,
about 175mg/g, about 200mg/g, 250mg/g, about 300mg/g, about 350mg/g, about
400mg/g, about 450mg/g, about 500 mg/g, about 550mg/g, or about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 1-(3,8-dihydroxy eicosanoyl) glycerol concentration of at least about 0.1mg/g,
about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about 2.5mg/g, about 3mg/g,
about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about 5.5mg/g, about 6mg/g,
about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout 25mg/g, about 30mg/g,
about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g, about 125mg/g, about
150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about 300mg/g, about 350mg/g,
about 400mg/g, about 450mg/g, about 500 mg/g, about 550mg/g, or about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol concentration of at least
about 0.1mg/g, about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about
2.5mg/g, about 3mg/g, about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about
5.5mg/g, about 6mg/g, about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout
25mg/g, about 30mg/g, about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g,
about 125mg/g, about 150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about
300mg/g, about 350mg/g, about 400mg/g, about 450mg/g, about 500 mg/g, about
550mg/g, or about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol concentration of at least
about 0.1mg/g, about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about
2.5mg/g, about 3mg/g, about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about
5.5mg/g, about 6mg/g, about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout
25mg/g, about 30mg/g, about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g,
about 125mg/g, about 150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about
300mg/g, about 350mg/g, about 400mg/g, about 450mg/g, about 500 mg/g, about
550mg/g, or about 600mg/g.
In one embodiment, the poplar-derived propolis propolis resin, or propolis resin
extract has a 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol concentration of at least
about 0.1mg/g, about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about
2.5mg/g, about 3mg/g, about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about
5.5mg/g, about 6mg/g, about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout
25mg/g, about 30mg/g, about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g,
about 125mg/g, about 150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about
300mg/g, about 350mg/g, about 400mg/g, about 450mg/g, about 500 mg/g, about
550mg/g, or about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol concentration of at least
about 0.1mg/g, about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about
2.5mg/g, about 3mg/g, about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about
5.5mg/g, about 6mg/g, about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout
25mg/g, about 30mg/g, about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g, about 125mg/g, about 150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about
300mg/g, about 350mg/g, about 400mg/g, about 450mg/g, about 500 mg/g, about
550mg/g, or about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 3,8-dihydroxy eicosanoic acid methyl ester concentration of at least about
0.1mg/g, about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about 2.5mg/g,
about 3mg/g, about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about 5.5mg/g,
about 6mg/g, about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout 25mg/g,
about 30mg/g, about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g, about
125mg/g, about 150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about 300mg/g,
about 350mg/g, about 400mg/g, about 450mg/g, about 500 mg/g, about 550mg/g, or
about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 3,8-dihydroxy heneicosanoic acid concentration of at least about 0.1mg/g,
about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about 2.5mg/g, about 3mg/g,
about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about 5.5mg/g, about 6mg/g,
about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout 25mg/g, about 30mg/g,
about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g, about 125mg/g, about
150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about 300mg/g, about 350mg/g,
about 400mg/g, about 450mg/g, about 500 mg/g, about 550mg/g, or about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 1-(3,8-dihydroxy heneicosanoyl) glycerol concentration of at least about
0.1mg/g, about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about 2.5mg/g,
about 3mg/g, about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about 5.5mg/g,
about 6mg/g, about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout 25mg/g,
about 30mg/g, about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g, about
125mg/g, about 150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about 300mg/g,
about 350mg/g, about 400mg/g, about 450mg/g, about 500 mg/g, about 550mg/g, or
about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol concentration of at least
about 0.1mg/g, about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about
2.5mg/g, about 3mg/g, about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about
5.5mg/g, about 6mg/g, about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout
25mg/g, about 30mg/g, about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g,
about 125mg/g, about 150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about
300mg/g, about 350mg/g, about 400mg/g, about 450mg/g, about 500 mg/g, about
550mg/g, or about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol concentration of at least
about 0.1mg/g, about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about
2.5mg/g, about 3mg/g, about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about
5.5mg/g, about 6mg/g, about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout
25mg/g, about 30mg/g, about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g,
about 125mg/g, about 150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about
300mg/g, about 350mg/g, about 400mg/g, about 450mg/g, about 500 mg/g, about
550mg/g, or about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol concentration of at
least about 0.1mg/g, about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about
2.5mg/g, about 3mg/g, about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about
5.5mg/g, about 6mg/g, about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout
25mg/g, about 30mg/g, about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g,
about 125mg/g, about 150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about
300mg/g, about 350mg/g, about 400mg/g, about 450mg/g, about 500 mg/g, about
550mg/g, or about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol concentration of at
least about 0.1mg/g, about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about
2.5mg/g, about 3mg/g, about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about
5.5mg/g, about 6mg/g, about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout
25mg/g, about 30mg/g, about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g,
about 125mg/g, about 150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about
300mg/g, about 350mg/g, about 400mg/g, about 450mg/g, about 500 mg/g, about
550mg/g, or about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 3,8-dihydroxy heneicosanoic acid methyl ester concentration of at least about
0.1mg/g, about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about 2.5mg/g,
about 3mg/g, about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about 5.5mg/g,
about 6mg/g, about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout 25mg/g,
about 30mg/g, about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g, about
125mg/g, about 150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about 300mg/g,
about 350mg/g, about 400mg/g, about 450mg/g, about 500 mg/g, about 550mg/g, or
about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 3,8-dihydroxy docosanoic acid concentration of at least about 0.1mg/g, about
0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about 2.5mg/g, about 3mg/g, about
3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about 5.5mg/g, about 6mg/g, about
7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout 25mg/g, about 30mg/g, about
40mg/g, about 50mg/g, about 75mg/g, about 100mg/g, about 125mg/g, about 150mg/g,
about 175mg/g, about 200mg/g, 250mg/g, about 300mg/g, about 350mg/g, about
400mg/g, about 450mg/g, about 500 mg/g, about 550mg/g, or about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 1-(3,8-dihydroxy docosanoyl) glycerol concentration of at least about
0.1mg/g, about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about 2.5mg/g,
about 3mg/g, about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about 5.5mg/g,
about 6mg/g, about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout 25mg/g,
about 30mg/g, about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g, about
125mg/g, about 150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about 300mg/g,
about 350mg/g, about 400mg/g, about 450mg/g, about 500 mg/g, about 550mg/g, or
about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol concentration of at least
about 0.1mg/g, about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about
2.5mg/g, about 3mg/g, about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about
5.5mg/g, about 6mg/g, about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout
25mg/g, about 30mg/g, about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g,
about 125mg/g, about 150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about
300mg/g, about 350mg/g, about 400mg/g, about 450mg/g, about 500 mg/g, about
550mg/g, or about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol concentration of at least
about 0.1mg/g, about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about
2.5mg/g, about 3mg/g, about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about
5.5mg/g, about 6mg/g, about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout
25mg/g, about 30mg/g, about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g,
about 125mg/g, about 150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about
300mg/g, about 350mg/g, about 400mg/g, about 450mg/g, about 500 mg/g, about
550mg/g, or about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol concentration of at least
about 0.1mg/g, about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about
2.5mg/g, about 3mg/g, about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about
5.5mg/g, about 6mg/g, about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout
25mg/g, about 30mg/g, about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g,
about 125mg/g, about 150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about
300mg/g, about 350mg/g, about 400mg/g, about 450mg/g, about 500 mg/g, about
550mg/g, or about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a 1-(3,8-dihacetoxy docosanoyl) 2,3-diacetoxy glycerol concentration of at least
about 0.1mg/g, about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about
2.5mg/g, about 3mg/g, about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about
5.5mg/g, about 6mg/g, about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout
25mg/g, about 30mg/g, about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g,
about 125mg/g, about 150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about
300mg/g, about 350mg/g, about 400mg/g, about 450mg/g, about 500 mg/g, about
550mg/g, or about 600mg/g.
In one embodiment, the poplar-derived propolis, propolis resin, or propolis resin
extract has a and 3,8-dihydroxy docosanoic acid methyl ester concentration of at least
about 0.1mg/g, about 0.5mg/g, about 1mg/g, about 1.5mg/g, about 2mg/g, about
2.5mg/g, about 3mg/g, about 3.5mg/g, about 4mg/g, about 4.5mg/g, about 5mg/g, about
5.5mg/g, about 6mg/g, about 7.5mg/g, about 10mg/g, about 15mg/g, about 20mg/gabout
25mg/g, about 30mg/g, about 40mg/g, about 50mg/g, about 75mg/g, about 100mg/g,
about 125mg/g, about 150mg/g, about 175mg/g, about 200mg/g, 250mg/g, about
300mg/g, about 350mg/g, about 400mg/g, about 450mg/g, about 500 mg/g, about
550mg/g, or about 600mg/g.
In various embodiments, the poplar-derived propolis, propolis resin, or propolis resin
extract additionally comprises any combination of two or more of CAPE, chrysin, galangin,
pinocembrin, pinobanksin, benzyl caffeate, benzyl ferulate, benzyl isoferulate, cinnamyl
caffeate, cinnamyl ferulate, pinostrobin chalcone, and caffeic acid.
In various embodiments, the composition comprises or is administered separately,
simultaneously or sequentially with at least one additional therapeutic agent, preferably the
at least one additional therapeutic agent is an anti-tumour agent, preferably the anti
tumour agent is selected from an anti-tumour food factor, a chemotherapeutic agent, or an
immunotherapeutic agent.
In various embodiments, the skin cancer therapy, the therapeutic agent, or the anti
tumour agent is effective to induce apoptosis, for example, induce apoptosis in one or more
skin cancer cells or in one or more neoplastic cells.
In one embodiment, the composition is a consumer good.
In one embodiment, the composition is a composition for topical administration.
In one embodiment, the topical composition comprises one or more penetrants,
photo-protectants, UV-protectants, vitamins, moisturizers, oils, hydrophilic or lipophilic
gelling agents, hydrophilic or lipophilic active agents, preserving agents, antioxidants,
solvents, fragrances, fillers, pigments, odor absorbers or dyestuffs.
In one embodiment the composition is a food, drink, food additive, drink additive,
dietary supplement, nutritional product, medical food, nutraceutical, medicament or
pharmaceutical.
In various embodiments, the composition is formulated for oral, topical, or parenteral
administration.
In one embodiment, a composition formulated for oral administration comprises
gamma-cyclodextrin.
In one embodiment, a composition formulated for topical administration comprises
alpha-cyclodextrin.
In one embodiment, a composition formulated for topical administration comprises
beta-cyclodextrin.
In one embodiment, the composition comprises one or more additional anti-epithelial
cancer agents.
In one embodiment, the composition is a pharmaceutical composition.
In various embodiments, the chemotherapeutic agent is selected from the group
comprising mitotic inhibitors, such as vinca alkaloids, including vincristine, vinblastine,
vinorelbine, vindesine, vinflunine, podophyllotoxin, taxanes, including docetaxel, larotaxel,
ortataxel, paclitaxel, and tesetaxel, and epothilones, such as ixabepilone; topoisomerase I
inhibitors, such as topotecan, irinotecan, camptothecin, rubitecan, and belotecan,
topoisomerase type II inhibitors, including amsacrine, etoposide, etoposide phosphate, and
teniposide, anthracyclines, such as aclarubicin, daunorubicin, doxorubicin, epirubicin,
idarubicin, amrubicin, pirarubicin, valrubicin, and zorubicin, and anthracenediones, such
mitoxantrone and pixantrone; antimetabolites, including dihydrofolate reductase inhibitors,
such as aminopterin, methotrexate, pemetrexed, thymidylate synthase inhibitors, such as
raltitrexed and pemetrexed, adenosine deaminase inhibitors, including pentostatin,
halogenated or ribonucleotide reductase inhibitors, such as cladribine, clofarabine, and fludarabine, thiopurines, including thioguanine and mercaptopurine, thymidylate synthase inhibitors, including fluorouracil, capecitabine, tegafur, carmofur, and floxuridine, DNA polymerase inhibitors, such as cytarabine, ribonucleotide reductase inhibitors, such as gemcitabine, hypomethylating agents, including azacitidine, and decitabine, and ribonucleotide reductase inhibitors, such as hydroxyurea; cell-cycle nonspecific antineoplastic agents, including alkylating agents such as nitrogen mustards, including mechlorethamine, cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, melphalan, prednimustine, bendamustine, uramustine, estramustine, nitrosoureas, including carmustine, lomustine, semustine, fotemustine, nimustine, ranimustine, and streptozocin, alkyl sulfonates, including busulfan, mannosulfan, and treosulfan, aziridines, including carboquone, thioTEPA, triaziquone, and triethylenemelamine, alkylating-like agents, including platinum agents such as cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, satraplatin, hydrazines, such as procarbazine, triazenes, such as dacarbazine, temozolomide, altretamine, and mitobronitol, and streptomycins, such as actinomycin, bleomycin, daunomycin,mitomycin, and plicamycin; photosensitizers, including aminolevulinic acid, methyl aminolevulinate, efaproxiral, and porphyrin derivatives, such as porfimer sodium, talaporfin, temoporfin, and verteporfin; enzyme inhibitors, including farnesyltransferase inhibitors such as tipifarnib, cyclin-dependent kinase inhibitors, such as alvocidib and seliciclib, proteasome inhibitors, such as bortezomib, phosphodiesterase inhibitors, such as anagrelide, IMP dehydrogenase inhibitors, such as tiazofurine, lipoxygenase inhibitors, such as masoprocol, and PARP inhibitors, such as olaparib; receptor antagonists, such as endothelin receptor antagonists including atrasentan, retinoid X receptor antagonists, such as bexarotene, and testolactone; and other chemotherapeutics, including amsacrine, trabectedin, retinoids such as alitretinoin and tretinoin, arsenic trioxide, asparagine depleters such as asparaginase or pegaspargase, celecoxib, demecolcine, elesclomol, elsamitrucin, etoglucid, and lonidamine.
It is intended that reference to a range of numbers disclosed herein (for example, 1 to
10) also incorporates reference to all rational numbers within that range (for example, 1,
1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9 and 10) and also any range of rational numbers within
that range (for example, 2 to 8, 1.5 to 5.5 and 3.1 to 4.7) and, therefore, all sub-ranges of
all ranges expressly disclosed herein are hereby expressly disclosed. These are only
examples of what is specifically intended and all possible combinations of numerical values
between the lowest value and the highest value enumerated are to be considered to be
expressly stated in this application in a similar manner.
In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission
that such documents, or such sources of information, in any jurisdiction, are prior art, or
form part of the common general knowledge in the art.
The invention may also be said broadly to consist in the parts, elements and features
referred to or indicated in the specification of the application, individually or collectively, in
any or all combinations of two or more of said parts, elements or features, and where
specific integers are mentioned herein that have known equivalents in the art to which the
invention relates, such known equivalents are deemed to be incorporated herein as if
individually set forth.
The present invention relates to fatty acid compounds and compositions comprising
these dihydroxy fatty acid glycerides having anti-epithelial cancer activity. Pharmaceutical
Compositions, for example anti-epithelial cancer compositions, provide and/or enhance anti
epithelial cancer efficacy, and in certain embodiments enhance the activity and physicochemical properties of compositions comprising these compounds, such as propolis and poplar extracts. Nutraceutical compositions, for example skin and gut health compositions provide health benefits. In certain embodiments, for example where propolis or propolis extracts or fractions or poplar extracts or fractions are present, the activity and physicochemical properties of the compositions are enhanced.
In one aspect, the invention relates to a method of treating or preventing an epithelial
cancer in a subject, the method comprising administering to a subject in need thereof an
effective amount of a a composition comprising a therapeutically effective amount of a
compound of formula (I): R1 (CH (CH R6
0 OR 4 OR5
R 1 =OH, OR 7 or0 OR3
OR2 (1)
or a pharmaceutically acceptable salt or solvate thereof, wherein R2, R3, R4 and Rs are
each independently H or acetyl (CH3CO-),
R6 is H or CH3, R7 is CH3 or C2 to C6 saturated or unsaturated hydrocarbon, and
x and y are each independently an integer from 3 to 14,
provided that when R6is H, x+ y is greater than 10 and less than or equal to 18, and
when R6 is CH3, x+y is greater than 9 and less than or equal to 17.
In one embodiment, x is greater than or equal to 4.In one embodiment, the invention
relates to a method of treating or preventing an epithelial cancer in a subject, the method
comprising administering to a subject in need thereof an effective amount of a composition
comprising a therapeutically effective amount of at least one compound selected from any
one or more of the group consisting of a) 3,8-dihydroxy eicosanoic acid, b) 1-(3,8-dihydroxy eicosanoyl) glycerol
HODr
c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol,
d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol,
0
e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol,
0
f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol,
0
0
0 00 D
O- 00 -
g) 3,8-dihydroxy eicosanoic acid methyl ester
h) 3,8-dihydroxy heneicosanoic acid,
j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxyglycerol,
HO 0 OH
[5 k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
I) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
0
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,
0
0 Ol
00 JO
n) 3,8-dihydroxy heneicosanoic acid methyl ester
o) 3,8-dihydroxy docosanoic acid,
p) 1-(3,8-dihydroxy docosanoyl) glycerol
q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol,
r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol,
0
s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol,
0
00O
t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol,
0
0
0
00
100
u) 3,8-dihydroxy docosanoic acid methyl ester,
OCH, OH or a pharmaceutically acceptable salt or solvate of any one of a) to u),
to a subject in need thereof.
The compounds and pharmaceutical compositions, for example anti-cancer
compositions, are in some embodiments used to treat or prevent epithelial cancers, or in
other embodiments, for example in which propolis, propolis extracts or fractions, propolis
resin, or propolis resin extract or poplar extracts or fractions are present, are used to improve skin health, and/or enhance the activity and physicochemical properties of propolis, propolis extracts or fractions, propolis resin, or propolis resin extract or materials with propolis contained.
Accordingly, provided that the anti-epithelial cancer compositions are formulated so as
to be suitable for administration to a mammalian subject, for example they consist of
materials that are safe to the human body, they can be used for manufacturing anti
epithelial cancer pharmaceutical compositions and drugs, as well as nutraceutical
compositions, consumer goods, such as beverages, foods, lotions, skin creams and the like.
Furthermore, as the anti-epithelial cancer activity of embodiments of the compositions
described herein is maintained for a sustained period, the dosage or frequency of
administration of the composition can be reduced, or higher efficacy is provided, or both.
The phrases "anti-epithelial cancer compositions" or "compositions having anti
epithelial cancer activity" (used interchangeably herein) of this invention contemplate any
kind of compositions. Examples include anti-epithelial cancer compositions containing
propolis, propolis resin, or propolis resin extract enriched in one or more compounds of
formula (I) or one or more pharmaceutically acceptable salts or solvates thereof and
cyclodextrin or anti-epithelial cancer compositions containing materials with propolis,
propolis resin, or propolis resin extract and cyclodextrin. Synergistic compositions, including
those which enhance any anti-epithelial cancer activity observed in either propolis or in
cyclodextrin alone are particularly contemplated. In certain embodiments the anti-epithelial
cancer compositions may be anti-basal cell carcinoma, anti-squamous cell carcinoma or
anti-melanoma compositions. In other embodiments, the anti-epithelial cancer compositions
are anti-gastrointestinal cancer compositions, such as anti-colorectal cancer, anti-gastric
cancer or anti-throat cancer compositions.
The term "and/or" can mean "and" or "or".
The terms "cancer" and "cancerous" refer to a physiological condition in mammals that
is typically characterized by abnormal or unregulated cell proliferation, cell survival, cell
motility, neoplasticity, and/or oncogenicity. Cancer and cancer pathology can be associated,
for example, with metastasis, interference with the normal functioning of neighbouring cells,
release of cytokines or other secretory products at abnormal levels, suppression or
aggravation of inflammatory or immunological response, neoplasia, premalignancy,
malignancy, invasion of surrounding or distant tissues or organs, such as lymph nodes, etc.
Specifically included are basal cell carcinomas, squamous cell carcinomas, melanomas, and
precancerous conditions, which can include dermal tumours, epithelial tumours, tumours of
the buccal cavity, for example, squamous cell cancers of the buccal cavity, carcinomas in
situ, as well as invasive basal cell, squamous cell, or melanoma cancers, and secondary
tumours derived therefrom. Also specifically included are cancers of the gastrointestinal
tract, such as colorectal cancers and precancerous conditions, which can include epithelial
tumours, nonepithelial tumours, carcinomas, for example, carcinomas in situ, as well as
invasive colorectal cancers. Also included are gastric cancers and precancerous conditions,
which can include epithelial tumours, adenocarcinomas, gastric lymphomas, carcinoid
tumours, stromal tumours. Also included are throat cancers and precancerous conditions,
which can include epithelial tumours, squamous cell carcinomas, adenocarcinomas. Cancers
of mucosal tissues are similarly specifically contemplated. Cancers may be, for example,
carcinomas in situ, as well as invasive cancers.
The term "comprising" as used in this specification means "consisting at least in part
of". When interpreting statements in this specification that include that term, the features,
prefaced by that term in each statement, all need to be present but other features can also
be present. Related terms such as "comprise" and "comprised" are to be interpreted in the
same manner.
An "effective amount" is the amount required to confer therapeutic effect. The
interrelationship of dosages for animals and humans (based on milligrams per meter
squared of body surface) is described by Freireich, et al. (1966). Body surface area can be
approximately determined from height and weight of the subject. See, e.g., Scientific
Tables, Geigy Pharmaceuticals, Ardley, New York, 1970, 537. Effective doses also vary, as
recognized by those skilled in the art, dependent on route of administration, excipient
usage, and the like.
