CN1279014C - 具有抗血管生成、抗肿瘤和促凋亡活性的类维生素a衍生物 - Google Patents
具有抗血管生成、抗肿瘤和促凋亡活性的类维生素a衍生物 Download PDFInfo
- Publication number
- CN1279014C CN1279014C CNB028150082A CN02815008A CN1279014C CN 1279014 C CN1279014 C CN 1279014C CN B028150082 A CNB028150082 A CN B028150082A CN 02815008 A CN02815008 A CN 02815008A CN 1279014 C CN1279014 C CN 1279014C
- Authority
- CN
- China
- Prior art keywords
- purposes
- compound
- cell
- tumour
- tumor
- 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.)
- Expired - Fee Related
Links
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 19
- 150000004492 retinoid derivatives Chemical class 0.000 title description 7
- 230000000861 pro-apoptotic effect Effects 0.000 title description 2
- 230000001772 anti-angiogenic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 93
- 230000033115 angiogenesis Effects 0.000 claims abstract description 5
- 230000007170 pathology Effects 0.000 claims abstract description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 57
- 230000006907 apoptotic process Effects 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 13
- 230000003013 cytotoxicity Effects 0.000 claims description 12
- 231100000135 cytotoxicity Toxicity 0.000 claims description 12
- 239000003005 anticarcinogenic agent Substances 0.000 claims description 11
- 201000011510 cancer Diseases 0.000 claims description 11
- 230000001575 pathological effect Effects 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 208000037976 chronic inflammation Diseases 0.000 claims description 6
- 208000037893 chronic inflammatory disorder Diseases 0.000 claims description 6
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 6
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 5
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 5
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 claims description 5
- 201000004681 Psoriasis Diseases 0.000 claims description 5
- 239000004037 angiogenesis inhibitor Substances 0.000 claims description 5
- 229940121369 angiogenesis inhibitor Drugs 0.000 claims description 5
- 238000012546 transfer Methods 0.000 claims description 5
- 206010039361 Sacroiliitis Diseases 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 claims description 3
- 206010027476 Metastases Diseases 0.000 claims description 3
- 208000018084 Bone neoplasm Diseases 0.000 claims description 2
- 208000017604 Hodgkin disease Diseases 0.000 claims description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
- 206010024305 Leukaemia monocytic Diseases 0.000 claims description 2
- 208000028018 Lymphocytic leukaemia Diseases 0.000 claims description 2
- 208000035490 Megakaryoblastic Acute Leukemia Diseases 0.000 claims description 2
- 206010052399 Neuroendocrine tumour Diseases 0.000 claims description 2
- 206010039491 Sarcoma Diseases 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 208000020700 acute megakaryocytic leukemia Diseases 0.000 claims description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
- 208000002458 carcinoid tumor Diseases 0.000 claims description 2
- 208000003747 lymphoid leukemia Diseases 0.000 claims description 2
- 201000006894 monocytic leukemia Diseases 0.000 claims description 2
- 208000025113 myeloid leukemia Diseases 0.000 claims description 2
- 208000016065 neuroendocrine neoplasm Diseases 0.000 claims description 2
- 201000011519 neuroendocrine tumor Diseases 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 71
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 59
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 56
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 238000002360 preparation method Methods 0.000 description 30
- 239000000047 product Substances 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 20
- 239000011734 sodium Substances 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- 239000002131 composite material Substances 0.000 description 18
- 238000010586 diagram Methods 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- 241000699666 Mus <mouse, genus> Species 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 230000022131 cell cycle Effects 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 238000005406 washing Methods 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- 239000012980 RPMI-1640 medium Substances 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 210000004881 tumor cell Anatomy 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 11