As used herein, an "extract" or a "fraction" of poplar is suitable for use in the present
invention provided it at least retains one or more anti-epithelial cancer activities, or
comprises one or more compounds of formula (I) or one or more pharmaceutically
acceptable salts or solvates thereof. Exemplary extracts or fractions of poplar for use herein
are those enriched in one or more compounds of formula (I) or one or more
pharmaceutically acceptable salts or solvates thereof. Examples of such functional extracts
include the anti-epithelial cancer preparation described herein in the Examples. It will be
appreciated that poplar extracts or fractions enriched in one of more of the compounds of
formula (I) can be prepared additively or subtractively, whereby at least partially isolated or
purified compounds of formula (I) may be added to a composition, such as poplar or a
poplar extract or fraction, or by removal from poplar or a poplar extract or fraction of
compounds other than one or more compounds of formula (I).
As used herein, an "extract" or a "fraction" of propolis is suitable for use in the present
invention provided it at least retains one or more anti-epithelial cancer activities or
efficacies exhibited by propolis, and/or comprises one or more compounds of formula (I) or
one or more pharmaceutically acceptable salts or solvates thereof. Exemplary extracts or
fractions of propolis for use herein are those enriched in one or more compounds of formula
(I) or one or more pharmaceutically acceptable salts or solvates thereof. Examples of such
functional extracts include the anti-epithelial cancer tincture described herein in the
Examples. It will be appreciated that propolis extracts or fractions enriched in one of more
of the compounds of formula (I) can be prepared additively or subtractively, whereby at
least partially isolated or purified compounds of formula (I) may be added to a composition,
such as propolis or a propolis extract or fraction, or by removal from propolis or a propolis
extract or fraction of compounds other than one or more compounds of formula (I).
As used herein, chromatography refers to a separation process in which compounds
dissolved or dispersed or otherwise transported in a solvent phase are contacted with a solid
phase whereby the solid phase selectively retards one or more of the compounds relative to
the other compounds present in the solvent, thus enabling separation to occur. Examples of
types of chromatographic processes include column chromatography, liquid
chromatography, gas chromatography, supercritical chromatography, size exclusion
chromatography, preparative chromatography, solid phase extraction. Chromatography
processes can be used to determine the concentration of a compound or compounds in a
mixture, identify unknown compounds, and/or isolate one or more compounds to, for
example obtain detailed structural analysis data, use as an analytical standard and/or for
bioassay.
Methods and assays to determine one or more biological effects elicited by one or
more of the compounds or compositions described herein, for example, compositions
comprising one or more compounds of formula (I), optionally together with propolis or
poplar extracts, are well known in the art and examples are described herein, and such
methods and assays can be used to identify or verify efficacy, for example, efficacy of one
or more one or more of the compounds or compositions described herein, including a
composition comprising one or more functional extracts or functional fractions of propolis,
such as propolis, a propolis extract, a poplar extract, or a propolis or poplar fraction
enriched in one or more compounds of formula (I) or one or more pharmaceutically
acceptable salts or solvates thereof. For example, an assay of the ability of one or more of the compounds or compositions described herein to increase one or more oncogenic traits in a cell, such as those described herein in the Examples, is amenable to verify efficacy of one or more of the compounds or compositions described herein, or to identify one or more functional extracts or functional fractions of propolis or poplar.
As used herein, "propolis" contemplates propolis produced by bees from any botantical
source. In one embodiment, the propolis is "poplar-derived" propolis. "Poplar-derived"
propolis is also known under different names, such as "Poplar" propolis. For example, the
propolis is derived principally from the bud and leaf exudates of one or more species of
poplars, and to a lesser extent birches, larches or willows. Propolis has been classified into
seven major classes based on plant source which gives rise to characteristic compounds
being present (Sforcin and Bankova, 2011. Propolis: is there a potential for the
development of new drugs? J. Ethnopharmacology, 133: 253-260.). These classes are
"Poplar" from Europe, North America, Southern South America, New Zealand which have
high levels of aglycone flavonoids such as chrysin and galangin; "Brazilian green", which
contains prenylated p-coumaric acids such as artepillan C; "Birch" from Russia also rich in
aglycone flavonoids such as apigenin, rhamnocitrin and kaemferide; "Red propolis" sourced
from Clusia species from Cuba, Brazil, Mexico, Venezuala which contains polyprenylated
benzophenones including nemorosone and xanthochymol; "Mediterranean" from Greece,
Sicily, Crete, Malta rich in diterpenes that are sourced from conifers; and "Pacific" from
Okinawa, Taiwan, Indonesia, which contain 'propolins'.
Identification and verification of the anti-cancer constituent(s) present in propolis resin
has been challenging because of the complex and multicomponent nature of the propolis
resin. "Poplar" propolis resin has also been shown to contain a number of types of
compounds, including sugars, glycerol, simple fatty acids, volatile oils and glycerol esters of
phenolic acids. A group of compounds not previously reported in propolis having hitherto
unknown anti cancer activities are described herein. These compounds are long chain fatty acids and their equivalent glycerides. Furthermore, these dihydroxy free fatty acids and glycerides may be partially to fully acetylated. These compounds have the structure of formula (I): R1 (CH (CH R6
0 OR4 OR5
R 1 =OH, OR 7 or0 OR 3
OR 2
wherein R2, R3, R4 and Rs are each independently H or acetyl (CH3CO-),
R6 is H or CH3, R7 is CH3 or C2 to C6 saturated or unsaturated hydrocarbon and
x and y are each independently an integer from 3 to 14,
provided that when R6is H, x+ y is greater than 10 and less than or equal to 18, and
when R6 is CH3, x+y is greater than 9 and less than or equal to 17.
As will be appreciated by those skilled in the art, the identity, and in certain cases the
suitability for particular uses, including use in the present invention, of propolis may be
determined by analysis of the composition of the propolis. The presence and amount of
specific compounds, (including the compounds discussed herein) - frequently referred to as
"marker compounds", allows a determination of the suitability of a particular source of
propolis, for example poplar-derived propolis compared to Brazilian propolis, for a particular
use. In certain embodiments of the present invention, the presence or amount of one or
more marker compounds is determined or assayed, for example as a preliminary grading
step, prior to formulation of the composition. In other embodiments, the presence or
amount of one or more marker compounds is determined and reported, for example, on an indicator associated with a composition as herein described, for example as an indication of efficacy or activity.
The "indicator" may be in any form, including, but not limited to, labelling
incorporated into the product, for example, etched or printed on the surface of the product
or composition, for example, an indicator printed or etched onto a capsule or tablet,
packaging or labelling associated with the product such as a label attached to, or
incorporated on, a package containing the product or composition, materials provided with,
but separate to, the product or composition, for example a Certificate of Analysis; a
website, a brochure, a pamphlet, or a display associated with the sale or marketing of the
product or composition.
The compounds of formula (I) may be isolated and/or purified from poplar-derived
propolis using methods known in the art. Exemplary methods are presented herein.
Similarly, compounds of formula (I) may be isolated and/or purified from botanical sources,
such as poplar and poplar extracts or exudates, again using methods known in the art.
Exemplary methods are also presented herein. These methods are also amenable to use in
determining the concentration or amount of one or more compounds of formula (I) or
pharmaceutically acceptable salt or solvate thereof present in a composition as herein
described, for example for the purposes of reporting said concentration or amount.
Alternatively, the compounds of formula (I) may be prepared synthetically using
methods well known in the art. For example, synthesis via the Grignard reaction (Smith,
Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and
Structure (6th ed.), New York: Wiley-Interscience, ISBN 0-471-72091-7) using known
starting materials is specifically contemplated in the synthesis of a compound of formula (I).
For example, it is contemplated that compounds of formula (I) could be prepared from the
starting materials 3,8-dihydroxyoctanoic acid; and a Grignard reagent selected from dodecyl
magnesium bromide, tridecyl magnesium bromide or tetradecyl magnesium bromide. These
Grignard reagents may be prepared from the corresponding long chain fatty alcohol
dodecan-1-ol (lauryl alcohol), 1-tridecanol or 1-tetradecanol (myristol alcohol). It is further
contemplated that the primary alcohol of the 3,8-dihydroxyoctanoic acid would be
selectively oxidized to the aldehyde to enable Grignard coupling of the starting materials.
The resultant 3,8-dihydroxy fatty acid can then be esterified using suitable lipases, or via
standard chemical esterification with glycerol, glycerol-2-acetate or glycerol 2,3-acetate to
give the main compounds of formula (I).
When used in respect of a composition described herein or a component of such a
composition, the phrases "enhanced activity" or "enhanced anti-epithelial cancer activity"
and grammatical equivalents and derivatives thereof is intended to mean that when present
in the composition, an equivalent amount or concentration of the anti-epithelial cancer
agent has increased anti-epithelial cancer activity compared to that of the agent in the
absence of the composition (such as the isolated agent), and/or the stability of the
composition is improved relative to the single component and/or the bioavailability of the
composition is improved relative to the single component. For example, the enhanced
activity is at least about 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165,
170, 175, 180, 185, 190, 195, 200%, or more of the original activity, and useful ranges
may be selected between any of these values (for example, from about 105 to about 200%,
from about 120 to about 200%, from about 140 to about 200%, from about 150 to about
200%, from about 180 to about 200%, and from about 190 to about 200%). In certain
embodiments, compositions may exhibit enhanced anti-epithelial cancer activity, that is,
exhibit at least about 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165,
170, 175, 180, 185, 190, 195, 200%, or more of the anti-epithelial cancer activity of
propolis alone, or of cyclodextrin alone. Similarly, preferred compositions are capable of
supporting the maintenance of enhanced anti-epithelial cancer activity, and can be said to
retain enhanced anti-epithelial cancer activity, ideally until utilized using the methods contemplated herein. The enhanced activity (including enhanced maintenance of activity) is believed, without wishing to be bound by any theory, to result from synergy amongst the various components of the compositions, or from improved stability of the composition or from improved bioavailability of the composition due to, for example, improved water dispersibility.
The term "oral administration" includes oral, buccal, enteral and intra-gastric
administration.
The term "parenteral administration" includes but is not limited to topical (including
administration to any dermal, epithelial or mucosal surface), subcutaneous, intravenous,
intraperitoneal, intramuscular and intratumoural (including any direct administration to a
tumour) administration.
The term "pharmaceutically acceptable carrier" is intended to refer to a carrier
including but not limited to an excipient, diluent or auxiliary that can be administered to a
subject as a component of a composition. Preferred carriers do not reduce the activity of
the composition and are not toxic when administered in doses sufficient to deliver an
effective amount of propolis or extracts thereof, or, when administered, of another anti
epithelial cancer agent.
The term "(s)" following a noun contemplates the singular or plural form, or both.
The term "subject" is intended to refer to an animal, preferably a mammal, more
preferably a mammalian companion animal or human. Preferred companion animals include
cats, dogs and horses. Other mammalian subjects include an agricultural animal, including a
horse, a pig, a sheep, a goat, a cow, a deer, or a fowl, or a laboratory animal, including a
monkey, a rat, or a mouse.
The term "treat" and its derivatives should be interpreted in their broadest possible
context. The term should not be taken to imply that a subject is treated until total
recovery. Accordingly, "treat" broadly includes maintaining a subject's disease progression or symptoms at a substantially static level, increasing a subject's rate of recovery, amelioration and/or prevention of the onset of the symptoms or severity of a particular condition, or extending a patient's quality of life. The term "treat" also broadly includes the maintenance of good health for sensitive individuals and building stamina for disease prevention.
Exemplary uses of the invention
The methods and compositions described herein may be used in the treatment or
prevention of epithelial cancers, neoplastic disorders associated with epithelial cells, and the
symptoms of such cancers, including the symptoms of cancer treatment, and associated
disorders.
In one example, the methods and compositions described herein may be used in the
treatment or prevention of skin cancers, such as melanomas, neoplastic disorders
associated with melanomas, and the symptoms of melanoma, melanoma treatment, and
associated disorders. Melanoma (also referred to as malignant melanoma) is a neoplastic
condition affecting melanocytes.
Melanomas are the least common, but most aggressive and threatening of the skin
cancers. Where possible, the preferred treatment is complete surgical removal which can
be curative if metastasis has not occurred.
The methods and compositions described herein may be used in the treatment or
prevention of basal cell carcinomas, neoplastic disorders associated with basal carcinoma
cells, and the symptoms of basal cell carcinoma, basal cell carcinoma treatment, and
associated disorders. Basal cell carcinoma is a neoplastic condition affecting the basal cells
of the dermis.
Basal cell carcinoma originates from lowest layer of the epidermis. Where possible, the
preferred treatment is complete surgical removal which can be curative.
In certain embodiments, the methods and compositions are used in the treatment or
prevention of squamous cell carcinomas, neoplastic disorders associated with squamous
carcinoma cells, and the symptoms of squamous cell carcinoma, squamous cell carcinoma
treatment, and associated disorders.
Squamous cell carcinoma is a neoplastic condition arising in cells of the middle layer of
epidermis. Although squamous cell carcinoma is less common than basal cell carcinoma,
metastases are more likely and can be fatal if not treated.
The invention provides methods and compositions for inhibiting skin tumour
formation, inhibiting skin tumour growth, inhibiting skin tumour metastasis, or treating or
preventing a skin cancer in a subject in need thereof. Without wishing to be bound by any
theory, applicants believe that inhibition occurs at least in part, for example, by prevention
of UV-initiated damage to DNA or the prevention or reduction in formation of reactive
oxygen species.
In certain embodiments, the invention also relates to methods of at least partially
reversing the resistance of a neoplastic cell in a subject suffering from a skin cancer to a
skin cancer therapy, or to a method of reversing, wholly or in part, the resistance of a skin
cancer-burdened patient to a skin cancer therapy, or to a method of re-sensitising one or
more tumours of a skin cancer-burdened patient which are, or are predicted to either be or
become, resistant to treatment with a skin cancer therapy, said methods comprising the
step of administering to said patient a composition comprising, consisting essentially of, or
consisting of propolis, propolis resin, or propolis resin extract enriched in one or more
compounds of formula (I) and cyclodextrin.
In one embodiment, the one or more tumours are or are predicted to be or to become
resistant to a skin cancer therapy due increased activation of one or more pro-cancer cell
survival signaling pathways within the one or more tumours or within the patient, including
increased activation of one or more of the AKT,JNK or JAK/STAT signaling pathways, for example within a sample from the patient, such as a tissue sample, a tumour biopsy, or a blood or plasma sample.
Pro-cancer cell survival signaling pathways implicated in the onset and development of
skin cancers are known in the art.
The methods and compositions may be used in the treatment or prevention of
melanomas, neoplastic disorders associated with melanoma cells, and the symptoms of
melanoma, melanoma treatment, and associated disorders.
The most common therapies are surgical excision of tumours and radiation therapy.
Chemotherapeutic agents may be used in combination surgery and/or radiation.
The methods and compositions may also be used for maintaining or improving skin
health.
This includes the treatment or prevention of a condition associated with poor skin
health, low immunity and skin inflammation. For example, the methods and compositions
are useful for or in the treatment or prevention of skin aging, sun burn, dermatitis, eczema,
psoriasis, ichthyosis and related inflammatory conditions, and in the treatment or
prevention of red, irritated, dry, cracked or itchy skin.
Propolis and materials comprising propolis
Propolis is available in New Zealand and elsewhere, commonly as a resinous sticky
solid. Propolis may be obtained from bee-hives with the resulting propolis held in storage,
for example to assess the propolis content. Typically the propolis, or an extract thereof, is
processed to a fine particulate form or a concentrated tincture. Various methods of
preparing active propolis, or an extract thereof, to a particulate form or concentrated
tincture are known. Most commonly, crude propolis is extracted using ethanol or
ethanol/water mixtures to produce a dilute tincture. Wax associated with the crude propolis
is at best poorly soluble in the solvent and so is mostly not extracted. Any extracted wax
can be removed by cooling the dilute tincture and then settling, filtration, or centrifugation.
The tincture can then be concentrated by partial to complete evaporation of the solvent to
give a concentrated tincture, optionally followed by freeze drying to give a powder.
Alternatively, the tincture can be spray dried to give a powder. Fractions can be prepared by
using methods known in the art such as chromatography (such as HPLC) using, for
example, a size exclusion matrix or a reverse phase matrix, or supercritical fractionation. A
typical solvent for use in such a chromatographic process is ethanol or another water
miscible alcohol.
In one embodiment propolis or concentrated propolis tincture is combined with other
compounds that enhance the properties of propolis, for example a compound that enhances
the ease of formulation or administration, or that enhances anti-epithelial cancer activity, or
that enhances the stability of one or more anti-epithelial cancer activities present in
propolis. Examples of additional compounds are those that improve the therapeutic benefits
of the propolis. Exemplary compositions in which one or more compounds present in
propolis, and in poplar-derived propolis in particular, including biologically active compounds
such as CAPE, caffeic acid, pinocembrin, benzyl caffeate, cinnamyl caffeate, benzyl ferulate,
cinnamyl ferulate, chrysin, tectochrysin, galangin, pinobanksin, pinostrobin chalcone, and
pinobanksin-3-acetate are added are specifically contemplated. In other examples,
additional compounds are included to improve or maintain the physiological benefits of the
composition, for example mannitol can be added to enhance the diuretic properties of the
resulting composition. Alternatively or additionally other compounds such as excipients,
and/or propellants could be added to improve the dosing, manufacturability or delivery
properties of the composition.
In particularly contemplated embodiments, dewaxed propolis resin, optionally with one
or more additional compounds added, is encapsulated with cyclodextrin and the admixture
dried. Further processing of the admixture, for example, to obtain a particle size distribution that enables ready admixture with the other components of the composition, ease of tableting, or ease of administration to a subject, is conducted.
In typical embodiments, the propolis or propolis resin is sterilized, for example by
heating to kill bacteria, protozoa, yeast, fungi and other organisms that naturally may be
present in the propolis.
Poplar extracts
As described in the Examples herein, exemplary compounds of formula (I) have been
identified in extracts prepared from poplar (Populus spp.), and particularly from exudates
prepared from buds, leaf material, and twigs. Without wishing to be bound by any theory,
applicant believes the compounds described herein are present in or associated with poplar
derived propolis and propolis resin. Those skilled in the art will recognise that for use in the
present invention, poplar or propolis extracts may be processed to a form suitable for
further processing and encapsulation, for example with cyclodextrin or extracted with a
solvent (e.g., alcohol) while maintaining the bioactive ingredients. Typically the propolis or
poplar extract is processed to a fine particulate form or a concentrated tincture.
Cyclodextrins and materials comprising cyclodextrin
Cyclodextrins are cyclic molecules composed of glucopyranose ring units which form
toroidal structures. The interior of the cyclodextrin molecule is hydrophobic and the exterior
is hydrophilic, making the cyclodextrin molecule water soluble. The degree of solubility can
be altered through substitution of the hydroxyl groups on the exterior of the cyclodextrin.
Similarly, the hydrophobicity of the interior can be altered through substitution, though
generally the hydrophobic nature of the interior allows accommodation of relatively
hydrophobic guests within the cavity. Accommodation of one molecule within another is
known as complexation and the resulting product is referred to as an inclusion complex.
Cyclodextrins are typically identified with reference to the number of monomeric units that
comprise the molecule, wherein alpha-cyclodextrin (a -cyclodextrin) comprises six monomeric units, beta-cyclodextrin (P -cyclodextrin) comprises seven monomeric units, and gamma-cyclodextrin (y -cyclodextrin) comprises eight monomeric units. Larger cyclodextrin molecules have been described, including a well-characterised cyclodextrin containing 32 1,4-anhydroglucopyranoside units.
Cyclodextrin molecules may conveniently be derivatised, by for example chemical
modification, for example to alter one or more of the physicochemical properties thereof.
Examples of cyclodextrin derivatives include methylated cyclodextrins,
sulfobutylcyclodextrin, maltosylcyclodextrin, hydroxypropylcyclodextrin, for example beta
hydroxylpropylcyclodextrin and gamma-hydroxypropylcyclodextrin, and salts thereof. Those
skilled in the art will recognise that various derivates of cyclodextrin may be suitable for
particular purposes, for example, certain derivatives of cyclodextrin are not be acceptable
for administration to human subjects, but are suitable for industrial uses.
Cyclodextrins comprising the anti-epithelial cancer compositions described herein may
be commercially available, or may be prepared independently by methods well known to
those skilled in the art. It will be apparent to those skilled in the art that cyclodextrins used
in the anti-epithelial cancer compositions for administration to a subject, for example a
cyclodextrin for manufacturing a beverage, food, or pharmaceutical should be safe to
human body, and preferably is a pharmaceutically acceptable cyclodextrin.
In particularly contemplated embodiments, alpha-cyclodextrin, gamma-cyclodextrin or
combinations comprising alphan-cyclodextrin, gamma-cyclodextrin, or both, are used. In
such embodiments, anti-epithelial cancer activity is substantially enhanced, as presented
herein in the examples. Such compositions comprising alpha-cyclodextrin and/or gamma
cyclodextrin can be formulated to provide, for example, enhanced mouth feel or palatability,
for example compositions comprising alpha-cyclodextrin and/or gamma-cyclodextrin and
propolis exhibit a strong tendency to mask any distasteful flavours present in the propolis.
Cyclodextrins suitable for use in the present invention can be obtained from
commercial sources, or can be prepared independently by methods well known in the art,
such as from starch by enzymatic conversion. In certain embodiments, CAVAMAX W6, W7
or W8 FOOD, an alpha, beta or gamma-cyclodextrin commercially supplied by Wacker AG, is
used.
In certain embodiments, such as those directed to topical application of compositions,
non-food grade cyclodextrins are used, for example, cyclodextrins including substituted
cyclodextrins from the CAVASOL range of cyclodextrins are contemplated.
Epithelial cancers
Epithelial cancers amenable to treatment using the compositions described herein
include carcinomas, such as squamous cell carcinomas, basal cell carcinomas,
adenocarcinomas, large cell carcinoms, small cell carcinomas, and transitional cell
carcinomas. It will be understood that carcinoma is the term generally used for a malignant
epithelial tumour. There are two main types of carcinomas, categorised by the type of
epithelium from which they are derived. These are squamous cell carcinomas, which are
derived from squamous epithelium, and adenocarcinomas, which are derived from glandular
epithelium.
In various embodiments, the epithelial cancer is selected from the group comprising
gastric carcinoma (intestinal type), gastric carcinoma (difuse type/mucinous), moderately
differentiated adenocarcinoma of the colon, poorly differentiated adenocarcinoma
(mucinous) of the colon, hepatocellular carcinoma including poorly differentiated
hepatocellular carcinoma, renal cell carcinoma (Grawitz tumor), endometrioid carcinoma,
carcinoma of the breast including invasive carcinoma of the breast, metastatic carcinoma
(lymph node), colorectal carcinoma, oral carcinomas including esophageal carcinoma,
pharyngeal cancer, or laryngeal cancer, skin cancer including basal cell skin cancer,
squamous cell skin cancer, and melanoma, and ovarian carcinoma.
The treatment of oral or throat cancer, also referred to as esophageal cancer,
pharyngeal cancer, or laryngeal cancer, and encompassing tumours that develop in the
tissues of the pharynx, nasopharynx, oropharynx, hypopharynx, larynx (voice box) or
tonsils, using the methods and compositions described herein is particularly contemplated.
Similarly, the treatment of gastric or stomach cancer, and of basal cell skin cancer,
squamous cell skin cancer, and melanoma, are particularly contemplated.
Compositions
Exemplary anti-epithelial cancer compositions comprise one or more compounds of
formula (I) or one or more pharmaceutically acceptable salts or solvates thereof together
with a pharmaceutically acceptable carrier.
Compositions suitable for administration to a subject may be formulated as a food,
drink, food additive, drink additive, dietary supplement, nutritional product, cosmeceutical,
medical food, nutraceutical, medical supply, medical device, medicament or pharmaceutical.
Appropriate formulations may be prepared by an art skilled worker with regard to that skill
and the teaching of this specification.
The compositions useful herein may be formulated to allow for administration to a
subject by any chosen route, including but not limited to oral or parenteral (including
topical, subcutaneous, intramuscular and intravenous) administration. Those skilled in the
art will appreciate that the route of administration to a subject will typically take into
account the purpose for which the composition is being administered - for example, where
a pharmaceutical composition is being administered to improve skin health or treat or
prevent a skin cancer, the route of administration will typically be chosen taking into
account the nature of the health aspect or skin cancer being targeted.
In general, for oral administration a dietary (a food, food additive or food supplement
for example), nutraceutical or pharmaceutical composition useful herein may be formulated
by a skilled worker according to known formulation techniques. In certain embodiments, compositions formulated for oral administration comprise gamma-cyclodextrin. In certain embodiments, compositions formulated for oral administration comprise alpha-cyclodextrin.
Thus, a pharmaceutical composition useful according to the invention may be
formulated with an appropriate pharmaceutically acceptable carrier (including excipients,
diluents, auxiliaries, and combinations thereof) selected with regard to the intended route of
administration and standard pharmaceutical practice. See for example, Remington's
Pharmaceutical Sciences, 16th edition, Osol, A. Ed., Mack Publishing Co., 1980.
While one suitable route of administration of certain embodiments, such as those
comprising one or more compounds of formula (I), is oral, it should be understood that any
mode of administration may be suitable for any composition, including administration by
multiple routes, including different routes for different agents. Therefore, inhalation (nasal
or buccal inhalation) and vaginal and rectal administration of any composition is also
contemplated. Intramedullar, epidural, intra-articular, and intra-pleural administration of
any composition is also contemplated. Administration of a composition, optionally with at
least one additional anti-epithelial cancer factor, by a first administration route accompanied
by separate, simultaneous or sequential administration of one or more other agents,
including one or more other anti-epithelial cancer agents, by a second administration route
is also contemplated; for example, oral administration of a composition accompanied by
topical administration of the at least one additional anti-epithelial cancer agent.
The compositions may also be formulated as a dosage form. A dosage form useful
herein may be administered orally as a powder, liquid, tablet or capsule. Suitable dosage
forms may contain additional agents as required, including emulsifying, antioxidant,
flavouring or colouring agents, or have an enteric coating. Suitable enteric coatings are
known. Enteric coatings surrounding the active ingredients and prevent the release of the
active ingredients in the stomach but allow release after the dosage form has left the
stomach. Dosage forms useful herein may be adapted for immediate, delayed, modified, sustained, pulsed or controlled release of the active components. Suitable formulations may contain additional agents as required, including emulsifying, antioxidant, flavouring or colouring agents.
Capsules can contain any standard pharmaceutically acceptable materials such as
gelatin or cellulose. Tablets can be formulated in accordance with conventional procedures
by compressing mixtures of the active ingredients with a solid carrier and a lubricant.
Examples of solid carriers include starch and sugar bentonite. Active ingredients can also
be administered in a form of a hard shell tablet or a capsule containing a binder, e.g.,
lactose or mannitol, a conventional filler, and a tabletting agent. Pharmaceutical
compositions can also be administered via the parenteral route. Examples of parenteral
dosage forms include aqueous solutions, isotonic saline or 5% glucose of the active agent,
or other well-known pharmaceutically acceptable excipient. Solubilising agents well-known
to those familiar with the art, can be utilized as pharmaceutical excipients for delivery of the
anti-epithelial cancer agent.
Injectable dosage forms may be formulated as liquid solutions or suspensions. Solid
forms suitable for solution in, or suspension in, liquid prior to injection may also be
prepared. The dosage form may also be emulsified. The one or more compounds of
formula (I) or one or more pharmaceutically acceptable salts or solvates thereof may be
mixed with carriers such as, for example, water, saline, dextrose, glycerol, ethanol, or the
like and combinations thereof.
Sustained-release preparations may be prepared. Suitable examples of sustained
release preparations include semi-permeable matrices of solid hydrophobic polymers
containing the one or more compounds of formula (I) or one or more pharmaceutically
acceptable salts or solvates thereof, optionally together with propolis, and/or a poplar
extract, and or cyclodextrin, and when present the at least one additional anti-epithelial
cancer agent. The matrices may be in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl- methacrylate), or poly(vinylalcohol)), polylactides (see US
3,773,919), copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradable
ethylene-vinyl acetate, and degradable lactic acid-glycolic acid copolymers such as the
LUPRON DEPOT T(injectable microspheres composed of lactic acid-glycolic acid copolymer
and leuprolide acetate).
Topical formulations comprising compositions, such as those comprising one or more
compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates
thereof, or enriched propolis, propolis resin, or propolis resin extact and cyclodextrin, and/or
when present the at least one additional anti-epithelial cancer agent, are particularly
contemplated. Topical formulations may be prepared as lotions, creams, ointments, pastes
or salves using known carriers for such applications. In certain embodiments, compositions
formulated for topical administration comprise alpha, beta or gamma-cyclodextrin.
In certain embodiments, topical formulations comprise one or more penetrants, such
as one or more alkyl lactates, one or more antioxidants, such as Vitamin E (alpha
tocopherol) or another naturally-occurring antioxidant including polyphenolic antioxidants
such as proanthocyanidins and chlorogenic, quinic, and ferulic acids, one or more photo
protectants or UV-protectants, such as TiO2 or carnosic acid, one or more lipids, collagen,
keratin or other proteins.
In certain embodiments, the topical compositions comprise one or more carriers that
are common in cosmetics, such as hydrophilic or lipophilic gelling agents, hydrophilic or
lipophilic active agents, preserving agents, antioxidants, solvents, fragrances, fillers, UV
protectants, pigments, odor absorbers and dyestuffs. Typically, the composition will contain
an amount conventionally used in the art, for example, from 0.01% to 20% relative to the
total weight of the composition. Depending on their nature and the specific embodiment,
these carriers are introduced into a lipid phase, into an aqueous phase, or into one or more phases, vesicles, such as one or more lipid vesicles, microparticles, or other components of the topical formulation.
In certain embodiments, and particularly when the composition is an emulsion, the
proportion of the lipid/fatty phase may range from 5% to 80% by weight, for example from
5% to 50% by weight relative to the total weight of the composition. The oils, emulsifiers
and co-emulsifiers contemplated for use in the composition in emulsion form are chosen
from those conventionally used in the art. When present, the emulsifier and co-emulsifier
are present in the composition in a proportion ranging from 0.3% to 30% by weight, for
example from 0.5% to 20% by weight, relative to the total weight of the composition.
In certain embodiments, the composition comprises one or more oils such as one or
more mineral oils, such as liquid petroleum jelly, oils of plant origin, such as avocado oil or
soybean oil, oils of animal origin, for example lanolin, synthetic oils, for example
perhydrosqualene, silicone oils, such as cyclomethicone, and fluoro oils, including
perfluoropolyethers. Fatty alcohols, such as cetyl alcohol, fatty acids and waxes, for
example carnauba wax or ozokerite, are also used as fatty substances in certain
embodiments.
In certain embodiments, the emulsifiers and co-emulsifiers are fatty acid esters of
polyethylene glycol, such as PEG stearate, or fatty acid esters of glycerol, such as glyceryl
stearate, or mixtures thereof.
The use of hydrophilic gelling agents is contemplated in certain formulations, where
such agents include carboxyvinyl polymers, such as carbomer, acrylic copolymers such as
acrylate/alkylacrylate copolymers, polyacrylamides, polysaccharides, natural gums and
clays, and lipophilic gelling agents including modified clays, for instance bentonites, metal
salts of fatty acids, hydrophobic silica and polyethylenes.
Dermabase cream, Unibase cream, and Vanicream are representative examples of
commercially available base creams for use as a pharmaceutically acceptable carrier in
certain embodiments.
The topical formulations will in certain embodiments also contain moisturizers,
depigmenting or pigmenting agents, antimicrobial agents, or free-radical scavengers.
In certain embodiments, topical compositions are formulated as aqueous formulations,
such as an aqueous skin cream, for example a water-in-oil or oil-in-water emulsion.
Such formulations may be administered directly, for example, applied directly on to a
wound, sprayed onto a surgical site, etc, or may be applied indirectly, such as by
impregnation into a bandage or dressing or sprayed onto surgical equipment, dressings and
the like.
Parenteral unit dosage forms comprising one or more compounds of formula (I) or one
or more pharmaceutically acceptable salts or solvates thereof, optionally with at least one
additional therapeutic agent, are also provided.
In one example, the anti-epithelial cancer composition is a powder that is obtained
after mixing a propolis tincture, for example a propolis tincture enriched in one or more of
the compounds of formula (I) or a pharmaceutically-acceptable salt or solvate thereof, with
cyclodextrin and one or more compounds of formula (I) or one or more pharmaceutically
acceptable salts or solvates thereof, then adding water and homogenizing the composition,
and then spray-drying or freeze-drying. Other exemplary anti-epithelial cancer
compositions of the present invention include solutions, including for example, those in
which propolis tincture or fraction thereof and cyclodextrin are mixed and then dispersed in
water, those in which propolis or materials with propolis contained and cyclodextrin are
independently dissolved or dispersed in water, and then admixed, for example by kneading,
and further those in which propolis powder or resin is firstly dissolved in another organic
solvent or organic solvent-water mixture in which it is soluble, such as for example ethanol, propylene glycol, ethyl acetate, isopropyl alcohol, and mixtures thereof with water, and the resultant solution is admixed with cyclodextrin, then added to water, and further mixed, for example by kneading and then dried by means known in the art, such as spray or freeze drying. Alternatively, water can be admixed with cyclodextrin at or below the solubility of cyclodextrin in water, to which propolis tincture is then admixed, further water is added and mixed, and then the resultant dispersion is dried by means known in the art, such as spray or freeze-drying. In certain embodiments, anti-epithelial cancer compositions prepared as powders as described above may be preferred, for example because they may maintain stronger anti-epithelial cancer activity or may maintain anti-epithelial cancer activity for a longer period than that of solutions of anti-epithelial cancer compositions prepared as described above.
The content of propolis, propolis resin or propolis resin extract enriched in at least one
compound of formula (I) and cyclodextrin of the present invention can be at any level as
long as the expected anti-epithelial cancer activity is realized. Similarly, the content of
compound(s) of formula (I), propolis, propolis resin or propolis resin extract and
cyclodextrin of the present invention can be at any level as long as the expected anti
epithelial cancer activity is realized.
Without wishing to be bound by any theory, the applicants believe that the propolis,
propolis resin, or propolis resin extract enriched in at least one compound of formula (I) in
the composition will be entirely encapsulated when the molar ratio of said propolis, propolis
resin, or propolis resin extract to cyclodextrin is no greater than 1:1.
In some embodiments the molar ratio of propolis, propolis resin, or propolis resin
extract enriched in at least one compound of formula (I) to cyclodextrin may exceed 1:1 in
the compositions. In such compositions the excess propolis, propolis resin, or propolis resin
extract will not be encapsulated by the cyclodextrin.
Other anti-epithelial cancer substances generally known can be combined with the
anti-epithelial cancer compositions, depending upon the application to which the
composition is to be put.
Without wishing to be bound by any theory, the applicants believe that the enhanced
anti-epithelial cancer activity observed in exemplary compositions of the present invention
comprising one or more compounds of formula (I) or one or more pharmaceutically
acceptable salts or solvates thereof and cyclodextrin may be due at least in part to a
synergy between the one or more compounds of formula (I) or one or more
pharmaceutically acceptable salts or solvates thereof, particularly when present as propolis
resin or concentrated fractions of propolis resin, and cyclodextrin. In certain embodiments,
the exemplary composition exhibiting a synergy is a composition comprising one or more
compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates
thereof, such as a propolis extract or fraction, propolis resin extract or a poplar extract or
exudate enriched in one or more compounds of formula (I) or one or more pharmaceutically
acceptable salts or solvates thereof, and alpha-cyclodextrin. In another contemplated
embodiment, the composition exhibiting a synergy is a composition comprising one or more
compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates
thereof, such as a propolis extract or fraction, propolis resin extract or a poplar extract or
exudate enriched in one or more compounds of formula (I) or one or more pharmaceutically
acceptable salts or solvates thereof, and gamma-cyclodextrin.
In one embodiment the present invention relates to use of propolis, propolis resin, or
propolis resin extract enriched in one or more compounds of formula (I) or one or more
pharmaceutically acceptable salts or solvates thereof and cyclodextrin, such as propolis and
alpha-cyclodextrin and/or gamma-cyclodextrin, optionally with at least one anti-epithelial
cancer agent, in the manufacture of a food, drink, food additive, drink additive, dietary supplement, nutritional product, medical food, nutraceutical, cosmeceutical, medical device, medical supply, medicament or pharmaceutical.
In one embodiment, exemplary compositions comprising propolis, propolis resin,
propolis resin extract, poplar extracts, or cyclodextrin is formulated for oral administration.
In another embodiment, the composition is formulated for parenteral, including topical,
administration. In certain embodiments, the composition is for inducing apoptosis, treating
or preventing a skin cancer, maintaining or improving skin health or one or more other uses
as described above.
In one embodiment the composition is in the form of a powder, a tablet, a caplet, a
pill, a hard or soft capsule or a lozenge.
In one embodiment the composition is in the form of a sachet, a dispensable powder,
granules, a suspension, an elixir, a liquid, a drink, or any other form that can be added to
food or drink, including for example water or fruit juice. In one embodiment the
composition is an enteral product, a solid enteral product or a liquid enteral product.
In one embodiment, the composition is in the form of a cream, ointment, a paste, a
drop solution including eye drops or ear drops, an inhaler or as an inhalable composition, a
dressing, a pad, or a spray.
In one embodiment the composition further comprises one or more constituents (such
as antioxidants) which prevent or reduce degradation of the composition during storage or
after administration.
In one embodiment, compositions useful herein include any edible consumer product,
particularly one which is able to carry one or more cyclodextrins. When the composition
comprises a proteinaceous factor as the at least one additional anti-epithelial cancer agent,
the edible consumer product is one able to carry protein. Examples of suitable edible
consumer products include baked goods, powders, liquids, confectionary products,
reconstituted fruit products, snack bars, food bars, muesli bars, spreads, sauces, dips, dairy products including ice creams, yoghurts and cheeses, drinks including dairy and non-dairy based drinks (such as milk drinks including milk shakes, and yogurt drinks), milk powders, sports or nutritional supplements including dairy and non-dairy based sports or nutritional supplements, food additives such as protein sprinkles and dietary supplement products including daily supplement tablets. Within this embodiment, a composition useful herein may also be an infant formula, in powder or liquid form. Suitable nutraceutical compositions useful herein may be provided in similar forms. Particularly contemplated are compositions additionally comprising milk or one or more milk products or components of milk, such as milk protein, whey protein, colostrums, milk fat, or any fractions of milk or one or more milk products or components of milk, such as a milk fat fraction, a milk protein fraction, a whey protein fraction, a colostrums fraction, or the like.
Compositions useful herein may further include other factors such as calcium, zinc,
magnesium, selenium, vitamin C, vitamin D, vitamin E, vitamin K2, complex carbohydrates,
edible or cooking oils including palm, olive, soybean, canola, corn, sunflower, safflower,
peanut, grape seed, sesame, nut, almond, cashew, hazelnut, macadamia, pecan, pistachio,
and walnut, and other edibles include acai, amaranth, apricot, argan, artichoke, avocado,
babassu, bean, blackcurrant seed, borage seed, borneo tallow nut, bottle gourd, buffalo
gourd, carob pod (algaroba), cohune, coriander seed, evening primrose, false flax, hemp,
kapok seed, lallemantia, meadowfoam seed, mustard, okra seed (hibiscus seed), perilla
seed, pequi, pine nut, poppyseed, prune kernel, pumpkin seed, quinoa, ramtil, rice bran,
tea (camellia), thistle, watermelon seed, or wheat germ oil, or a combination thereof.
In various embodiments, compositions may comprise at least one additional
therapeutic agent, wherein the at least one additional therapeutic agent is an antibiotic,
such as an aminoglycoside, such as amikacin, gentamicin, kanamycin, neomycin, netilmicin,
streptomycin, tobramicin, or paromomycin; an ansamycin, such as geldanamycin, or
herbimycin; a carbacephem, such as loracarbef; carbapenems, such as, ertapenem, doripenem, imipenem/cilastatin, or meropenem; cephalosporins (first generation), such as cefadroxil, cefazolin, cefalotin or cefalothin, or cefalexin; cephalosporins (second generation), such as cefaclor, cefamandole, cefoxitin, cefprozil, or cefuroxime; cephalosporins (third generation), such as cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, or ceftriaxone; cephalosporins (fourth generation), such as cefepime; cephalosporins (fifth generation), such as ceftobiprole; glycopeptides, such as teicoplanin, or vancomycin; macrolides, such as azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, or spectinomycin; monobactams, such as aztreonam; penicillins, such as amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, meticillin, nafcillin, oxacillin, penicillin, piperacillin, or ticarcillin; polypeptides, such as bacitracin, colistin, or polymyxin b; quinolones, such as ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, or ofloxacin; sulfonamides, such as mafenide, sulfonamidochrysoidine (archaic), sulfacetamide, sulfadiazine, sulfamethizole, sulfanilimide (archaic), sulfasalazine, sulfisoxazole, trimethoprim, or trimethoprim-sulfamethoxazole (co-trimoxazole) (tmp-smx); tetracyclines, such as demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline; others such as arsphenamine, chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, quinupristin/dalfopristin, rifampicin (rifampin in US), thiamphenicol, tinidazole, dapsone, clofazimine; or a cyclic lipopeptides, such as daptomycin, a glycylcycline, such as tigecycline, or an oxazolidinones, such as linezolid.
In other embodiments, the at least one additional therapeutic agent is an antifungal,
such as a polyene antifungal, such as natamycin, rimocidin, filipin, nystatin, amphotericin B,
candicin; imidazoles, such as miconazole, ketoconazole, clotrimazole, econazole, bifonazole,
butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, or tioconazole; triazoles, such as fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, or terconazole; thiazoles such as abafungin; allylamines, such as terbinafine, amorolfine, naftifine, or butenafine; echinocandins, such as anidulafungin, caspofungin, or micafungin; others such as benzoic acid, ciclopirox, tolnaftate, undecylenic acid, flucytosine or 5-fluorocytosine, griseofulvin, haloprogin, and sodium bicarbonate; or alternatives such as allicin, tea tree oil, citronella oil, iodine, lemon grass, olive leaf, orange oil, palmarosa oil, patchouli, lemon myrtle, neem seed oil, coconut oil, zinc, or selenium.
Alternatively the agent is selected from any of those described herein.