- CCRCUPLGCSFEDV-UHFFFAOYSA-N cinnamic acid methyl ester Natural products COC(=O)C=CC1=CC=CC=C1 CCRCUPLGCSFEDV-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 10
- 230000008020 evaporation Effects 0.000 description 10
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 10
- CCRCUPLGCSFEDV-BQYQJAHWSA-N methyl trans-cinnamate Chemical compound COC(=O)\C=C\C1=CC=CC=C1 CCRCUPLGCSFEDV-BQYQJAHWSA-N 0.000 description 10
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 210000004204 blood vessel Anatomy 0.000 description 9
- 230000004069 differentiation Effects 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 238000000935 solvent evaporation Methods 0.000 description 9
- 239000006228 supernatant Substances 0.000 description 9
- 230000004083 survival effect Effects 0.000 description 9
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 8
- 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 8
- 210000003725 endotheliocyte Anatomy 0.000 description 8
- -1 phosphate tyrosine kinase inhibitor Chemical class 0.000 description 8
- 238000011160 research Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000007605 air drying Methods 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 230000012010 growth Effects 0.000 description 7
- 108010082117 matrigel Proteins 0.000 description 7
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 238000012545 processing Methods 0.000 description 7
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 7
- 230000004862 vasculogenesis Effects 0.000 description 7
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
- 210000003711 chorioallantoic membrane Anatomy 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 238000002791 soaking Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 230000002792 vascular Effects 0.000 description 6
- NQBWNECTZUOWID-UHFFFAOYSA-N (E)-cinnamyl (E)-cinnamate Natural products C=1C=CC=CC=1C=CC(=O)OCC=CC1=CC=CC=C1 NQBWNECTZUOWID-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 101000573199 Homo sapiens Protein PML Proteins 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 206010033128 Ovarian cancer Diseases 0.000 description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 description 5
- NQBWNECTZUOWID-QSYVVUFSSA-N cinnamyl cinnamate Chemical compound C=1C=CC=CC=1\C=C/C(=O)OC\C=C\C1=CC=CC=C1 NQBWNECTZUOWID-QSYVVUFSSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 210000004907 gland Anatomy 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000007912 intraperitoneal administration Methods 0.000 description 5
- 208000020816 lung neoplasm Diseases 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 229960001727 tretinoin Drugs 0.000 description 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 4
- 229930012538 Paclitaxel Natural products 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 206010060862 Prostate cancer Diseases 0.000 description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 4
- 108010038912 Retinoid X Receptors Proteins 0.000 description 4
- 102000034527 Retinoid X Receptors Human genes 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 108050007852 Tumour necrosis factor Proteins 0.000 description 4
- 102000018594 Tumour necrosis factor Human genes 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 231100000433 cytotoxic Toxicity 0.000 description 4
- 230000001472 cytotoxic effect Effects 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 208000005017 glioblastoma Diseases 0.000 description 4
- 102000054896 human PML Human genes 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 210000001161 mammalian embryo Anatomy 0.000 description 4