The efficacy of a composition useful according to the invention can be evaluated both
in vitro and in vivo. See, e.g., the examples below. Briefly, in one embodiment the
composition can be tested for its ability, to for example, inhibit neoplastic cell proliferation
in vitro. For in vivo studies, the composition can be fed to, injected into, or topically applied
to an animal (e.g., a mouse) and its effects on skin cancer cell survival, proliferation,
metastasis, or one or more symptoms of a skin cancer or associated disease or disorder are
then assessed. Based on the results, an appropriate dosage range, frequency, and
administration route can be determined.
The compositions useful herein may be used alone or in combination with one or more
other anti-epithelial cancer agents, or one or more additional therapeutic agents. The anti
epithelial cancer agent or additional therapeutic agent may be or comprise a food, drink,
food additive, drink additive, food component, drink component, dietary supplement,
nutritional product, medical food, nutraceutical, cosmeceutical, medical device, medical
supply, medicament or pharmaceutical. The anti-epithelial cancer agent or additional
therapeutic agent is preferably effective to attenuate one or more neoplastic diseases or
disorders or one or more of the symptoms of one or more neoplastic diseases or disorders,
or otherwise confer a benefit on the subject to whom it is administered. Preferred therapeutic agents include therapeutic food factors, immunogenic or immunostimulatory agents, wound healing agents, and the like.
It should be understood that the additional anti-epithelial cancer or therapeutic agents
listed above (both food based and pharmaceutical agents) may also be employed in a
method according to the invention where they are administered separately, simultaneously
or sequentially with a composition useful herein.
As will be appreciated, the dose of the composition administered, the period of
administration, and the general administration regime may differ between subjects
depending on such variables as the severity of symptoms of a subject, the type of disorder
to be treated, the mode of administration chosen, and the age, sex and/or general health of
a subject. However, by way of general example, from about 1 mg to about 5000 mg per kg
body weight of a composition useful herein is administered, 1 mg to about 4000 mg per kg
body weight of a composition useful herein is administered, 1 mg to about 3000 mg per kg
body weight of a composition useful herein is administered, 1 mg to about 2000 mg per kg
body weight of a composition useful herein is administered, 1 mg to about 1000 mg per kg
body weight of a composition useful herein is administered, per administration or per day,
preferably about 5 to about 100 mg per kg, preferably per day. In one embodiment, the
administration is of from about 0.05 mg to about 250 mg per kg body weight of a
composition useful herein.
In various embodiments, sufficient composition is administered to deliver from about
0.001 mg to about 50 mg of a compound of formula (I) or a pharmaceutically acceptable
salt or solvate thereof per kg body weight, from about 0.001 mg to about 40 mg per kg
body weight, from about 0.001 mg to about 30 mg per kg body weight, from about 0.001
mg to about 20 mg per kg body weight, from about 0.001 mg to about 10mg per kg body
weight, from about 0.001 mg to about 5 mg per kg body weight, from about 0.001 mg to
about 1 mg per kg body weight, from about 0.001 mg to about 0.5 mg per kg body weight, from about 0.001 mg to about 0.1 mg per kg body weight, or from about 0.001 mg to about
0.05 mg of a compound of formula (I) or a pharmaceutically acceptable salt or solvate
thereof per kg body weight, per administration or per day.
It should be appreciated that administration may include a single dose, such as a
single daily dose, or administration of a number of discrete divided doses as may be
appropriate. It should be understood that a person of ordinary skill in the art will be able
without undue experimentation, having regard to that skill and this disclosure, to determine
an effective dosage regime (including dose and timing of administration) for a given
condition.
The present invention also relates to a dietary, nutraceutical, cosmeceutical or oral
pharmaceutical composition comprising, consisting essentially of or consisting of one or
more compounds of formula (I) or one or more pharmaceutically acceptable salts or
solvates thereof, optionally together with propolis or a material comprising propolis in
combination with cyclodextrin. In certain embodiments the composition consists essentially
of about 1 to 99 wt % propolis, propolis resin, or propolis resin extract enriched in one or
more compounds of formula (I) or one or more pharmaceutically acceptable salts or
solvates thereof and about 1 to 80 wt % cyclodextrin. For example, the composition
consists essentially of about 20 to 80 wt % propolis, propolis resin, or propolis resin extract
enriched in one or more compounds of formula (I) or one or more pharmaceutically
acceptable salts or solvates thereof and about 20 to 80 wt % cyclodextrin. In another
example, the composition consists essentially of about 20 to 40 wt % propolis, propolis
resin, or propolis resin extract enriched in one or more compounds of formula (I) or one or
more pharmaceutically acceptable salts or solvates thereof and about 60 to 80 wt %
cyclodextrin.
Dietary, nutraceutical, cosmeceutical or oral pharmaceutical compositions comprising,
consisting essentially of or consisting of propolis, propolis resin, or propolis resin extract enriched in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof or a material comprising propolis, propolis resin, or propolis resin extract that is encapsulated by cyclodextrin are provided. In certain embodiments the composition consists essentially of about 1 to 30 wt % propolis, propolis resin, or propolis resin extract enriched in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof and about 70 to 99 wt
% cyclodextrin. For example, the composition consists essentially of about 10 to 25 wt
% propolis, propolis resin, or propolis resin extract enriched in one or more compounds of
formula (I) or one or more pharmaceutically acceptable salts or solvates thereof and about
75 to 90 wt % cyclodextrin. In another example, the composition consists essentially of
about 20 to 30 wt % propolis, propolis resin, or propolis resin extract enriched in one or
more compounds of formula (I) or one or more pharmaceutically acceptable salts or
solvates thereof and about 70 to 80 wt % cyclodextrin.
In one embodiment a composition comprises propolis, propolis resin, or propolis resin
extract enriched in one or more compounds of formula (I) or one or more pharmaceutically
acceptable salts or solvates thereof or a propolis fraction enriched in one or more
compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates
thereof. In one embodiment the composition comprises at least about 1, 5, 10, 15, 20, 25,
30, 35, 40, 45, 50, 60, 70, 80, 90, or 99% by weight propolis, propolis resin, propolis resin
extract or a propolis fraction, and useful ranges may be selected from any of these values
(for example, from about 1 to about 25% by weight, from about 1 to about 30% by weight,
from about 5 to about 30% by weight, from about 15 to about 30% by weight, from about
20 to about 30% by weight, from about 25 to about 30% by weight, from about 10 to about
50% by weight, from about 15 to about 50% by weight, from about 40 to about 99% by
weight, from about 45 to about 99% by weight, from about 50 to about 99% by weight,
from about 55 to about 99% by weight, from about 60 to about 99% by weight, from about
65 to about 99% by weight, from about 70 to about 99% by weight, from about 75 to about
99% by weight, from about 80 to about 99% by weight, from about 85 to about 99% by
weight, from about 90 to about 99% by weight, or from about 95 to about 99% by weight).
In one embodiment a composition comprises cyclodextrin, for example alpha
cyclodextrin and/or gamma-cyclodextrin. In one embodiment the composition comprises at
least about 1,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,oratleast
about 90% by weight cyclodextrin, and useful ranges may be selected from any of these
values (for example, from about 1 to about 99% by weight, from about 5 to about 99% by
weight, from about 10 to about 99% by weight, from about 15 to about 99% by weight,
from about 20 to about 99% by weight, from about 25 to about 99% by weight, from about
30 to about 99% by weight, from about 35 to about 99% by weight, from about 40 to about
99% by weight, from about 45 to about 99% by weight, from about 50 to about 99% by
weight, from about 55 to about 99% by weight, from about 60 to about 99% by weight,
from about 65 to about 99% by weight, from about 70 to about 99% by weight, from about
75 to about 99% by weight, from about 80 to about 99% by weight, from about 85 to about
99% by weight, from about 90 to about 99% by weight, or from about 95 to about 99% by
weight).
When used in combination with another anti-epithelial cancer agent or therapeutic
agent, the administration of a composition useful herein and the other anti-epithelial cancer
agent or therapeutic agent may be simultaneous or sequential. Simultaneous administration
includes the administration of a single dosage form that comprises all components or the
administration of separate dosage forms at substantially the same time. Sequential
administration includes administration according to different schedules, preferably so that
there is an overlap in the periods during which the composition useful herein and other
therapeutic agent are provided.
Additionally, it is contemplated that a composition in accordance with the invention
may be formulated with additional active ingredients which may be of benefit to a subject in
particular instances. For example, therapeutic agents that target the same or different
facets of the disease process may be used.
Accordingly, "foods and beverages comprising anti-epithelial cancer compositions" of
this invention can be used for general foods and health food. Since the anti-epithelial cancer
compositions of the present invention mask the taste of propolis, they can be eaten as they
are or in the form of powder. They can be used as an ingredient or raw material for cake,
biscuit, cookie, chocolate, sweets and other confectionary, including drops or chewing gum.
The compositions may be added to water as a drink, can be used as a taste modifier for
beverages such as milk, tea, coffee, hot chocolate, etc., and as an ingredient or raw
material for fruit juice beverages, sports drink, etc.
Exemplary anti-epithelial cancer compositions and methods for preparing such
compositions will now be described with reference to the following examples.
Example 1: Initial bioassay guided fractionation of propolis tincture
This example describes an assessment of the anti-gastrointestinal cancer activity of
fractions of propolis produced by preparative chromatography. This study was performed
using proliferation assays in the human colon cancer adenocarcinoma cell line, DLD-1.
2O Production of propolis tincture fractions by column chromatography
Fractionation was carried out using a glass column packed with Merck Lichroprep CI8
reversed phase stationary phase (16 x 4 cm) which had been washed with methanol
(MeOH) (200 ml) and equilibrated with 20% aqueous ethanol (EtOH) (500 ml). Propolis
tincture dry solids (5.446 g) dissolved in EtOH (5 ml) was loaded onto the top of the column
using a piston pump. Elution was carried out as a stepped gradient (250 ml) consisting of
20%, 30%, 40%, 50%, 60%, 70%, 80%, and 90% aqueous EtOH, followed by two 100%
EtOH steps, then elution with 2-propanol (IPA),ethyl acetate (EtOAc), acetone, and
chloroform (CHCl3). Solvent from the various fractions was removed under vacuum on a
rotary evaporator followed by freeze drying overnight. The two 100% EtOH fractions were
pooled as were the remaining four non-polar fractions (IPA, EtOAc, acetone, and CHCl3) for
biological assay work due to their relatively low masses. The fractions are shown in Table 1
according to the percentage of ethanol used in the elution step from the column, e.g. 20%,
30%, 40%, 50%, 60%, 70%, 80%, and 90% aqueous EtOH, and 100% EtOH.
Table 1. Propolis fractionation mass and test sample numbers
Sample Fraction mass / of recovered Test Sample ID Elution solvent # (g) mass
1 Propolis fraction 1 20% EtOH 0.1127 2.07
2 Propolis fraction 2 30% EtOH 0.0658 1.21
3 Propolis fraction 3 40% EtOH 0.2408 4.42
4 Propolis fraction 4 50% EtOH 0.5022 9.22
5 Propolis fraction 5 60% EtOH 2.2333 41.01
6 Propolis fraction 6 70% EtOH 0.9843 18.07
7 Propolis fraction 7 80% EtOH 0.4697 8.62
8 Propolis fraction 8 90% EtOH 0.2413 4.43
9 Propolis fraction 9 100% EtOH (2) 0.3018 5.54
10 Propolis fraction 10 IPA, EtOAc, 0.042 0.77
acetone, and
CHC13
11 Propolis tincture dry solids
l0 Materials and methods for the anti-gastrointestinal cancer anti-proliferative assay for DLD-1 human colon adenocarcinoma cells, KYSE-30 human oesophageal squamous cell carcinoma and NCI-N87 human gastric carcinoma
Test samples shown above in Table 1 obtained by the fractionation of propolis tincture
dry solids were assessed for their ability to modulate the viability and proliferation of human
colorectal adenocarcinoma cells (DLD-1) as assessed by the MTT assay. The propolis
tincture dry solids starting material was also included in the bioassay. A positive control, 5
fluorouracil (5-FU) was included in addition to an unsupplemented cell control (negative control) in the study. In later examples, test samples were also assessed for the ability to modulate the viability and proliferation of human oesophageal cells (KYSE-30) and human gastric carcinoma cells (NCI-N87) as assessed by the MTT assay.
Description of test materials and test methods
Human gastro-intestinal cancer cell lines DLD-1, KYSE-30 and NCI-N87 were revived
from cryostorage and cultured in the presence of the test and reference samples. The
culture conditions for the cells were those described by the supplier of the cells (ATCC). An
MTT assay was then performed on the cultures to determine the effect of the samples on
the cell proliferation.
The methodology was based on the procedures reported by:
Smolka, AJ, Goldenring, JR, Gupta, S and Charles E Hammond, CE. Inhibition of gastric H,K
ATPase activity and gastric epithelial cell IL-8 secretion by the pyrrolizine derivative
ML 3000. (2004). BMC Gastroenterology. 4: 4.
Chailler, P and Menard, D (2005). Establishment of Human Gastric Epithelial (HGE) Cell
Lines Exhibiting Barrier Function, Progenitor, and Prezymogenic Characteristics.
Journal of Cellular Physiology 202: 263-274.
Trainer, D.L., Kline, T., McCabe, F.L., Faucette, L.F., Field, J., Chaikin, M., Anzano, M.,
Rieman, D., Hoffstein, S., Li, D-J., Gennaro, D., Buscarino, C., Lynch, M., Poste, G.
And Greig, R. (1988). Biological characterization and oncogene expression in
human colorectal carcinoma cells lines. International Journal of Cancer 41: 287
296.
Shimada, Y, Imamura, M, Wagata, T, Yamaguchi, N, Tobe, T. (1992) Characterization of 21
newly established Esophageal Cancer Cell Lines. Cancer 69: 277 - 284.
Sutter, AP, Hopfner, M, Huether, A, Maaser, K, Scherubi, H. (2006) Targeting the epithelial
growth factor receptor by erlotinib (Tarceva T M ) for the treatment of esophageal
cancer. Inter, J Cancer. 118: 1814 - 1822
Pelyi, I. (1989) Heterogeneity of the Response to Inducers of Differentiation and to
Cytostatics of Tumor Cell Populations. Pathology Research & Practice. 184: 11-17.
Fritzsche, C, Zeller, G, Knaup, KX, Roemer, K. (2004) No anti-apoptotic effects of single
copies of mutant p33 genes in drug-treated tumor cells. Anti-Cancer Drugs. 15: 679
688.
Yang, Y, Zhou, Z, He, S, Fan, T, et al. (2012) Treatment of prostate carcinoma with
(Galectin-3)-targeted HPMA copolymer-(G3-C12)-5-Fluorouracil conjugates.
Biomaterials. 33: 2260-2271.
Nakagawa, Y., Iinuma, M., Naoe, T., Nozawa, Y. And Akao, Y. (2007). Characterized
mechanism of a-mangostin-induce cell death: Caspase-independent apoptosis with
release of endonuclease-G from mitochondria and increased miR-143 expression in
human colorectal cancer DLD-1 cells. Bioorganic & Medicinal Chemistry 15: 5620
5628.
Minegaki, T., Takara, K., Hamaguchi, R., Tsujimoto, M. And Nishiguchi, K. (2013). Factors
affecting the sensitivity of human-derived esophageal carcinoma cell lines to 5
fluorouracil and cisplatin. Oncology Letters 5: 427-434.
Nakamura, A., Nakajima, G., Okuyama, R., Kuramochi, H., Kondoh, Y., Kanemura, T.,
Takechi, T., Yamamoto, M. And Hayashi, K. (2014). Enhancement of 5-fluorouracil
induced cytotoxicity by leucovorin in 5-fluorouracil-resistant gastric cancer cells with
upregulated expression of thymidylate synthase. Gastric Cancer 17: 188-195.
Tankiewicz-Kwedlo, A., Pawlak, D., Domaniewski, T. And Buczko, W. (2010). Effect of
erythropoietin, 5-fluorouracil and SN-38 on the growth of DLD-1 cells.
Pharmacological Reports 62: 926-937.
Sample Preparation
Working solutions were prepared by dissolving the test fractions in 15% ethanol
(ETOH)/HBSS to a concentration of 2 mg/ml solids.
Experimental Procedures Characterisation of the Test System 1. Human colorectal adenocarcinoma cells were obtained from ATCC (CCI-221, DLD-1). 2. Human gastric carcinoma cells were obtained from ATCC (CRL-5822, NCI-N87). 3. Human oesophageal squamous cell carcinoma cells were obtained from Sigma Aldrich (ECACC, KYSE-30) 4. The DLD-1 cell medium obtained from GIBCO was Dulbecco's Modified Eagle's Medium (DMEM) had 10% Foetal Bovine Serum (FBS), 100U/ml Penicillin and 100mg/ml Streptomycin added. The medium was stored at 40 C 5. The NCI-N87 cell medium obtained from Sigma was RPMI-1640 medium modified to contain 2 mM L-glutamine, 10 mM HEPES, 1 mM sodium pyruvate, 4500 mg/L glucose, and 1500 mg/L sodium bicarbonate. The medium was stored at 40 C 6. The KYSE-30 cell medium obtained from Sigma was Ham's F12:RPMI-1640 (50:50) medium modified to contain 2 mM L-glutamine. For the complete medium 10% FBS, 100U/ml Penicillin and 2.5pg/ml Gentamicin was added. The medium was stored at 4 0 C. 7. Penicillin-streptomycin solution consisting of 10000units/mL penicillin, 10 mg/ml streptomycin in 0.9% NaCl, stored at -20 0 C was obtained from Sigma (#P-0781). 8. Trypsin-EDTA solution consisting of 0.25% Trypsin/EDTA was obtained from Invitrogen (15400054). 9. Phosphate buffered saline (PBS) was prepared in-house. 10. Hanks Balanced Salt Solution (HBSS), stored at 40 C was obtained from GIBCO (14185-052). 11. Foetal Bovine Serum, stored at -200 C was obtained from GIBCO (10091-148). 12. MTT Reagent, 100 mg/vial, obtained from SIGMA (M-2128) was dissolved in PBS at 10 mg/ml and stored at -20 C. 5 mg/ml MTT solution was prepared in PBS and stored at 4OC as working solution. 13. MTT lysis buffer consisting of 10 % sodium dodecyl sulphate (SDS)/45% Dimethyl Formamide was prepared by dissolving 20 g SDS in 100 mL of double-distilled water (DDW), adding 90 mL of Dimethyl Formamide, adjusting the pH to 4.7 using glacial acetic acid, and then diluting with DDW to a final volume of 200 ml. 14. 5-Fluorouracil (5-FU) was obtained from Sigma (F-6627). Working solutions in 15 %
ETOH/HBSS were prepared as required and then diluted to the required concentration just prior to bioassay. Medium preparation
The medium for the propagation of each of the cells lines is given above. Each
medium was prepared following the instructions of the manufacturer and supplemented with
penicillin-streptomycin solution (10ml per litre). FBS (at 10%) was added just before use.
Culturing of cells 1. Each of the cell lines were revived from cryostorage. 2. Following initial propagation using the media described above (see Medium Preparation), the culture was sub-cultured using the trypsin-EDTA as follows. The media was removed and 5ml of the trypsin-EDTA solution added and incubated at 37°C for 5 min or until all the cells had detached. The trypsin was neutralised by adding an equal volume of DMEM medium and the culture centrifuged at 300g (1200rpm) for 5 min at 4°C. 3. The supernatant was decanted and the cell pellets re-suspended in medium DMEM, FBS (10%), penicillin (100units/ml), streptomycin (100pg/ml). The cells were cultured at 37°C in 5% C0 2 /95% air. 4. After reaching confluence, the cells were detached using trypsin-EDTA and centrifuged as described in 2 above. 5. The supernatants were discarded and the cells re-suspended in DMEM and supplements as described in 3 above at 1.0 x 104 cells per ml. 6. Into each well of three 96 well plates, 180pl of the cells (1,800 cells/well) or medium was added. The plates were incubated at 5% C0 2 /95% air at 37°C for 48 h which was sufficient to allow the cells to adhere. 7. To each well, 20pl of each of the test samples or positive control was added. For the 'medium' or'cells only' controls, 20pl of 15%ETOH/HBSS was added to each well. Each sample was assessed in replicates of 3 - 6, while the controls on each of three micro-titer plates were assessed in replicates of 3 - 9 (combined triplicates). The final concentration of the sample in each well was 200 pg/ml unless noted. 8. The total volume in each well was 200pl. 9. The plates were incubated at 37°C in 5% C0 2 /95% air for 19 h. Cell Proliferation Assay 1. On completion of the incubation, 20 pl of MTT working solution (5 mg/ml) was added to all wells and incubated for 3-4 hr at 370 C in 5% C0 2/95% air. 2. During this incubation period it was noted that a strong colour unexpectedly appeared in some of the wells of a number of samples, in both the Cells plus Sample wells and the Sample plus Medium Blank wells. At the end of this period the supernatants were removed from each well and each well was gently washed with HBSS twice, to remove the purple colour, before adding the MTT lysis buffer as described in Step 3 below.
3. 100 pl of MTT lysis buffer was then added and the plates incubated overnight at 37 0 C in 5% C02/95% air. The plates were centrifuged at 1200rpm for 10 minutes to pellet any remaining insoluble material. From each well 200pl aliquots were transferred to fresh 96 well plates. The plates were read by a VersaMax microplate reader at 570 nm. 4. Results were expressed as the percentage proliferation of cells cultured in the presence of the sample in comparison to the cells only control. The blank reading was subtracted from all wells as a background reading.
Results
A summary of the effects of controls and test samples on the proliferation of the DLD
1 cells for propolis fractions S#1 - S#10 and comparative propolis dry solids S#11 is
presented in Table 2 below, where NC = Negative Control (cells only), PC = Positive Control
(5-fluorouracil, tested at 7.50 ng/ml). In the Table, OD is Optical Density measured at 570
nm; SEM is the Standard Error of the Measurement associated with the Mean Optical
Density value measured; p is the probability value that the measurement is statistically
significant via the Student t-test, here taken to be < 0.05 (NS = not significant);
% inhibition is the percentage reduction of proliferation compared to the negative control, with
a large number indicating the test compound has anticancer proliferation potential.
Table 2. Effects of the propolis fraction samples on the proliferation of DLD-1 cells.
0 Sample ID & number of replicates, Mean (OD SEM p Values / Inhibition
n 570nm) (<0.05)
NC-1 Cells Only, n=9 0.7047 0.0252 1.00 0.00
PC-1 Cells - 5-FU, 7.50ng/ml, n=9 0.6575 0.0172 NS 6.69
Cells - S#1. Propolis Fraction #1, 200 0.2246 0.0297 2E-08 68.13
pg/ml, n=6
Cells - S#2. Propolis Fraction #2, 200 0.1919 0.0250 2E-08 72.77
pg/ml, n=5
Cells - S#3. Propolis Fraction #3, 200 0.5359 0.0153 2.3E-04 23.95
pg/ml, n=6
Cells - S#4. Propolis Fraction #4, 200 0.5779 0.0203 3.2E-03 17.99
pg/ml, n=6
Cells - S#5. Propolis Fraction #5, 200 0.4159 0.0172 1.2E-06 40.97 pg/ml, n=6
Cells - S#6. Propolis Fraction #6, 200 0.6488 0.0197 NS 7.93
pg/ml, n=6
Cells - S#7. Propolis Fraction #7, 200 0.6037 0.0135 9.2E-03 14.32
pg/ml, n=6
Cells - S#8. Propolis Fraction #8, 200 0.1970 0.0152 1E-08 72.04
pg/ml, n=6
Cells - S#9. Propolis Fraction #9, 200 0.5932 0.0194 7.OE-03 15.82
pg/ml, n=6
Cells - S#10. Propolis Fraction #10, 0.6375 0.0309 NS 9.54
200 pg/ml, n=6
Cells - S#11. Propolis tincture dry 0.4750 0.0207 2E-05 32.59
solids, 200 pg/ml, n=6
The most active propolis fractions were found to be fractions S#1, S#2, S#5 and S#8.
Propolis fractions S#1, S#2 and S#5 contained known propolis phenolics and flavonoids and
so were not investigated further in this work. Further studies were conducted to determine
the compounds present in propolis fraction S#8, which was shown by HPLC to not contain
any previously identified phenolic compounds. These studies are described in Example 2.
Example 2: Bioassay guided fractionation of the non-phenolic fraction
This example describes the further bioassay-guided fractionation of the propolis
fraction S#8 prior to compound identification. Four further sub-fractions numbered S#28 to
S#31 were produced. This study was performed using the proliferation of the colon cancer
adenocarcinoma cell line DLD-1 by MTT assays as described in Example 1.
Preparative HPLC to produce sub-fractions S#28 to S#31
The 90% aqueous EtOH elution fraction (propolis fraction S#8) produced for
Example 1 was further fractionated by preparative HPLC. The propolis fraction S#8 was
dissolved in neat EtOH, and then chromatographed by preparative HPLC on a Phenomenex
Synergi C-12 column (4p,-RP Max 80A 250 x 30 mm) using a Gilson 321 preparative pump
and Agilent 1100 series diode array detector. Injection volumes of between 0.5 and 1.5 ml were employed. A flow rate of 20 ml/min. was employed. Solvents were 80% aqueous
MeOH (containing 0.1% TFA) and EtOAc/MeOH (4:1 vol/vol). The initial eluent composition
consisted of the 80% aqueous methanol. The solvent composition was held for 5 minutes at
the initial conditions before the EtOAc/MeOH solvent concentration was increased linearly to
100% over 35 minutes. The chromatography was carried out at room temperature (18
200C). Fractions were collected manually with online detection carried out at 210 nm, 268
nm and 327 nm and also by evaporative light scattering detection (ELSD). The main
components of this fraction were quite non-polar, eluting late in the chromatogram, and
showed minimal UV absorption at the wavelengths typically used for analysis on other
propolis fractions containing phenolics, i.e., 268 and 327 nm. However, ELSD revealed a
complex mix of components. Due to the destructive nature of ELSD preparative HPLC
fractions were collected manually with online detection carried out at 210 nm. As the
chromatography did not produce distinct isolated peaks but rather broad rises and falls in
the baseline four fractions were collected during the run and all were prepared for biological
assay.
Materials and methods for the DLD-1 colon cancer anti-proliferative assay
Test samples shown below in Table 3 were assessed for their ability to modulate the
viability and proliferation of human colorectal adenocarcinoma cells (DLD-1) as assessed by
the MTT assay. A positive control, 5-fluorouracil (5-FU) was included in addition to an
unsupplemented cell control (NC, negative control) in the study. The concentration of 5-FU
was increased from Example 1 to induce a stronger antiproliferative response. The DLD-1
anti-proliferation assay was performed as described in Example 1.
Table 3. Test Samples Sample No Test Sample ID and Sample No Test Sample and concentration concentration
S#28 90% F1, 200 pg/ml NC-1 Cells only
S#29 90% F2, 200 pg/ml PC-1 Cells + 5-FU 0.65 pg/ml
S#30 90% F3, 200 pg/ml PC-2 Cells + 5-FU 1.95 pg/ml
S#31 90% F4, 200 pg/ml
The samples were dissolved as working solutions at 2 mg/ml in 15% EtOH in HBSS.
In the assay the final concentration of the samples was 200 pg/ml, with a final EtOH
concentration of 1.5%.
Results and Discussion
A summary of the effects of the positive control and test samples on the proliferation
of the cells after 24 hours incubation is presented in Table 4, where NC = Negative Control
(cells only), PC = Positive Control (5-fluorouracil, tested at 0.65 and 1.95 pg/ml). In the
Table, OD is Optical Density measured at 570 nm; SEM is the Standard Error of the
Measurement associated with the Mean Optical Density value measured; p is the probability
value that the measurement is statistically significant via the Student t-test, here taken to
be < 0.05 (NS = not significant); % inhibition is the percentage reduction of proliferation
compared to the negative control, with a large number indicating the test compound has
anticancer proliferation potential.
Table 4. Effect of the propolis sub-fraction samples on DLD-1 cell proliferation.
0 Sample ID & number of Mean (OD 570nm) SEM P Values (<0.05) / Inhibition
replicates, n
NC-1 Cells only, n=12 0.3239 0.0135 NS 0.00
PC-1 Cells + 5-FU, 0.65 pg/ml, 0.3023 0.0154 NS 6.66
n=12
PC-2 Cells + 5-FU, 1.95 pg/ml, 0.2689 0.0116 5.3E-03 16.96
n=12
Cells + S#28. 90% F1, n=6 0.1909 0.0137 1.3E-05 41.06
Cells + S#29. 90% F2, n=6 0.2528 0.0106 3.3E-03 21.96
Cells + S#30. 90% F3, n=5 0.0000 N/A N/A 100
Cells + S#31. 90% F4, n=6 0.2776 0.0118 4.2E-02 14.30
All of the propolis sub-fraction samples tested inhibited the proliferation of the DLD-1
colon cancer cells. The most active fraction was S#30 90 % F3, which completely inhibited
proliferation and was cytotoxic at the concentration tested. Further work was carried out in
Example 3 to identify the nature of the bioactive compounds present in the test samples
used in Examples 1 (propolis fraction S#8) and 2 (propolis sub-fraction S#30).
Example 3: Identification of glycerides in propolis as active compounds
This example describes the isolation and identification of novel dihydroxy fatty acid
glycerides from NZ propolis resin fractions equivalent to Example 1 (propolis fraction S#8)
and 2 (propolis sub-fraction S#30). 1 gram of 40 % propolis tincture containing 40
% propolis resin (400 mg dry solids) was fractionated using a silica gel column using a
stepwise solvent gradient to produce 14 fractions with weight distribution given in Table 5.
Each fraction was analysed by UHPLC using both a UV (268 nm for detection of phenolics)
and ELSD detector (for detection of all compounds). Propolis resin and selected fractions
were also analyzed by LC-MS to enable structural elucidation. Purified subfractions were
also analysed by NMR. Washing the column sequentially with hexane, hexane/diethyl ether
and diethyl ether eluted most of the phenolic material from the silica (fractions 1-2; 3-7; 8
9 respectively) including flavonoids, caffeate and ferulate esters. A brown coloured fraction
remained on the silica. Elution of the brown colour began when ethyl acetate was employed
(fractions 11-12). Most of the remaining dark colour was then eluted with acetone and
methanol (fractions 13, 14). The mass distribution shows that most of the propolis mass is
in the diethyl ether fractions which had a light yellow colour, however a significant
percentage of the total mass was eluted in the fractions eluted with ethyl acetate (fractions
11, 12). Water soluble material was recovered in fractions 13, 14 or retained on the
column.
Table 5. Weight and solvent gradient for silica gel fractionation of propolis.
Fraction Eluant Volume (ml) Weight (mg) / of total
eluted
1 Hexane 10 1 0.3
2 Hexane 10 <1 < 0.3
3 20%/ ether /hexane 10 1 0.3
4 400/ ether /hexane 10 2 0.6
5 40% ether/hexane 10 8 2.3
6 60%/ ether /hexane 10 10 2.8
7 60%/ ether /hexane 10 62 17.5
8 Diethyl ether 10 70 19.8
9 Diethyl ether 10 51 14.4
10 Dichloromethane 20 53 15.0
11 Ethyl acetate 20 47 13.3
12 Ethyl acetate 20 38 10.7
13 Acetone/ methanol 11 3.1
14 Methanol 3 0.8
Results and discussion
The novel compounds appeared as sharp peaks in the 34-44 minutes region of an
ELSD chromatogram of fractions 12, 13. The late peaks observed in the ELSD which were
sharp and well resolved were able to be linked to a set of peaks seen in LC-MS runs of crude
propolis and enriched fractions 12 and 13. No UV absorption was associated with these
peaks. Mass spectrometry (MS) shows good peaks in positive ion mode where M+1 and
M+Na peaks were observed. The main components of this set of compounds have
molecular weights of 460, 474, 488 and 502, equating to a homologous series where the
components differed by a methylene group. All of the mass spectra had common peaks at
159 and 117 atomic mass units (amu). In the negative ion mode the compounds had
quasi-molecular ions at M+45 due to formate adducts. High resolution MS gave a molecular
formula of C25H4807 for the 460 molecular weight compound and extra methylenes for the
others in the series. Sub-fractions of crude fractions 12, 13 were then fully acetylated to aid
the separation of the compounds of interest and to provide more definitive spectroscopic
data. The mass spectra of the peracetylated mixture showed in general that the compounds had formed triacetates as indicated by the molecular weight increase by 3 X 42 atomic mass units.
The initial chromatographic fractionation described above was repeated several times
to generate more of the enriched fractions 11 - 13. The compounds of interest were also
readily separated from these enriched fractions by silica gel chromatography to yield
sufficient material for NMR analysis. The spectra showed the presence of four acetate
groups, including a single acetate which was present in some of the natural compounds. A
substituted glycerol was present and the acid attached to the glycerol was also hydroxylated
at the 3 position. The rest of the molecule was comprised of a fatty acid chain which also
has a second hydroxyl group. The fatty acid is a dihydroxy C20, C21 C22 or C23 for the
main compounds. The compounds are thus glycerides.
GC-MS analysis of a TMS treated glyceride rich fraction produced by reversed phase
column chromatography showed the natural mixture of hydroxylated fatty acid lipids
present in propolis was quite complex. This fraction had the common fatty acids already
known to be present in propolis (palmitic, oleic and stearic acid) along with the
monoglycerides. The complexity was reduced by base hydrolysis to remove both the
glycerol and acetyl moieties to give four major and a number of minor dihydroxy fatty acids.
This fitted with the structural type described above, but did not identify where the acetyl
group resides. This combined with the range of fatty acids and positional/stereo isomers for
the hydroxyl groups gives rise to the large number of analogues. The main compounds
identified by chromatographic isolation followed by structural elucidation using MS and NMR
were monoacylglycerides of dihydroxy C20, C21 C22 or C23 fatty acids (esterification at
position C1 of glycerol). The fatty acids in the monoglycerides were predominantly straight
chain C20-C22. The fatty acid was hydroxylated at position C3, and a second hydroxyl
group was separated from the first by at least one methylene group; and was not on the
final methyl group of the fatty acid. The glycerol moiety may be acetylated at one or both of the hydroxyls at position C2 and C3. Further work was carried out in Example 4 to determine the position of the acetyl groups, and the position of the second hydroxyl group on the fatty acids.
Example 4: Production of a glyceride concentrate and isolation and purification of glycerides
In this example, the position of the second hydroxyl group on the fatty acids was
determined, as was the placement of the acetyl group. Individual glyceride compounds were
also isolated. A large-scale extract was prepared from 1.1 kg of dewaxed propolis resin
using ethyl acetate as the solvent. The propolis resin was coarsely chopped and soaked in
ethyl acetate at room temperature with mechanical stirring for 2 hrs. The solvent with
dissolved extract was filtered but not concentrated. Around 20 % of this extract solution
was chromatographed using silica gel, after first absorbing the extract onto a portion of
silica gel and evaporating the ethyl acetate using a rotary evaporator. The pre-absorbed
solid was then applied to the top of a large silica gel column and the column eluted with 1:1
hexane/ether and 8 x 150 ml fractions were collected, then the column was eluted with
diethyl ether for 4 further 150 ml fractions before beginning elution with ethyl acetate. The
4 ethyl acetate fractions (fractions #13 - #16) collected were much darker in colour than
the earlier fractions. A final fraction (#17) was collected after elution with acetone. Silica
TLC (visualisation using phosphomolybdic acid in ethanol followed by heat) and LC-MS were
used to track progression of the purification process. The glyceride rich fractions from silica
gel chromatography were then combined and subjected to reversed phase C18 column
chromatography using mixtures of water and ethanol without acid to yield a final glyceride
rich fraction (GLY-conc). This process was repeated with more of the ethyl acetate extract
as required.
Analysis of all the fractions by LC-MS showed that the ethyl acetate fractions #13
#16 and acetone fraction #17 contained the main glyceride compounds. These fractions
were also rich in the brown coloured material, consistent with Example 3. Fractions #13
and #14 were combined; and #15 and #16 were also combined. The #13/#14 combined
fraction was used for structural identification as follows. Approximately 100 mg of the
#13/#14 mixture was mixed with 4 ml THF:MeOH:H20 and 55 mg LiOH. This was stirred
at ice temperature for 30 minutes and then at room temperature for 48 hrs. The reaction
mixture was acidified with acetic acid and extracted with chloroform. The dried extract was
then esterified with diazomethane and subjected to silica gel chromatography (ethyl
acetate/hexane). A fraction comprising one main spot (Rf approximately 0.3 with 1:1
EtOAc:hexane, visualisation by phosphomolybdic acid in ethanol with heat) was collected.
This purified sample was then analysed by GC-MS after treatment with BSTFA. The 9 free
fatty acid peaks numbered 4 - 12 resulting from hydrolysis of the glycerides in the MS
spectrum were a homologous series. Major peak 4 had a characteristic peak at 383
(corresponding to loss of methyl and TMSOH) while the subsequent major peaks 5 (397), 7
(411), 10 (425) 11 (439) and 12 (453) were the C19 through to C24 dihydroxy fatty acids
(methyl ester TMS ethers). Another feature was fragment ions at m/z 301 and 247 seen
for all the peaks. These fragments, especially the 301 fragment, are characteristic of 3,8
dihydroxy acid TMS ethers that were obtained by the saponification, methylation and
sialylation of 3-acetoxy, 8-hydroxy fatty acid glycerols esterified at position C2 on the
glycerol [Asai, T., Hara, N., Kobayashi, S., Kohshima, S., Fujimoto, Y. (2009). Acylglycerols
(=glycerides) from the glandular trichome exudate on the leaves of Paulownia tomentosa.
Helvetica Chimica Acta. 92: 1473-1494]. The other possible dihydroxy acids 3,6; 3,7; and
3,9 have different fragmentation patterns. Thus the dihydroxy acids in the glyceride fraction
are the C19 to C24 3,8-dihydroxy fatty acids. The relative peak size indicates that the C20
and C22 chain lengths were the dominant compounds. Minor peaks 6, 8, 9, 13 with almost identical MS fragmentation to larger peaks were also seen. Peak 9 was very similar to 10 and peak 12 was very similar to 13. These minor peaks were iso-versions of the C22 and
C24 acids i.e. a branched methyl at the terminal end of the fatty acid. This fits with
evidence from NMR on the per-acetylated compound which suggested minor amounts of
methyl branching.
The #15/16 combined fraction was then used for preparative HPLC followed by
Sephadex LH20 size exclusion chromatography to obtain two mono-acetate compounds
GLY-1Ac-1, and GLY-1Ac-2 (C20 and C21 dihydroxy fatty acid monoacetates respectively).
Fraction #17 was used for preparative HPLC followed by Sephadex LH20 size exclusion
chromatography to obtain three no-acetate compounds GLY-Ac-1, GLY-Ac-2 and GLY
OAc-3 (C20, C21 and C22 dihydroxy fatty acid monoglycerides respectively). The
separation progress was tracked using HPLC with ELSD and the purity of the individual
compounds isolated was assessed to be >95% by HPLC, LC-MS and NMR.
Example 5: Production of glyceride concentrate, free fatty acids, methyl esters, diacetates, peracetates and cyclodextrin complexes
Hydrolysis of a sample of the glyceride concentrate obtained in Example 4 to produce
free fatty acids (FFA-conc) was performed as described in Reis et al (Reis, M.G., De Faria,
A.D., Do Amaral, M.D.C.E., Marsaioli, A.J. (2003). Oncidinol - A novel diacylglycerol from
Ornithophora radicans Barb. Rodr. (Orchidaceae) floral oil. Tetrahedron Letters 44: 8519
8523). Approx. 100 mg of the glyceride concentrate was mixed with 4 ml THF:MeOH:H20
and 55 mg LiOH. This was stirred at ice temperature for 30 minutes and then at room
temperature (RT) for 48 hrs. The reaction mixture was acidified with acetic acid and
extracted with chloroform. The free fatty acid mixture was purified using silica gel
chromatography (ethyl acetate/hexane).
A sample of the purified free fatty acid mixture was also methylated to produce
dihydroxy fatty acid methyl esters (ME-conc). Methylation was performed by addition of
diazomethane solution (Aldrich, trimethylsilyldiazomethane, 2.OM solution in hexanes) to 10
mg of free fatty acid mixture. After reacting for 1 hr at room temperature the reaction was
quenched with acetic acid and the solution evaporated to dryness under N2. The methyl
ester mixture was purified using silica gel chromatography (ethyl acetate/hexane). A
fraction comprising one main spot (Rf approximately 0.3 with 1:1 EtOAc:Hex, visualisation
phosphomolybdic acid in ethanol followed by heat) was collected.
Dihydroxy fatty acid glyceride diacetates (GLY-2Ac-1 mix) were prepared by partial
acetylation of the glyceride concentrate (15 mg stirred at room temperature with 1
equivalent of acetic anhydride overnight in THF, containing a catalytic amount of
dimethylaminopyridine). The reaction mixture was purified to give one spot on TLC.
Per-acetylation of the glyceride rich fraction (PerAc-conc)-was carried out by
dissolving the partially purified glyceride fraction (approx. 150 mg) in acetic anhydride (20
mL) and adding a small amount of dimethyl amino pyridine. After stirring at room
temperature overnight the reaction was worked up by adding methanol and toluene
(approx. 20 mL of each) and evaporating to dryness using a rotary evaporator. The residue
was the chromatographed on silica gel using hexane/ethyl acetate mixtures to obtain a
purified peracetate mixture (approx. 80 mg).
Cyclodextrin complexes of the glyceride concentrate obtained in Example 4 were
produced as follows. Approximately 400 mg of glyceride concentrate was accurately
weighed into a flask. 1.2 g of ethanol was then added to the vial, and the contents stirred to
dissolve the solids to make a 25 % by mass solution of glycerides in ethanol. The glycerides
rapidly dissolved in the ethanol. Approximately 300 mg of alpha, beta and gamma
cyclodextrins were separately accurately weighed into mortars. Approximately 400 mg of
the 25 % glycerides tincture was then added by calibrated syringe to each mortar containing one of the cyclodextrins. The contents of each mortar were then mixed to a uniform paste with a pestle. An excess of water was then added to each mortar and the contents mixed until a light yellow uniform dispersion of the complex in water was obtained.
The contents of each mortar were added to a weighed round bottom flask. The flask
contents were frozen by rotating the flask in a dry ice/acetone mixture. The flask contents
were then freeze-dried. 370 mg of gamma-cyclodextrin glyceride complex (g-CD GLY conc);
390 mg of beta-cyclodextrin glyceride complex (P-CD GLY conc); and 360 mg of alpha
cyclodextrin glyceride complex (a-CD GLY conc) were recovered from the flasks.