- 230000000050 nutritive effect Effects 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 229960001592 paclitaxel Drugs 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 229930002330 retinoic acid Natural products 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 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 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000287828 Gallus gallus Species 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 206010029113 Neovascularisation Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 244000309466 calf Species 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- YVPJCJLMRRTDMQ-UHFFFAOYSA-N ethyl diazoacetate Chemical compound CCOC(=O)C=[N+]=[N-] YVPJCJLMRRTDMQ-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 231100000225 lethality Toxicity 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- 230000005012 migration Effects 0.000 description 3
- 238000013508 migration Methods 0.000 description 3
- JPXMTWWFLBLUCD-UHFFFAOYSA-N nitro blue tetrazolium(2+) Chemical compound COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC(=CC=2)[N+]([O-])=O)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=C([N+]([O-])=O)C=C1 JPXMTWWFLBLUCD-UHFFFAOYSA-N 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 108090000064 retinoic acid receptors Proteins 0.000 description 3
- 102000003702 retinoic acid receptors Human genes 0.000 description 3
- 230000000007 visual effect Effects 0.000 description 3
- VXWBQOJISHAKKM-UHFFFAOYSA-N (4-formylphenyl)boronic acid Chemical compound OB(O)C1=CC=C(C=O)C=C1 VXWBQOJISHAKKM-UHFFFAOYSA-N 0.000 description 2
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000029816 Collagenase Human genes 0.000 description 2
- 108060005980 Collagenase Proteins 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 229930182566 Gentamicin Natural products 0.000 description 2
- 229910010082 LiAlH Inorganic materials 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 235000018259 Solanum vestissimum Nutrition 0.000 description 2
- 240000002825 Solanum vestissimum Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000003527 anti-angiogenesis Effects 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 239000007975 buffered saline Substances 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 230000007541 cellular toxicity Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000002975 chemoattractant Substances 0.000 description 2
- 210000000349 chromosome Anatomy 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 229960002424 collagenase Drugs 0.000 description 2
- 201000010897 colon adenocarcinoma Diseases 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 201000010989 colorectal carcinoma Diseases 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 210000003038 endothelium Anatomy 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 210000001365 lymphatic vessel Anatomy 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- PKAHQJNJPDVTDP-UHFFFAOYSA-N methyl cyclopropanecarboxylate Chemical class COC(=O)C1CC1 PKAHQJNJPDVTDP-UHFFFAOYSA-N 0.000 description 2
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical class COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 description 2
- 230000004089 microcirculation Effects 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 239000004417 polycarbonate Substances 0.000 description 2
- 229920000515 polycarbonate Polymers 0.000 description 2
- 239000008389 polyethoxylated castor oil Substances 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 210000004765 promyelocyte Anatomy 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 231100000820 toxicity test Toxicity 0.000 description 2
- 230000005945 translocation Effects 0.000 description 2
- 229910052720 vanadium Inorganic materials 0.000 description 2
- 230000002227 vasoactive effect Effects 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 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 2
- 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 2
- 230000003442 weekly effect Effects 0.000 description 2
- QGVLYPPODPLXMB-UBTYZVCOSA-N (1aR,1bS,4aR,7aS,7bS,8R,9R,9aS)-4a,7b,9,9a-tetrahydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-1,1a,1b,4,4a,7a,7b,8,9,9a-decahydro-5H-cyclopropa[3,4]benzo[1,2-e]azulen-5-one Chemical compound C1=C(CO)C[C@]2(O)C(=O)C(C)=C[C@H]2[C@@]2(O)[C@H](C)[C@@H](O)[C@@]3(O)C(C)(C)[C@H]3[C@@H]21 QGVLYPPODPLXMB-UBTYZVCOSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- YJGVMLPVUAXIQN-LGWHJFRWSA-N (5s,5ar,8ar,9r)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5h-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one 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-LGWHJFRWSA-N 0.000 description 1