Example 6: Antiproliferative activity of dihydroxy fatty acid glycerides against human skin cancer cell lines: melanoma cell line A-2058
This example shows that a number of glyceride compounds present in NZ propolis
have novel anti-skin cancer activity against the human melanoma cell line A-2508. This
example also describes the general in-vitro bioassay method for determining the anti
proliferative activity of purified fractions and highly purified glycerides against human skin
cancer cell lines; and the activity of these test compounds against human melanoma cell
line A-2058. The three human skin cancer cell lines were:
1) Human Melanoma cell line (A-2058). 2) Human Epidermoid (Squamous) Carcinoma cell line (A-431). 3) Human Basal Cell Carcinoma cell line (TE 354.T).
The cell lines were revived from cryostorage and cultured in the presence of the test
and reference samples. An MTT assay was then performed on the cultures to determine the
effect of the samples on the cell viability and proliferation. The percentage standard error of
the mean was assessed and extreme outliers were removed if the SEM% >15. Preliminary
statistical significance was assessed with an independent Student t-test at a 0.05 (with
and without outliers). The methodology was based on the procedures reported by:
Ahn, NG, Campbell JS (1993). Metabolic labeling of mitogen-activated protein kinase
in A431 cells demonstrates phosphorylation on serine and threonine residues. Proc Natl
Acad Sci. 90: 5143 - 5147.
Galan-Cobo, A et al (2014). Functional inhibition of aquaporin-3 with a gold-based
compound induces blockage of cell proliferation. J Cellul. Physiol. 229: 1787 - 1801.
Roomi, MW, Kalinovsky, Jet al (2013) Effect of a nutrient mixture on matrix
metalloproteinase-9 dimers in various human cancer cell lines. Inter J Oncol. 44: 936 - 942.
Huang, HC, Lin, MK et al (2013). Cardenolides and bufadienolide glycosides from
Kalanchoe tubiflora and evaluation of cytotoxicity. Planta Medica. 79: 1362 - 1369.
Tilli, CMLJ, Stavast-Kooy, AJW et al (2003). The garlic-derived organosulfur
component ajoene decreases basal cell carcinoma tumor size by inducing apoptosis. Arch
Dermatol Res. 295: 117 - 123.
Sample Preparation
The test samples were dissolved in 15% Ethanol (EtOH)/HBSS to make a working
solution, which was then diluted 10 times to give a final concentration in the cells of 50
pg/ml unless noted.
Experimental Procedures Characterisation of the Test System 1. Human melanoma cell line (A-2058, ATCC CRL11147) was obtained from ATCC,
Bethesda, MD, USA. 2. Human squamous (epidermoid) carcinoma cell line (A-431, ATCC CRL1555) was
obtained from ATCC, Bethesda, MD, USA. 3. Human basal cell carcinoma cell line (TE 354.T, ATCC CRL7762) was obtained from
ATCC, Bethesda, MD, USA. 4. Dulbecco's Modified Eagle's Medium (DMEM) was obtained from GIBCO (12100-038). 10% Foetal Bovine Serum (FBS), 100U/ml Penicillin and 100mg/ml Streptomycin
were added before use.
5. Penicillin-streptomycin solution, stored at -20°C consisting of 10000 units/ml
penicillin and 10mg/ml streptomycin in 0.9% NaCl was obtained from Sigma (#P
0781).
6. Trypsin-EDTA solution consisting of 0.25% Trypsin/EDTA was obtained from
Invitrogen (#15400054).
7. Phosphate buffered saline (PBS) was prepared in-house. 8. Hanks Balanced Salt Solution (HBSS), stored at 4°C was obtained from GIBCO (# 14185-052).
9. Foetal Bovine Serum (FBS) stored at -20° C was obtained from GIBCO (# 10091 148).
10. MTT Reagent, 100 mg/vial, was obtained from Sigma (M-2128) and then dissolved in PBS at 10 mg/ml and stored at -20 GC. A 5mg/ml MTT solution was prepared in PBS
and stored at 4OC as the working solution. 11. MTT lysis buffer: 10 % sodium dodecyl sulphate (SDS)/45% Dimethyl Formamide was prepared by dissolving 20 g SDS in 100 ml of double-distilled water (DDW), and then adding 90 ml of Dimethyl Formamide to the solution. The pH was adjusted to 4.7 by glacial acetic acid, and DDW added up to a final volume of 200 ml. 12. 5-Fluorouracil (5-FU) was supplied by Sigma (F-6627). Three working solutions
were prepared at 19.5pg/ml, 6.5pg/ml and 1.95pg/ml dissolved in 15% Ethanol/HBSS. Final concentrations were 1.95pg/ml (15pM), 0.65pg/ml (5pM) and
0.195pg/ml (1.5pM).
Medium Preparation
The culture conditions for the cells were those suggested by the supplier of the cells
(ATCC). The medium for the propagation of each of the cells lines was DMEM as given
above. The medium was prepared following the ATCC instructions and supplemented with
penicillin-streptomycin solution (10ml per litre). FBS (at 10%) was also added just before
use.
Culturing of Cells: 1. Each of the cell lines obtained from the American Type Culture Collection USA was revived from cryostorage. 2. Following initial propagation using the DMEM media described above the cultures were sub-cultured using trypsin-EDTA. The media was removed and 5ml of the trypsin-EDTA solution added and incubated at 370 C for 5 min or until all the cells had detached. The trypsin was neutralised by the addition of an equal volume of the DMEM and the suspension was centrifuged at 300g (1200rpm) for 5 min at 40 C.
3. The supernatant was decanted and the cell pellets re-suspended in DMEM that contained FBS (10%), penicillin (100 units/ml), streptomycin (100pg/ml).
4. After reaching confluence, the cells were detached using trypsin-EDTA as described in 2 above and centrifuged. 5. The supernatants were discarded and the cells re-suspended in DMEM and supplements as described in 3 above at varying concentrations of cells per ml. The cell concentration of the A-431 culture was increased from 1 x 104 to 5 x 104
cells/ml, whereas the concentrations of the other two cell lines (A2058 and TE 354.T), were increased to 2 x 104 cells/ml.
6. For the three cell lines, into each well of 96 well plates, 180pl of the cells or medium was added. The plates were incubated using 5% C0 2 /95% air at 370 C for varying time periods to allow the cells to adhere. For the A-431 culture, the pre-incubation time was 3hrs, whereas the pre-incubation times for the other two cell lines (A2058 and TE 354.T) were 24hrs.
7. 20pl of each of the test compounds or 5-FU was added to each well. To the wells labelled 'medium' or 'cells only', 20pl of 15%ETOH/HBSS was added. The number of times each test sample or control was assessed is noted in the Examples tables. 8. The total volume in each well was 200pl. 9. The plates were further incubated at 370 C in 5% C0 2/95% air for 24hr. Cell Proliferation Assay 1. On completion of the incubation, 20 pl of MTT working solution (5mg/ml) was added to all wells and the plates incubated for 3-4 hr at 370 C in 5% C0 2 /95% air. The plates were monitored every 30-60 minutes and if a few cells showed the presence of crystals then the lysis buffer was added as in Step 2. 2. 100 pl of MTT lysis buffer was then added and the plates incubated overnight at 37 0 C in 5% C0 2/95% air. The plates were centrifuged at 300g (1200rpm) for 10 minutes to pellet any remaining insoluble material. From each well a 200pl aliquot was transferred to fresh 96 well plates. The plates were read in a VersaMax microplate reader at 550 nm.
3. Results were expressed as the percentage absorbance of cells cultured in the presence of the sample in comparison to that of the cells only control. The blank reading was subtracted from all wells as a background reading.
The glyceride test samples GLY-lAc-1 and GLY-lAc-2 (dihydroxy fatty acid glyceride
acetylated at position C3 of the glycerol, C20 and C21 fatty acid respectively) and GLY-OAc
1, GLY-0Ac-2 and GLY-Ac-3 (dihydroxy fatty acid glyceride containing no acetates, C20,
C21, and C22 fatty acid respectively) were tested at a final concentration of 50 pg/ml, and
compared against the negative control NC-1 (cells only); positive controls PC-1, PC-2, PC-3
consisting of 5-FU at a test concentration of 0.195, 0.65 and 1.95 pg/ml respectively; and
PC-4 consisting of glycerol monopalmitate (MGP) tested at 50 pg/ml.
Results and discussion
This example shows that a number of glyceride compounds present in NZ propolis
have novel anti-skin cancer activity against the human melanoma cell line A-2508.The
bioassay results are shown in Table 6. In the Table, OD is Optical Density measured at 570
nm; SEM is the Standard Error of the Measurement associated with the Mean Optical
Density value measured; p is the probability value that the measurement is statistically
significant via the Student t-test, here taken to be < 0.05; % inhibition is the percentage
reduction of proliferation compared to the negative control, with a large number indicating
the test compound has anticancer proliferation potential.
Table 6: Antiproliferative activity of dihydroxy fatty acid glycerides against human melanoma cell line A-2508
0 Sample ID & number of Mean (OD 570nm) SEM P Values (<0.05) / Inhibition
replicates, n
NC-1 Cells only, n=6 0.1260 0.0046 1 0.00
PC-1 Cells + 5-FU, 0.195 pg/ml, 0.1339 0.0067 NS 0
n=6
PC-2 Cells + 5-FU, 0.65 pg/ml, 0.1187 0.0043 NS 5.78
n=6
PC-3 Cells + 5-FU, 1.95 pg/ml, 0.1383 0.0045 NS 0
n=6
PC-4 Cells + MGP, 50 pg/ml, n=3 0.0548 0.0016 1.7E-05 56.5
S#12 Cells + GLY-1Ac-1, 50 0.0249 0.0037 2.4E-05 80.2
pg/ml, n=2
S#13 Cells + GLY-1Ac-2, 50 0.0236 0.0006 1.4E-06 81.3
pg/ml, n=2
S#14 Cells + GLY-OAc-1, 50 0.0157 0.0001 1.3E-05 87.5
pg/ml, n=2
S#15 Cells + GLY-OAc-2, 50 0.0106 0.0001 9.7E-06 91.6
pg/ml, n=2
S#16 Cells + GLY-OAc-3, 50 0.0358 0.0055 5.2E-05 71.6
pg/ml, n=2
All of the highly purified compounds inhibited proliferation of human melanoma skin
cancer cell lines by 72 - 92 % when tested at 50 pg/ml. The most potent of these
compounds was the non-acetylated dihydroxy fatty acid glyceride GLY-0Ac-2 with a fatty
acid chain length of 22 carbons. The antiproliferative activity of these dihydroxy fatty acid
glycerides was superior to the positive control monoglycerol palmitate (MGP), also tested at
50 pg/ml. The 5-fluorouracil had low and non-significant activity at the three concentrations
tested of 0.195, 0.65 and 1.95 pg/ml.
L0 Example 7: Antiproliferative activity of dihydroxy fatty acid glycerides against human epidermoid carcinoma A-431
This example shows that a number of glyceride compounds present in NZ propolis
have novel anti-skin cancer activity against the human epidermoid cancer cell line A-431.
The glyceride test samples GLY-lAc-1 (C20 dihydroxy fatty acid glyceride acetylated at
position C3 of the glycerol) and GLY-OAc-1 (C20 dihydroxy fatty acid glyceride containing no
acetates on the glycerol) were tested for their antiproliferative activity against human
epidermoid carcinoma cell line A-431 at a final concentration of 50 pg/ml. The cell
proliferation assay was performed as described in Example 6. The test samples were
compared against the negative control NC-1 (cells only); positive controls PC-1, PC-2, PC-3 consisting of 5-FU at a test concentration of 0.195, 0.65 and 1.95 pg/ml respectively; and
PC-4 consisting of glycerol monopalmitate (MGP) tested at 50 pg/ml.
The bioassay results are shown in Table 7. In the Table, OD is Optical Density
measured at 570 nm; SEM is the Standard Error of the Measurement associated with the
Mean Optical Density value measured; p is the probability value that the measurement is
statistically significant via the Student t-test, here taken to be < 0.05 (NS = not
significant); % inhibition is the percentage reduction of proliferation compared to the
negative control, with a large number indicating the test compound has anticancer
proliferation potential.
Table 7: Antiproliferative activity of dihydroxy fatty acid glycerides against human epidermoid cancer cell line A-431
0 Sample ID & number of Mean (OD 570nm) SEM P Values (<0.05) / Inhibition
replicates, n
NC-1 Cells only, n=6 0.2621 0.0158 NS 0.00
PC-1 Cells + 5-FU, 0.195 pg/ml, 0.2364 0.0064 NS 9.8
n=6
PC-2 Cells + 5-FU, 0.65 pg/ml, 0.2416 0.0111 NS 7.8
n=6
PC-3 Cells + 5-FU, 1.95 pg/ml, 0.2561 0.0086 NS 2.3
n=6
PC-4 Cells + MGP, 50 pg/ml, n=3 0.0360 0.0034 2.5E-05 86.3
S#12 Cells + GLY-iAc-1, 50 0.0507 0.0037 3.3E-04 80.6
pg/ml, n=3
S#14 Cells + GLY-OAc-1, 50 0.0484 0.0025 3.6E-05 81.5
pg/ml, n=3
The two monoglyceride compounds tested, GLY-lAc-1 and GLY-OAc-1, have almost
identical levels of inhibition of proliferation at 80.6 and 81.5 % respectively when tested at
50 pg/ml. This example shows that the number of acetates on the glycerol is not significant
with respect to activity. The antiproliferative activity of these dihydroxy fatty acid glycerides
was similar to the positive control monoglycerol palmitate (MGP), also tested at 50 pg/ml.
The 5 fluorouracil had low and non-significant activity at the three concentrations tested of
0.195, 0.65 and 1.95 pg/ml.
Example 8: Antiproliferative activity of dihydroxy fatty acid glycerides against human basal cell carcinoma TE 354.T
The glyceride test samples GLY-1Ac-1 (C20 dihydroxy fatty acid glyceride acetylated
at position C3 of the glycerol) and GLY-0Ac-1 (C20 dihydroxy fatty acid glyceride containing
no acetates on the glycerol) were tested for their antiproliferative activity against human
basal cell carcinoma cell line TE 345.T at a final concentration of 50 pg/ml. The cell
proliferation assay was performed as described in Example 6. The test samples were
compared against the negative control NC-1 (cells only); positive controls PC-1, PC-2, PC-3
consisting of 5-FU at a test concentration of 0.195, 0.65 and 1.95 pg/ml respectively; and
PC-4 consisting of glycerol monopalmitate tested at 50 pg/ml.
This example shows that a number of glyceride compounds present in NZ propolis
have novel anti-skin cancer activity against the human basal cancer cell line TE 354.T. The
bioassay results are shown in Table 8. In the Table, OD is Optical Density measured at 570
nm; SEM is the Standard Error of the Measurement associated with the Mean Optical
Density value measured; p is the probability value that the measurement is statistically
significant via the Student t-test, here taken to be < 0.05 (NS = not significant); %
inhibition is the percentage reduction of proliferation compared to the negative control, with
a large number indicating the test compound has anticancer proliferation potential.
Table 8: Antiproliferative activity of dihydroxy fatty acid glycerides against human basal cell carcinoma cell line TE 354.T
0 Sample ID & number of Mean (OD 570nm) SEM P Values (<0.05) / Inhibition
replicates, n
NC-1 Cells only, n=6 0.2696 0.0096 NS 0.00
PC-1 Cells + 5-FU, 0.195 pg/ml, 0.2548 0.0051 NS 5.49
n=6
PC-2 Cells + 5-FU, 0.65 pg/ml, 0.2656 0.0061 NS 1.49
n=6
PC-3 Cells + 5-FU, 1.95 pg/ml, 0.2553 0.0070 NS 5.31
n=6
PC-4 Cells + MGP, 50 pg/ml, n=3 0.2277 0.0065 0.0247 15.6
S#12 Cells + GLY-1Ac-1, 50 0.1959 0.0037 1.3E-03 27.3
pg/ml, n=3
S#14 Cells + GLY-OAc-1, 50 0.1672 0.0236 1.7E-03 38.0
pg/ml, n=3
The two monoglyceride compounds tested, GLY-1Ac-1 and GLY-0Ac-1, have similar
levels of inhibition of proliferation at 27.3 and 38.0 % respectively when tested at 50 pg/ml.
This example shows that having zero acetates on the glycerol gives an improvement in
bioactivity for this skin cancer cell line. The antiproliferative activity of these dihydroxy fatty
acid glycerides was superior to the positive control monoglycerol palmitate (MGP), also
tested at 50 pg/ml. The 5 fluorouracil had low and non-significant activity at the three
concentrations tested of 0.195, 0.65 and 1.95 pg/ml.
Example 9: Antiproliferative activity of dihydroxy fatty acid glycerides and derivatives against human colon adenocarcinoma cell line DLD-1
This example shows the antiproliferative activity of individual glycerides GLY-1Ac-1
and GLY-1Ac-2 (dihydroxy fatty acid glyceride acetylated at position C3 of the glycerol, C20
and C21 fatty acid chain length) and GLY-Ac-1 and GLY-OAc-2 (non-acetylated dihydroxy
fatty acid glycerides, C20 and C21 fatty acid chain length) were tested for anti-proliferative
activity at a final concentration of 50 pg/ml against colon adenocarcinoma cell line DLD-1.
GLY-1Ac-1 was also retested in a second assay at 50 and 25 pg/ml to provide an indicative
dose response. The cell proliferation assay was performed as described in Examples 1 and
2. The test samples were compared against the negative control NC-1 (cells only); positive
controls PC-1, PC-2 consisting of 5-FU at a test concentration of 0.65 and 1.95 pg/ml
respectively; and PC-3 consisting of glycerol monopalmitate (MGP) tested at 50 pg/ml. The cells only data NC-1 for the first and NC-2 second bioassay trials are also included in the table.
This example shows that a number of glyceride compounds present in NZ propolis
have novel anti-gastrointestinal cancer activity against the human colon adenocarcinoma
cell line DLD-1. The bioassay results are shown in Table 9. In the Table, OD is Optical
Density measured at 570 nm; SEM is the Standard Error of the Measurement associated
with the Mean Optical Density value measured; p is the probability value that the
measurement is statistically significant via the Student t-test, here taken to be < 0.05 (NS
= not significant); % inhibition is the percentage reduction of proliferation compared to the
negative control, with a large number indicating the test compound has anticancer
proliferation potential.
Table 9: Antiproliferative activity of dihydroxy fatty acid glycerides against human adenocarcinoma cell line DLD-1
0 Sample ID & number of Mean (OD 570nm) SEM P Values (<0.05) / Inhibition
replicates, n
NC-1 Cells only, n=3 0.4035 0.0131 1 0.00
PC-1 Cells + 5-FU, 0.65 pg/ml, 0.3626 0.0392 NS 10.1
n=3
PC-2 Cells + 5-FU, 1.95 pg/ml, 0.3173 0.0267 NS 21.3
n=3
PC-3 Cells + MGP, 50 pg/ml, n=3 0.1133 0.0111 1.6E-04 71.9
S#12 Cells + GLY-iAc-1, 50 0.1277 0.0008 1.1E-04 68.3
pg/ml, n=3
S#13 Cells + GLY-iAc-2, 50 0.0347 0.0104 6.4E-04 91.4
pg/ml, n=2
S#14 Cells + GLY-OAc-1, 50 0.0810 0.0036 8.3E-04 79.9
pg/ml, n=2
S#15 Cells + GLY-OAc-2, 50 0.0979 0.0141 1.8E-04 75.7
pg/ml, n=3
NC-2 Cells only (trial 2), n=6 0.3269 0.0379 1 0.00
S#4a Cells + GLY-iAc-1, 50 pg/ml 0.0191 0.0193 1.5E-05 94.2
(trial 2), n=6
S#4b Cells + GLY-lAc-1, 25 pg/ml 0.2832 0.0134 NS 13.3
(trial 2), n=6
The inhibition of proliferation for all monoglycerides with one or zero acetates attached
to glycerol was in the range 68 - 91 % when tested at 50 pg/ml. The most potent of these
compounds in the first assay was the mono-acetylated dihydroxy fatty acid glyceride GLY
lAc-2. The antiproliferative activity of these dihydroxy fatty acid glycerides was similar to or
superior to the positive control monoglycerol palmitate (MGP), also tested at 50 pg/ml. GLY
1Ac-1 was retested at 50 and 25 pg/ml. The antiproliferative activity was 94 % at 50 pg/ml
but only 13 % at 25 pg/ml, and so the LD50 for this compound is somewhere between 25
and 50 pg/ml. The 5-fluorouracil had low and non-significant activity at the two
concentrations tested of 0.65 and 1.95 pg/ml.
Example 10: Antiproliferative activity of dihydroxy fatty acid glycerides mixtures, derivates and cyclodextrin complexes against human adenocarcinoma cell line DLD-1
This example shows the antiproliferative activity against the human colon cancer cell
line DLD-1 of a purified glyceride fraction GLY-conc; derivatives of the purified glycerides
including free fatty acids (FFA-conc), methyl esters (ME-conc) and peracetylated glycerides
(PerAc-conc); and cyclodextrin complexes of the glycerides g-CD GLY-conc (gamma
cyclodextrin encapsulated glyceride concentrate), and a-CD GLY-conc (alpha-cyclodextrin
encapsulated glyceride concentrate). These fractions and samples were prepared as
described in Examples 4 and 5, and were tested for anti-proliferative activity at a final
effective concentration of 50 pg/ml glyceride concentrate against colon adenocarcinoma cell
line DLD-1. The cyclodextrin-encapsulated glycerides samples containing 25 % by mass
glyceride concentrate were tested at a concentration of 200 pg/ml, which is equivalent to 50
pg/ml glycerides. The test samples were compared against the negative control NC-1 (cells
only); positive controls PC-1, PC-2, PC-3 consisting of 5-FU at a test concentration of 6.5,
19.5 and 58.5 pg/ml; and PC-4 consisting of glycerol monopalmitate tested at 50 pg/ml.
The bioassay results are shown in Table 10. In the Table, OD is Optical Density measured at
570 nm; SEM is the Standard Error of the Measurement associated with the Mean Optical
Density value measured; p is the probability value that the measurement is statistically
significant via the Student t-test, here taken to be < 0.05 (NS = not significant);
% inhibition is the percentage reduction of proliferation compared to the negative control, with
a large number indicating the test compound has anticancer proliferation potential.
Table 10: Antiproliferative activity of dihydroxy fatty acid glyceride concentrates, derivatives and complexes against human colon adenocarcinoma cell line DLD-1
0 Sample ID & number of Mean (OD 570nm) SEM P Values (<0.05) / Inhibition
replicates, n
NC-1 Cells only, n=6 0.3269 0.0379 1 0.00
PC-1 Cells + 5-FU, 6.5 pg/ml, n=6 0.3222 0.0337 NS 1.44
PC-2 Cells + 5-FU, 19.5 pg/ml, 0.3301 0.0202 NS 0.00
n=6
PC-3 Cells + 5-FU, 58.5 pg/ml, 0.2883 0.0054 NS 11.8
n=6
PC-4 Cells + MGP, 50 pg/ml, n=5 0.0052 0.0022 3.1E-05 98.4
S#9 Cells + GLY-conc, 50 pg/ml, 0.0600 0.0126 1.6E-04 81.6
n=5
S#10 Cells + FFA-conc, 50 pg/ml, 0.2935 0.0074 NS 10.2
n=6
S#11 Cells + ME-conc, 50 pg/ml, 0.1720 0.0061 2.4E-03 47.4
n=6
S#12 Cells + PerAc-conc, 50 0.2648 0.0152 NS 19.0
pg/ml, n=6
S#13 Cells + g-CD GLY-conc, 200 0.2356 0.0104 4.2E-02 27.9
pg/ml, n=6
S#15 Cells + a-CD GLY-conc, 200 0.2205 0.0121 2.3E-02 32.6
pg/ml, n=6
This example shows that a glyceride mixture isolated from NZ propolis; derivatives of
the glycerides including free fatty acids, alkyl esters and peracetates; and cyclodextrin
encapsulated glycerides have novel anti-gastrointestinal cancer activity against the human
colon adenocarcinoma cell line DLD-1. The most potent of the test substances, with inhibition of proliferation of 82 % is the monoglyceride concentrate. The most potent of the derivatives and complexes were the methylesters at 47 % inhibition followed by the alpha and gamma cyclodextrin complexes at 33 and 28 % respectively. The peracetates and free fatty acids had the lowest antiproliferative activity at 19 and 10 % respectively. It is likely that the test concentration of these derivatives was too low. The 5-fluorouracil had low and non-significant activity at the concentrations tested of 6.5, 19.5 and 58.5 pg/ml.
Example 11: Antiproliferative activity of dihydroxy fatty acid glycerides against human gastric carcinoma cell line NCI-N87
This example shows the antiproliferative activity of individual glycerides GLY-1Ac-1
and GLY-1Ac-2 (dihydroxy fatty acid glyceride acetylated at position C3 of the glycerol, C20,
C21, C22 fatty acid chain lengths), GLY-Ac-1, GLY-Ac-2, GLY-OAc-3 (non-acetylated
dihydroxy fatty acid glycerides, C20, C21, C22 fatty acid chain lengths) and GLY-2Ac-1 mix
(dihydroxy fatty acid glyceride acetylated at positions C2 and C3 on the glycerol, mixture of
dihydroxy fatty acid chain lengths) were tested for anti-proliferative activity at a final
concentration of 50 pg/ml against human gastric carcinoma cell line NCI-N87. GLY-1Ac-1
was also tested at 25 and 10 pg/ml to provide an indicative dose response. The cell
proliferation assay was performed as described in Examples 1 and 2. The test samples were
compared against the negative control NC-1 (cells only); positive controls PC-1, PC-2, PC-3
consisting of 5-FU at a test concentration of 6.5, 19.5 and 58.5 pg/ml; and PC-4 consisting
of glycerol monopalmitate (MGP) tested at 50 pg/ml. The bioassay results are shown in
Table 11. In the Table, OD is Optical Density measured at 570 nm; SEM is the Standard
Error of the Measurement associated with the Mean Optical Density value measured; p is
the probability value that the measurement is statistically significant via the Student t-test,
here taken to be < 0.05; % inhibition is the percentage reduction of proliferation compared to the negative control, with a large number indicating the test compound has anticancer proliferation potential.
Table 11: Antiproliferative activity of dihydroxy fatty acid glycerides against human gastric cancer cell line NCI-N87
Sample ID & number of Mean (OD 570nm) SEM P Values (<0.05) / Inhibition
replicates, n
NC-1 Cells only, n=6 0.0864 0.0128 1.00 0.00
PC-1 Cells + 5-FU, 6.5 pg/ml, n=6 0.0693 0.0062 NS 19.83
PC-1 Cells + 5-FU, 19.5 pg/ml, 0.0792 0.0067 NS 8.32
n=6
PC-1 Cells + 5-FU, 58.5 pg/ml, 0.0793 0.0023 NS 8.22
n=6
PC-4 Cells + MGP, 50 pg/ml, n=6 0.0000 0.0000 N/A 100
S#1 Cells + GLY-OAc-1, 50 pg/ml, 0.0000 0.0000 N/A 100.00
n=6
S#2 Cells + GLY-OAc-2, 50 pg/ml, 0.0000 0.0000 N/A 100.00
n=6
S#3 Cells + GLY-OAc-3, 50 pg/ml, 0.0000 0.0000 5.OE-05 99.97
n=6
S#4a Cells + GLY-iAc-1, 50 0.0000 0.0000 N/A 100.00
pg/ml, n=6
S#4b Cells + GLY-iAc-1, 25 0.0118 0.0016 1.9E-02 86.38
pg/ml, n=2
S#4c Cells + GLY-iAc-1, 10 0.0530 0.0041 3.2E-02 38.61
pg/ml, n=6
S#7 Cells + GLY-iAc-2, 50 pg/ml, 0.0000 0.0000 N/A 100.00
n=6
S#8 Cells + GLY-2Ac-1 mix, 50 0.0414 0.0042 2.5E-02 52.08
pg/ml, n=4
This example shows that a large number of glyceride compounds present in NZ
propolis have novel and very potent anti-gastrointestinal cancer activity against the human
gastric cancer cell line NCI-N87. All the isolated no-acetate and monoacetate compounds
were cytotoxic (100 % inhibition of proliferation) when tested at 50 pg/ml. The mixture of
diacetate glyceride compounds, GLY-2Ac-1 mix were strongly antiproliferative but not cytotoxic at 52 % inhibition. Reducing the test concentration of the mono-acetate compound GLY-1Ac-1 from 50 to 25 pg/ml reduced the anti-proliferative activity to 86
% (still very strongly active). Reducing the test concentration still further from 25 to 10 pg/ml
reduced the anti-proliferative activity to 39 %. The LD50 is therefore somewhere between
25 and 10 pg/ml. The 5-fluorouracil had low and non-significant activity at the
concentrations tested of 6.5, 19.5 and 58.5 pg/ml, with the highest activity obtained at 6.5
pg/ml. The glycerol monopalmitate (MGP) was also cytotoxic at the test concentration of 50
pg/ml.
Example 12: Antiproliferative activity of dihydroxy fatty acid glycerides mixtures, derivatives and cyclodextrin complexes against human gastric carcinoma cell line NCI-N87
This example shows the antiproliferative activity against the human gastric carcinoma
cell line NCI-N87 of a purified glyceride fraction GLY-conc; derivatives of the purified
glycerides including free fatty acids (FFA-conc), methyl esters (ME-conc) and peracetylated
glycerides (PerAc-conc); and cyclodextrin complexes of the glycerides g-CD GLY-conc
(gamma-cyclodextrin encapsulated glyceride concentrate), and a-CD GLY-conc (alpha
cyclodextrin encapsulated glyceride concentrate). These fractions and samples were
prepared as described in Examples 4 and 5, and were tested for anti-proliferative activity at
a final effective concentration of 50 pg/ml glyceride concentrate against gastric carcinoma
cell line NCI-N87. The cyclodextrin-encapsulated glycerides samples containing 25 % by
mass glyceride concentrate were tested at a concentration of 200 pg/ml, equivalent to 50
pg/ml glycerides. The test samples were compared against the negative control NC-1 (cells
only); positive controls PC-1, PC-2, PC-3 consisting of 5-FU at a test concentration of 6.5,
19.5 and 58.5 pg/ml; and PC-4 consisting of glycerol monopalmitate (MGP) tested at 50
pg/ml. The bioassay results are shown in Table 12. In the Table, OD is Optical Density
measured at 570 nm; SEM is the Standard Error of the Measurement associated with the
Mean Optical Density value measured; p is the probability value that the measurement is
statistically significant via the Student t-test, here taken to be < 0.05 (NS = not
significant); % inhibition is the percentage reduction of proliferation compared to the
negative control, with a large number indicating the test compound has anticancer
proliferation potential.
Table 12: Antiproliferative activity of dihydroxy fatty acid glyceride concentrates, derivatives and complexes against human gastric carcinoma cell line NCI-N87
0 Sample ID & number of Mean (OD 570nm) SEM P Values (<0.05) / Inhibition
replicates, n
NC-1 Cells only, n=6 0.0864 0.0128 1.000 0.00
PC-1 Cells + 5-FU, 6.5 pg/ml, n=6 0.0693 0.0062 NS 19.83
PC-1 Cells + 5-FU, 19.5 pg/ml, 0.0792 0.0067 NS 8.32
n=6
PC-3 Cells + 5-FU, 58.5 pg/ml, 0.0793 0.0023 NS 8.22
n=6
PC-4 Cells + MGP, 50 pg/ml, n=6 0.0000 0.0000 N/A 100
S#9 Cells + GLY-conc, 50 pg/ml, 0.0150 0.0039 2.2E-02 82.65
n=2
S#10 Cells + FFA-conc, 50 pg/ml, 0.0388 0.0056 6.6E-03 55.14
n=6
S#11 Cells + ME-conc, 50 pg/ml, 0.0260 0.0039 2.5E-03 69.86
n=5
S#12 Cells + PerAc-conc, 50 0.0347 0.0058 1.4E-02 59.89
pg/ml, n=4
S#13 Cells + g-CD GLY-conc, 200 0.0299 0.0042 3.8E-03 65.41
pg/ml, n=5
S#14 Cells + p-CD GLY-conc, 200 0.0193 0.0033 3.2E-03 77.67
pg/ml, n=4
S#15 Cells + a-CD GLY-conc, 200 0.0274 0.0022 i.OE-03 68.34
pg/ml, n=6
This example shows that a glyceride mixture isolated from NZ propolis; derivatives
including free fatty acids, alkyl esters and peracetates; and cyclodextrin-encapsulated
glycerides have novel anti-gastrointestinal cancer activity against the human gastric
carcinoma cell line NCI-N87. The most potent of the test substances, with inhibition of proliferation of 82 % is the monoglyceride concentrate. The most potent of the derivatives and complexes were the methylesters at 70 % inhibition, beta-cyclodextrin complex at 78
% alpha cyclodextrin complex at 68 % and gamma cyclodextrin complex at 65
% respectively. The peracetates and free fatty acids had lower but still strong antiproliferative
activity at 60 and 55 % respectively. The 5-fluorouracil had low and non-significant activity
at the concentrations tested of 6.5, 19.5 and 58.5 pg/ml, with the highest activity obtained
at 6.5 pg/ml. The glycerol monopalmitate (MGP) was cytotoxic at the test concentration of
50 pg/ml.
Example 13: Antiproliferative activity of dihydroxy fatty acid glycerides against human oesophageal carcinoma cell line KYSE-30
This example shows the antiproliferative activity of individual glycerides GLY-1Ac-1
and GLY-1Ac-2 (dihydroxy fatty acid glyceride acetylated at position C3 of the glycerol, C20,
C21 fatty acid chain length respectively), GLY-Ac-1, GLY-Ac-2, GLY-0Ac-3 (non
acetylated dihydroxy fatty acid glycerides, C20, C21, C22 fatty acid chain length
respectively) and GLY-2Ac-1 mix (dihydroxy fatty acid glyceride acetylated at positions C2
and C3 of the glycerol, mixture of fatty acid chain lengths) were tested for anti-proliferative
activity at a final concentration of 50 pg/ml against human oesophageal carcinoma cell line
KYSE-30. GLY-1Ac-1 was also tested at 25 and 10 pg/ml to provide an indicative dose
response. The cell proliferation assay was performed as described in Examples 1 and 2. The
test samples were compared against the negative control NC-1 (cells only); positive controls
PC-1, PC-2, PC-3 consisting of 5-FU at a test concentration of 6.5, 19.5 and 58.5 pg/ml;
and PC-4 consisting of glycerol monopalmitate (MGP) tested at 50 pg/ml. The bioassay
results are shown in Table 13. In the Table, OD is Optical Density measured at 570 nm;
SEM is the Standard Error of the Measurement associated with the Mean Optical Density
value measured (NS = not significant); p is the probability value that the measurement is statistically significant via the Student t-test, here taken to be < 0.05; % inhibition is the percentage reduction of proliferation compared to the negative control, with a large number indicating the test compound has anticancer proliferation potential.
Table 13: Antiproliferative activity of dihydroxy fatty acid glycerides against human oesophageal carcinoma cell line KYSE-30
Sample ID & number of Mean (OD 570nm) SEM P Values (<0.05) / Inhibition
replicates, n
NC-1 Cells only, n=6 0.1519 0.0072 1.000 0.00
PC-1 Cells + 5-FU, 6.5 pg/ml, n=6 0.1336 0.0083 NS 12.02
PC-2 Cells + 5-FU, 19.5 pg/ml, 0.1407 0.0053 NS 7.34
n=6
PC-3 Cells + 5-FU, 58.5 pg/ml, 0.1263 0.0064 2.4E-02 16.85
n=6
PC-4 Cells + MGP, 50 pg/ml, n=6 0.0385 0.0047 1.2E-07 74.68
S#1 Cells + GLY-OAc-1, 50 pg/ml, 0.0732 0.0131 3.7E-04 51.78
n=5
S#2 Cells + GLY-OAc-2, 50 pg/ml, 0.1076 0.0087 2.9E-03 29.13
n=6
S#3 Cells + GLY-OAc-3, 50 pg/ml, 0.0269 0.0045 1.2E-06 82.28
n=4
S#4a Cells + GLY-iAc-1, 50 0.0206 0.0062 2.1E-07 86.46
pg/ml, n=4
S#4b Cells + GLY-iAc-1, 25 0.0766 0.0097 1.3E-04 49.55
pg/ml, n=5
S#4c Cells + GLY-iAc-1, 10 0.1378 0.0083 NS 9.23
pg/ml, n=6
S#7 Cells + GLY-iAc-2, 50 pg/ml, 0.1006 0.0163 1.2E-02 33.76
n=5
S#8 Cells + GLY-2Ac-1 mix, 50 0.1137 0.0033 7.3E-04 25.13
pg/ml, n=6
This example shows that a number of glyceride compounds presentin NZ propolis
have novel and potent anti-gastrointestinal cancer activity against the human oesophageal
carcinoma cell line KYSE-30. All the isolated no-acetate and monoacetate compounds were
moderately to strongly antiproliferative (34 - 86 %) when tested at 50 pg/ml, with the most potent being GLY-lAc-1. The mixture of diacetate glyceride compounds, GLY-2Ac-1 mix, was moderately antiproliferative at 25 % inhibition. Reducing the test concentration of the mono-acetate compound GLY-lAc-1 from 50 to 25 pg/ml reduced the antiproliferative activity to 50 % (still strongly active). Reducing the test concentration further from 25 to 10 pg/ml reduced the antiproliferative activity to a statistically insignificant level of 9 %. The
LD50 is therefore around 25 pg/ml. The 5-fluorouracil had low but significant activity of 17
% when tested at 58.5 pg/ml, but non-significant activity at the lower concentrations of 6.5
and 19.5 pg/ml. The glycerol monopalmitate (MGP) had strong antiproliferative activity of
75 % when tested at 50 pg/ml.
Example 14: Antiproliferative activity of dihydroxy fatty acid glycerides mixtures, and derivatives against human oesophageal squamous carcinoma cell line KYSE 30
This example shows the antiproliferative activity against the human oesophageal
squamous carcinoma cell line KYSE-30 of a purified glyceride fraction GLY-conc; derivatives
of the purified glycerides including free fatty acids (FFA-conc), methyl esters (ME-conc) and
peracetylated glycerides (PerAc-conc). These fractions and samples were prepared as
described in Examples 4 and 5, and were tested for anti-proliferative activity at a final
effective concentration of 50 pg/ml glyceride concentrate against oesophageal squamous
carcinoma cell line KYSE-30. The test samples were compared against the negative control
NC-1 (cells only); positive controls PC-1, PC-2, PC-3 consisting of 5-FU at a test
concentration of 6.5, 19.5 and 58.5 pg/ml; and PC-4 consisting of glycerol monopalmitate
(MGP) tested at 50 pg/ml. The bioassay results are shown in Table 14. In the Table, OD is
Optical Density measured at 570 nm; SEM is the Standard Error of the Measurement
associated with the Mean Optical Density value measured; p is the probability value that the
measurement is statistically significant via the Student t-test, here taken to be < 0.05 (NS
= not significant); % inhibition is the percentage reduction of proliferation compared to the negative control, with a large number indicating the test compound has anticancer proliferation potential.
Table 14: Antiproliferative activity of dihydroxy fatty acid glyceride concentrates and derivatives against human oesophageal squamous carcinoma cell line KYSE 30
Sample ID & number of Mean (OD 570nm) SEM P Values (<0.05) / Inhibition
replicates, n
NC-1 Cells only, n=6 0.1519 0.0072 1.000 0.00
PC-1 Cells + 5-FU, 6.5 pg/ml, n=6 0.1336 0.0083 NS 12.02
PC-2 Cells + 5-FU, 19.5 pg/ml, 0.1407 0.0053 NS 7.34
n=6
PC-3 Cells + 5-FU, 58.5 pg/ml, 0.1263 0.0064 2.4E-02 16.85
n=6
PC-4 Cells + MGP, 50 pg/ml, n=6 0.0385 0.0047 1.2E-07 74.68
S#9 Cells + GLY-conc, 50 pg/ml, 0.1137 0.0033 7.2E-04 44.03
n=6
S#10 Cells + FFA-conc, 50 pg/ml, 0.0850 0.0039 i.OE-05 21.47
n=6
S#11 Cells + ME-conc, 50 pg/ml, 0.1193 0.0028 1.8E-03 27.59
n=6
S#12 Cells + PerAc-conc, 50 0.1100 0.0028 2.9E-04 32.03
pg/ml, n=6
This example shows that a glyceride mixture isolated from NZ propolis; derivatives
including free fatty acids, alkyl esters and peracetates have novel anti-gastrointestinal
cancer activity against the human oesophageal squamous carcinoma cell line KYSE-30. The
most potent of the test substances, with inhibition of proliferation of 44 % is the
monoglyceride concentrate. The most potent of the derivatives were the peracetates at 32
% inhibition. The methyl esters and free fatty acids had slightly lower antiproliferative
activity at 28 and 21 % respectively. The 5-fluorouracil had low but significant activity of
16.8 % inhibition at the concentration tested of 58.5 pg/ml, but non-significant activity at the lower concentrations of 6.5 and 19.5 pg/ml. The glycerol monopalmitate (MGP) had strong antiproliferative activity of 75 % when tested at 50 pg/ml.
Example 15: Isolation of dihydroxy fatty acid glycerides from Poplar trees.
This example shows that certain species or hybrids of poplar are a source for
dihydroxy fatty acid glycerides found in New Zealand propolis, and are thus an alternative
botanical source of these glycerides to propolis or to chemical synthesis.
Samples of poplar buds, twigs and leaf material were collected from the Plant and
Food Research poplar collection at Aokautere (Manawatu, NewZealand) and from the
Wellington Regional Council nursery at the Akura Conservation Centre (Masterton, New
Zealand) from September to February. Most samples were from coppiced trees as these
were easily accessed.
Samples were weighed and extracted with absolute ethanol at room temperature for
approximately 2 hrs. The samples were extracted as is without maceration or slicing. The
extracts were dried and weighed and samples of each prepared for LC-MS analysis by
making up solutions in ethanol at 5 mg/ml. Samples of leaf and flower material were
collected from two Paulownia tomentosa trees, and from mature willow tree leaf and buds in
the Hutt Valley, for comparative analysis. The material was extracted by dipping the plant
material into ethyl acetate to extract the waxy outer layers of the material only.