- OOCCDEMITAIZTP-QPJJXVBHSA-N (E)-cinnamyl alcohol Chemical compound OC\C=C\C1=CC=CC=C1 OOCCDEMITAIZTP-QPJJXVBHSA-N 0.000 description 1
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- NIBFJPXGNVPNHK-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-4-carbaldehyde Chemical group C1=CC(C=O)=C2OC(F)(F)OC2=C1 NIBFJPXGNVPNHK-UHFFFAOYSA-N 0.000 description 1
- AHEASPYYWCOKMO-UHFFFAOYSA-N 2-(1-adamantyl)-4-(4-bromophenyl)phenol Chemical compound C1=C(C23CC4CC(CC(C4)C2)C3)C(O)=CC=C1C1=CC=C(Br)C=C1 AHEASPYYWCOKMO-UHFFFAOYSA-N 0.000 description 1
- NYJXKHIVLGWPCF-UHFFFAOYSA-N 2-(1-adamantyl)-4-bromophenol Chemical compound OC1=CC=C(Br)C=C1C1(C2)CC(C3)CC2CC3C1 NYJXKHIVLGWPCF-UHFFFAOYSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- KSILMCDYDAKOJD-UHFFFAOYSA-N 2-aminoisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(N)C(=O)C2=C1 KSILMCDYDAKOJD-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- ARUBXNBYMCVENE-UHFFFAOYSA-N 4-(4-bromophenyl)phenol Chemical compound C1=CC(O)=CC=C1C1=CC=C(Br)C=C1 ARUBXNBYMCVENE-UHFFFAOYSA-N 0.000 description 1
- VVTNSTLJOVCBDL-UHFFFAOYSA-N 4-[[3,5-bis(trimethylsilyl)benzoyl]amino]benzoic acid Chemical compound C[Si](C)(C)C1=CC([Si](C)(C)C)=CC(C(=O)NC=2C=CC(=CC=2)C(O)=O)=C1 VVTNSTLJOVCBDL-UHFFFAOYSA-N 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 229940088872 Apoptosis inhibitor Drugs 0.000 description 1
- 101100448366 Arabidopsis thaliana GH3.12 gene Proteins 0.000 description 1
- 238000011725 BALB/c mouse Methods 0.000 description 1
- 241000208328 Catharanthus Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- 102100022641 Coagulation factor IX Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108010076282 Factor IX Proteins 0.000 description 1
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 1
- 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 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001111421 Pannus Species 0.000 description 1
- SHGAZHPCJJPHSC-UHFFFAOYSA-N Panrexin Chemical compound OC(=O)C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- 230000010799 Receptor Interactions Effects 0.000 description 1
- NCYCYZXNIZJOKI-OVSJKPMPSA-N Retinaldehyde Chemical compound O=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-OVSJKPMPSA-N 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 238000006932 Simmons-Smith cyclopropanation reaction Methods 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- NDQKGYXNMLOECO-UHFFFAOYSA-N acetic acid;potassium Chemical compound [K].CC(O)=O NDQKGYXNMLOECO-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000964 angiostatic effect Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000000158 apoptosis inhibitor Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 229940064804 betadine Drugs 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- HXLVDKGPVGFXTH-UHFFFAOYSA-N butyl(dimethyl)silane Chemical group CCCC[SiH](C)C HXLVDKGPVGFXTH-UHFFFAOYSA-N 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 230000008355 cartilage degradation Effects 0.000 description 1
- 230000034196 cell chemotaxis Effects 0.000 description 1
- 230000018486 cell cycle phase Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000013000 chemical inhibitor Substances 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- ASQQEOXYFGEFKQ-UHFFFAOYSA-N dioxirane Chemical compound C1OO1 ASQQEOXYFGEFKQ-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000010595 endothelial cell migration Effects 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 238000001976 enzyme digestion Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 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
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- ISNBJLXHBBZKSL-UHFFFAOYSA-N ethyl n-[2-(1,3-benzothiazole-2-carbonylamino)thiophene-3-carbonyl]carbamate Chemical compound C1=CSC(NC(=O)C=2SC3=CC=CC=C3N=2)=C1C(=O)NC(=O)OCC ISNBJLXHBBZKSL-UHFFFAOYSA-N 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
- 230000005284 excitation Effects 0.000 description 1