All samples were analysed using the LC-MS method developed for the glycerides
present in propolis as described in Example 4. This analysis method was able to detect the
novel dihydroxy fatty acid glycerides at very low levels, along with other glycerides (if
present).
Results
Qualitative levels of dihydroxy fatty acid glycerides in twig, leaf or buds of a variety of
poplar species are shown in Table 15.
Table 15: Qualitative glyceride content in New Zealand poplar cultivars.
Cultivar Populus hybrid/clone Plant part Twig Leaf Bud Kulu ciliata Wall. ex Royle np np ND Oxford maximowiczii Henry x berolinensis Dipp. np np ND Pecam maximowiczii x nigra np np ND Selwyn deltoides x nigra +++ +++ ND Tasman X euramericana Guinier (=X canadensis ++ ++ Moench) Luisa X euramericana Guinier (=X canadensis +++ +++ ND Avanzo Moench) Fraser X euramericana Guinier (=X canadensis +++ ++ ND Moench) Yunnan yunnanensis Dode np np ND Geyles maximowiczii x nigra np np ND Italica nigra L. np np ND np = glycerides not present, ++ moderate levels of glycerides, +++ high levels of glycerides, ND = not determined.
The analysis showed that the same dihydroxy fatty acid glycerides seen in propolis
were present in many of the more commonly planted New Zealand poplar cultivars
analysed. The glycerides were found on leaves, twigs and buds of many poplars and
appeared to be generally associated with the resin on these parts.
The fatty acid profile for the glycerides was mostly the same as that seen in the
propolis, suggesting poplar is the source of the propolis glycerides. It is anticipated that the
individual glycerides could be isolated from poplar exudates in a similar manner to that used
in Example 4. Poplar cultivars such as 'Tasman' and 'Fraser' are typical examples of the
widely planted Populus x Euramerica (also known as Canadian poplar and Carolina poplar)
while Populus deltoides x nigra hybrids such as Selwyn are also common in New Zealand.
The dihydroxy fatty acid glycerides were generally found to be absent in some of the other
cultivars such as the P. maximowiczii x nigra clones and the Chinese poplar species 'Yunan'.
Glycerides were absent in hybrids not containing a cross with deltoides. These types of glycerides were also absent in samples of willow leaf and buds, while in Paulownia low levels of different types of glycerides were present, showing that these plant species are not the source of the glyceride in propolis, and are not suitable plant species for isolating the glyceride compounds described herein.
Example 16: Determination of the chirality of the novel glycerides
This example shows that the naturally occurring novel dihydroxy fatty acid glycerides
have 3R, 8R stereochemistry. Chiral analysis of alcohol groups of organic molecules is
generally performed by using chiral derivatisation reagents. These reagents are available in
R and S forms and usually contain an aromatic group which when attached to the alcohol
group is able to affect, by shielding, the 1H NMR chemical shifts of neighbouring groups.
The variation in the shift of neighbouring groups for the separately prepared R and S
derivatives indicates the original alcohol chirality. For the novel glycerides the
stereochemistry of the alcoholic groups of the 3, 8-dihydroxy fatty acids is of most interest.
As the length of the fatty acid chain has no effect of the chemical shift of the protons at C
2,-3 and -8 positions, a crude glyceride mixture was used for this work.
Preparation of R, S diesters and 1H-NMR analysis
The crude glyceride mixture was hydrolysed using LiOH as described in Example 4.
The free fatty acid methyl ester was then prepared from the hydrolysed glyceride mixture
as described in Example 4 by using diazomethane. R- and S- a-methoxyphenylacetic acid
(MPA), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) and 4
dimethylaminopyridine (DMAP) were purchased from Sigma. The chiral ester derivatisation
method used was that described by Freire et al 2005. 10 mg of the dihydroxy free fatty acid
methyl ester mixture was dissolved in approximately 0.8 mL CH2C2 (dry) in a 5 mL reaction
vial. The solution was stirred at room temperature using a magnetic stirrer and 23 mg of R
a-methoxyphenylacetic acid, 10 pL of EDC and a catalytic amount of DMAP were added.
The reaction was worked up by washing the reaction solution with water, 1M HCI, sodium bicarbonate and water. The organic layer was dried under vacuum and purified using a small silica gel column to obtain the diester product (approximately 8 mg). The S-diester was obtained in a similar fashion. 1H NMR samples were dissolved in CDC13 and run at
500MHz. The products were then examined by 1H NMR.
Results and discussion
The signals for H-2, H-3 and H-8 were sufficiently well separated for detailed analysis.
The first observation was that the two products were single species by NMR. This would
only be the case if the original alcohols were chiral, i.e. the C-3 and C-8 hydroxyls are
stereospecific, each either R or S. The changes in the shifts of these derivatives,A(S-R),
are shown in Table 16. Based on comparison with similar compounds in the literature
(Tables 17 and 18), the results show that the stereochemical configuration is 3R, 8R for all
the glycerides.
Table 16: 1H NMR chemical shift differences between R and S MPA esters for
3,8 dihydroxy fatty acid methyl esters.
Hydrogen 5 5 DiR 5 DiS A5(S-R)
Dihydroxy fatty fatty acid fatty acid
acid methyl methyl ester methyl ester
ester
Ha-C(2) 2.5 2.6 2.43 -0.17
Hb-C(2) 2.41 2.5 2.35 -0.15
H-3 4.0 5.22 5.15 -0.07
H-8 3.6 4.8 4.9 +0.1
Confirmation of stereochemistry by comparison with the literature
The changes in the shifts of A5(S-R) can then be compared with relevant examples
from the literature to confirm the stereochemistry. There are two examples in the literature where direct comparisons are valid and a similar derivatisation agent has been used, these are 3,7-diacetoxy docosahexanoic acid, otherwise known as byrsonic acid (Reis et al 2007), and 1-acetyl-2-(3,7-diacetoxyeiconsaonyl)-glycerol, otherwise known as oncidinol (Reis et al 2003). Byrsonic acid was hydrolysed to remove the acetoxy groups to produce a 3,7 dihydroxy fatty acid. 3,7 diesters were then prepared using the chiral derivatisation agent
Mosher's acid (methoxy{trifluoromethyl}phenylacetic acid), and were then examined by 1H
NMR. The changes in A 5(S-R) were as shown in Table 17 which allowed Reis et al 2007 to
assign the acid as (3R,7R)-3,7-dihydroxy docosanoic acid.
Table 17: 1H NMR chemical shift differences between R and S Mosher esters
for 3,7 dihydroxy fatty acid methyl esters derived from byrsonic acid.
Hydrogen A5(S-R)
Ha-C(2) -0.11
Hb-C(2) -0.13
H-3 -0.08
H-7 +0.07
Similarly, Reis et al 2003 also hydrolyzed oncidinol to remove the glycerol and acetoxy
groups to give a 3,7 dihydroxy fatty acid, the acid was derivatized to a diester using Mosher
acid and the 3,7 diester was examined by 1H NMR. The changes in A(S-R) as shown in
Table 18 enabled the acid to be assigned as a 3R,7R dihydroxy acid.
Table 18: 1H NMR chemical shift differences between R and S Mosher esters
for 3,7 dihydroxy fatty acid methyl esters derived from oncidinol.
Hydrogen A 5(S-R)
Ha-C(2) -0.11
Hb-C(2) -0.12
H-3 -0.06
H-7 +0.08
For both byrsonic acid and oncinidol, the results are very similar to those seen for the
novel glycerides in Table 16. The A5(S-R) values are negative for H-2 and H-3 and positive
for the remote hydroxyl position H8, confirming that the stereochemical configuration is 3R,
8R for all the glycerides.
Freire F, Seco JM, Quiho6 E, Riguera R. The prediction of the absolute stereochemistry of
primary and secondary 1,2-diols by 1H NMR spectroscopy: principles and applications.
Chemistry 2005 19;11(19):5509-22).
Reis, M.G., De Faria, A.D., Dos Santos, I.A., Amaral, M.D.C.E., Marsaioli, A.J. Byrsonic acid
- The clue to floral mimicry involving oil-producing flowers and oil-collecting bees.
Journal of Chemical Ecology. 2007, 33 (7), pp. 1421-1429
Reis, M.G., De Faria, A.D., Do Amaral, M.D.C.E., Marsaioli, A.J. Oncidinol - A novel
diacylglycerol from Ornithophora radicans Barb. Rodr. (Orchidaceae) floral oil. 2003.
Tetrahedron Letters. 44 (46), pp. 8519-8523
Anti-epithelial cancer compositions of this invention, including those comprising
propolis or an extract or fraction thereof enriched in compounds of formula (I) and
cyclodextrin, and those comprising isolated or purified compounds derived from propolis or
fraction thereof can be used in the pharmaceutical and medical fields, for example in
medical devices, medical supplies, and pharmaceuticals and in consumer goods including
foods and beverages, compositions, nutraceuticals, cosmeceuticals, and functional foods.
Methods of using such compositions, for example in the treatment of epithelial cancers,
such as skin cancers and symptoms thereof have application in the medical field.
1. A method of treating or preventing an epithelial cancer in a subject or of inducing
apoptosis of one or more neoplastic epithelial cells in a subject, the method comprising
administering an effective amount of one or more compounds of formula (I): R1 (CH (CH y R6
O OR4 OR5
R 1 =OH, OR 7or0 OR 3
OR 2
(1)
wherein R2, R3, R4 and Rs are each independently H or acetyl (CH3CO-),
R6 is H or CH3, R7 is CH3 or C2 to C6 saturated or unsaturated hydrocarbon and
x and y are each independently an integer from 3 to 14,
provided that when R6is H, x+ y is greater than 10 and less than or equal to 18, and
when R6 is CH3, x+y is greater than 9 and less than or equal to 17,
or one or more pharmaceutically acceptable salts or solvates thereof, to a subject in
need thereof.
2. A pharmaceutical composition comprising a therapeutically effective amount of a
compound of a compound of formula (I): R1 (CH (CH y R6
0 OR4 OR5
R 1 =OH, OR 7or0 OR 3
OR 2
(1)
wherein R2, R3, R4 and Rs are each independently H or acetyl (CH3CO-),
R6 is H or CH3, R7 is CH3 or C2 to C6 saturated or unsaturated hydrocarbon and
x and y are each independently an integer from 3 to 14,
provided that when R6is H, x+ y is greater than 10 and less than or equal to 18, and
when R6 is CH3, x+y is greater than 9 and less than or equal to 17.
3. The composition of claim 2, wherein R6 is H.
4. The composition of claim 2, wherein R6 is CH3.
5. The pharmaceutical composition according to claim 2 or 3 comprising a therapeutically
effective amount of at least one compound selected from any one or more of
a) 3,8-dihydroxy eicosanoic acid,
b) 1-(3,8-dihydroxy eicosanoyl) glycerol,
c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol,
d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol,
e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol,
f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol,
g) 3,8-dihydroxy eicosanoic acid methyl ester
h) 3,8-dihydroxy heneicosanoic acid,
i) 1-(3,8-dihydroxy heneicosanoyl) glycerol,
j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol,
k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,
1) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,
m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,
n) 3,8-dihydroxy heneicosanoic acid methyl ester
o) 3,8-dihydroxy docosanoic acid,
p) 1-(3,8-dihydroxy docosanoyl) glycerol,
q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol,
r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol,
s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol, t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, and u) 3,8-dihydroxy docosanoic acid methyl ester, or a pharmaceutically acceptable salt or solvate of any one of a) to u), for use in treating or preventing an epithelial cancer.
6. The use of a compound of formula (I): R1 (CH (CH R6
0 OR4 OR5
R 1 =OH, OR 7or0 OR3
OR 2
(1)
wherein R2, R3, R4 and Rs are each independently H or acetyl (CH3CO-),
R6 is H or CH3, R7 is CH3 or C2 to C6 saturated or unsaturated hydrocarbon and
x and y are each independently an integer from 3 to 14,
provided that when R6is H, x+ y is greater than 10 and less than or equal to 18, and
when R6 is CH3, x+y is greater than 9 and less than or equal to 17,
in the manufacture of a composition for use in inhibiting epithelial tumour formation,
inhibiting epithelial tumour growth, inhibiting epithelial tumour metastasis or treating or
preventing epithelial cancer in a subject; inducing apoptosis of one or more neoplastic
epithelial cells in a subject; increasing the responsiveness of a subject to an epithelial
cancer therapy; increasing the sensitivity of an epithelial tumour in a subject to an
epithelial cancer therapy; resensitising one or more epithelial cancer cells in a subject
that are resistant to treatment; at least partially reversing the resistance of a neoplastic
cell in a subject suffering from epithelial cancer to an epithelial cancer therapy;
reversing, wholly or in part, the resistance of an epithelial cancer-burdened patient to
an epithelial cancer therapy; or re-sensitising one or more tumours of an epithelial
cancer-burdened patient which are, or are predicted to either be or become, resistant to
Claims (1)
- treatment with an epithelial cancer therapy to treatment with an epithelial cancertherapy.7. The use of claim 6, wherein the subject is a human subject.8. The use of claim 6 or 7, wherein the compound is a compound as defined in any one ofclaims 2, 3 or 4.9. The use of at least one compound selected from any one or more of the groupconsisting ofa) 3,8-dihydroxy eicosanoic acid,b) 1-(3,8-dihydroxy eicosanoyl) glycerol,c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy glycerol,d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol,e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol,f) 1-(3,8-diacetoxy eicosanoyl) 2,3-diacetoxy glycerol,g) 3,8-dihydroxy eicosanoic acid methyl esterh) 3,8-dihydroxy heneicosanoic acid,i) 1-(3,8-dihydroxy heneicosanoyl) glycerol,j) 1-(3,8-dihydroxy heneicosanoyl) 2-acetoxy glycerol,k) 1-(3,8-dihydroxy heneicosanoyl) 3-acetoxy glycerol,1) 1-(3,8-dihydroxy heneicosanoyl) 2,3-diacetoxy glycerol,m) 1-(3,8-diacetoxy heneicosanoyl) 2,3-diacetoxy glycerol,n) 3,8-dihydroxy heneicosanoic acid methyl estero) 3,8-dihydroxy docosanoic acid,p) 1-(3,8-dihydroxy docosanoyl) glycerol,q) 1-(3,8-dihydroxy docosanoyl) 2-acetoxy glycerol,r) 1-(3,8-dihydroxy docosanoyl) 3-acetoxy glycerol,s) 1-(3,8-dihydroxy docosanoyl) 2,3-diacetoxy glycerol,t) 1-(3,8-diacetoxy docosanoyl) 2,3-diacetoxy glycerol, andu) 3,8-dihydroxy docosanoic acid methyl ester,or a pharmaceutically acceptable salt or solvate of any one of a) to u), optionally with at least one additional therapeutic agent, in the manufacture of a composition for use in inhibiting epithelial tumour formation, inhibiting epithelial tumour growth, inhibiting epithelial tumour metastasis or treating or preventing epithelial cancer in a subject; inducing apoptosis of one or more neoplastic epithelial cells in a subject; increasing the responsiveness of a subject to an epithelial cancer therapy; increasing the sensitivity of an epithelial tumour in a subject to an epithelial cancer therapy; resensitising one or more epithelial cancer cells in a subject that are resistant to treatment; at least partially reversing the resistance of a neoplastic cell in a subject suffering from epithelial cancer to an epithelial cancer therapy; reversing, wholly or in part, the resistance of an epithelial cancer-burdened patient to an epithelial cancer therapy; or re-sensitising one or more tumours of an epithelial cancer-burdened patient which are, or are predicted to either be or become, resistant to treatment with an epithelial cancer therapy to treatment with an epithelial cancer therapy.10. A composition of any one of claims 2 to 5 for use in inhibiting epithelial tumourformation, inhibiting epithelial tumour growth, inhibiting epithelial tumour metastasis ortreating or preventing epithelial cancer in a human subject; inducing apoptosis of oneor more neoplastic epithelial cells in a human subject; increasing the responsiveness ofa human subject to an epithelial cancer therapy; increasing the sensitivity of anepithelial tumour in a human subject to an epithelial cancer therapy; resensitising oneor more epithelial cancer cells in a human subject that are resistant to treatment; atleast partially reversing the resistance of a neoplastic cell in a human subject sufferingfrom epithelial cancer to an epithelial cancer therapy; reversing, wholly or in part, theresistance of an epithelial cancer-burdened human patient to an epithelial cancertherapy; or re-sensitising one or more tumours of an epithelial cancer-burdened humanpatient which are, or are predicted to either be or become, resistant to treatment withan epithelial cancer therapy to treatment with an epithelial cancer therapy.11. The composition of claim 10 for use in the treatment or prevention of epithelial cancer.12. A method of isolating or purifying a compound or mixture of compounds of formula (I)from propolis or poplar, or an extract or exudate thereof comprising the steps of a. providing a poplar extract, poplar-derived propolis, or an extract or exudate thereof, and b. isolating or purifying the compound from the poplar, propolis, or an extract or exudate thereof.13. The method of claim 12 wherein the poplar extract, poplar-derived propolis, or extractor exudate thereof is from Populus deltoides, hybrids of Populus deltoids includingPopulus deltoides x nigra or Populus euramericana Guinier including cultivars, crossesand hybrids thereof.14. The method of claim 13 wherein the Populus euramericana Guinier is a cultivar selectedfrom the following group: Selwyn, Tasman, Luisa Avanzo, and Fraser.15. The method of any one of claims 12 to 14 comprising one or more of the followingsteps:a. fractionating the poplar, propolis, or extract or exudate thereof bychromatography, for example, column chromatography, reverse phasechromatography, normal phase chromatography, or supercritical fluidchromatography, and/or solvent partitioning and/or supercritical extraction toproduce one or more fractions comprising one or more of the compounds offormula (I),b. fractionating the poplar, propolis, or extract or exudate thereof or one or morefractions, by preparative HPLC and/or polymeric resin fractionation to produceone or more fractions comprising one or more of the compounds of formula(I), and, optionally,c. further purifying the one or more compounds of formula (I) from the one ormore fractions of step b) and/or step c).16. A composition or product comprising one or more compounds of formula (I) wherein theamount and/or concentration of one or more compounds of formula (I) is specified on anindicator associated with the composition or product.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2023201100A AU2023201100B2 (en) | 2016-03-24 | 2023-02-24 | Therapeutic compositions and uses thereof |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ718379 | 2016-03-24 | ||
NZ71837916 | 2016-03-24 | ||
AU2017237651A AU2017237651A1 (en) | 2016-03-24 | 2017-03-24 | Therapeutic compositions and uses thereof |
PCT/NZ2017/050031 WO2017164750A1 (en) | 2016-03-24 | 2017-03-24 | Therapeutic compositions and uses thereof |
AU2023201100A AU2023201100B2 (en) | 2016-03-24 | 2023-02-24 | Therapeutic compositions and uses thereof |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2017237651A Division AU2017237651A1 (en) | 2016-03-24 | 2017-03-24 | Therapeutic compositions and uses thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2023201100A1 true AU2023201100A1 (en) | 2023-03-30 |
AU2023201100B2 AU2023201100B2 (en) | 2024-06-13 |
Family
ID=
Also Published As
Publication number | Publication date |
---|---|
WO2017164750A1 (en) | 2017-09-28 |
JP2019515943A (en) | 2019-06-13 |
AU2017237651A1 (en) | 2018-11-01 |
JP2022046588A (en) | 2022-03-23 |
CN109310660B (en) | 2023-07-11 |
CN109310660A (en) | 2019-02-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2023202398A1 (en) | Propolis and extracts thereof for the treatment of skin cancers and improvement of skin health | |
US10420804B2 (en) | Therapeutic compositions and uses thereof | |
JP6444984B2 (en) | Therapeutic compositions comprising propolis extract and uses thereof | |
JP2022046588A (en) | Therapeutic compositions and uses thereof | |
Gao et al. | Effects of N-trans-feruloyltyramine isolated from laba garlic on antioxidant, cytotoxic activities and H2O2-induced oxidative damage in HepG2 and L02 cells | |
US20130310332A1 (en) | Maple tree-derived products and uses thereof | |
Pham et al. | DPPH radical scavenging and xanthine oxidase inhibitory activity of Terminalia macroptera leaves | |
Wen et al. | Optimizing nucleophilic depolymerization of proanthocyanidins in grape seeds to dimeric proanthocyanidin B1 or B2 | |
Benincasa et al. | Qualitative and quantitative analysis of phenolic compounds in spray-dried olive mill wastewater | |
JP2008156265A (en) | A-type proanthocyanidin oligomer fraction and method for producing the same | |
Kaur et al. | Isolation of embelin from and evaluation of its anti-cancer potential in Embelia ribes breast cancer | |
US20160022753A1 (en) | Compositions derived from sweet potato greens and methods of preparation and use | |
Macedo et al. | Bioactive compounds from Actinidia arguta fruit as a new strategy to fight glioblastoma | |
KR101963841B1 (en) | Antioxidant composition comprising polyamine compounds isolated from Quercus Mongolica pollen extracts | |
JP5976025B2 (en) | Method for producing hyaluronic acid synthesis promoter, hyaluronic acid synthesis promoter, method for producing HAS2 mRNA expression promoter, and HAS2 mRNA expression promoter | |
Omar | Compounds from A. platanoides bark, v. Corymbosum roots & topical formulations using maple syrup | |
Zhang | Surface functionalization of bioactive glasses with natural molecules of biological significance | |
AU2006347123A1 (en) | Composition for preventing and/or treating tumor containing component originating in the bark of tree belonging to the genus Acacia |