- 229960004222 factor ix Drugs 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- CEAZRRDELHUEMR-UHFFFAOYSA-N gentamicin Chemical class O1C(C(C)NC)CCC(N)C1OC1C(O)C(OC2C(C(NC)C(C)(O)CO2)O)C(N)CC1N CEAZRRDELHUEMR-UHFFFAOYSA-N 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 230000002687 intercalation Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- MFKOGXVHZUSUAF-UHFFFAOYSA-N methyl 3-(4-bromophenyl)prop-2-enoate Chemical class COC(=O)C=CC1=CC=C(Br)C=C1 MFKOGXVHZUSUAF-UHFFFAOYSA-N 0.000 description 1
- WNFQGEHRFXJKKS-UHFFFAOYSA-N methyl 3-(4-bromophenyl)prop-2-ynoate Chemical class COC(=O)C#CC1=CC=C(Br)C=C1 WNFQGEHRFXJKKS-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 231100000028 nontoxic concentration Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- QGVLYPPODPLXMB-QXYKVGAMSA-N phorbol Natural products C[C@@H]1[C@@H](O)[C@]2(O)[C@H]([C@H]3C=C(CO)C[C@@]4(O)[C@H](C=C(C)C4=O)[C@@]13O)C2(C)C QGVLYPPODPLXMB-QXYKVGAMSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical compound OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000011158 quantitative evaluation Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 108010059301 retinoic acid receptor gamma Proteins 0.000 description 1
- SDZJLEFFNHKNHJ-UHFFFAOYSA-N rhodium;dihydrate Chemical compound O.O.[Rh] SDZJLEFFNHKNHJ-UHFFFAOYSA-N 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 238000003211 trypan blue cell staining Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 210000003954 umbilical cord Anatomy 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 230000006459 vascular development Effects 0.000 description 1
- 230000004218 vascular function Effects 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- ABDKAPXRBAPSQN-UHFFFAOYSA-N veratrole Chemical compound COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 150000002266 vitamin A derivatives Chemical class 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 230000029663 wound healing Effects 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
- 229960000641 zorubicin Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/54—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings and other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C62/30—Unsaturated compounds
- C07C62/32—Unsaturated compounds containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/734—Ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Rheumatology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Urology & Nephrology (AREA)
- Dermatology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Hematology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Indole Compounds (AREA)
Abstract
式(I)的化合物,其中R、R′、R″、A和D具有本文中所述的含义,可用作治疗以血管生成改变为特征的病理情况的药物和抗肿瘤药。
Description
本发明涉及类维生素A衍生物,它被赋予抗肿瘤抗血管生成、促凋亡(pro-apoptotic)抗炎活性,具有通式(I):
其中:
R代表烷基、环烷基、杂环烷基、苯基、取代的苯基、金刚烷基,其中至少一个CH可以取代有C-卤素或C-烷基并且一个CH2可以被O、S、CH-卤素、CH-芳基、CH-杂芳基、CH-芳基烷基、CH-杂芳基烷基、CH-氨基取代;
R′代表OR、OCOR、CORIV;
R′-D代表O-(CH2)n-O;其中n=1-3;
D代表H、OH、O-烷基、(CH2)n-NH2、(CH2)n-NH-烷基、(CH2)n-OH,其中n=1-4;
R″代表四唑、SO3H、NHSO3H、CHO、COOH、COO-烷基.CONHOH、CONH-芳基、CONH-C6H4OH、CH2OR;PO3H2;CO-(CH2)n-芳基,其中n=0-4;
R代表H、烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、SO3H、α或βD-和L-糖基;
RIV代表H、OH、OR;
[A]代表[C(RV,RVI)-C(RVII,RVIII)]n、[C(RIX)=C(RX)]n、[C≡C]n,其中n=0-3;
RV、RVI、RVII、RVIII代表H、烷基、卤素、OH、OR、NO2、NH2、芳基、-O-、-CH2-、CX2-(其中X是卤素)、-CH(R)-;RIX、RX代表H、OH、卤素、烷基、芳基、CN、NO2、COOR。
维生素A及其生物活性衍生物维生素A醛和维生素A酸,在视觉方面起着重要作用,是生殖系统必需的,在胚胎生长期间起形态发生剂的作用,并以有机体的生长为基础调节大范围的细胞类型的生长和分化[M.Sporn,A.Roberts,D.Goodman,The Retinoids,Raven Press,New York1994]。维生素A酸及其衍生物的生物作用是通过与属于两个家族的核受体相互作用介导的:第一个名为RAR(维生素A酸受体),第二个名为RXR(类维生素AX受体)[P.Chambon,FASEB J.,1996,10,940-54]。每一家族分成3个亚型(α、β、γ),它们由三个不同的基因编码。
全-反式-维生素A酸(ATRA)与RAR和RXR结合,而9-顺式RA仅与RXR结合。
类维生素A,无论是天然还是合成的维生素A类似物,都对细胞增殖、分化和凋亡产生重大影响:这些性能被充分开发用于控制肿瘤和皮肤病学病理情况、以及与变化的血管生成有关的病理情况。
成年人中的血管生成在正常情况下是静止的,但是它代表一种正常功能,例如在伤口愈合,或者在女性生殖周期期间子宫内膜的重建中。
当血管功能降低以及组织灌注不足时,这种血管生成反应受到生理刺激。
更一般地,可以断言,在生理条件下,血管生成构成正反馈以响应不足灌注、或者氧和营养物质的供应降低,例如在动脉闭塞的情况下,在组织物质生长的情形下发生(例如,伴随形成肌肉组织的新血管形成);以及在与氧和营养物质需求增加有关的工作负荷增加的情况下发生。
在局部缺血的时候,由于动脉部分或完全闭塞,为维持灌注,必需要形成侧支血管。
众所周知,原发肿瘤的生长得到肿瘤组织的良好血管形成的支持。适当供给氧和营养物质促进了肿瘤自身的快速生长。
已证实血管生成的程度在肿瘤的预后方面可以是一个极其负面的因素(van Hinsbergh VW,Collen A,Koolwijk P;Ann.Oncol.,10 Suppl.,4:60-3,1999;Buolamwini JK;Curr.,Opin,Chem.,Biol,3(4):500-9,1999Aug.)。
还了解到,肿瘤细胞生物学方面的基础阶段是获得转移能力。
转移的肿瘤细胞能够丧失与周围结构的粘附性,侵入血管和淋巴管并在它们能够继续复制其自身的远处其它组织定殖。
转移在疾病的临床史上也是一个关键的事情,它是因癌症死亡的主要原因。它与肿瘤位置或相邻区域存在血管组织密切相关并受其促进。
肿瘤细胞穿过周围结构的迁移使这些细胞能够到达肿瘤内血管,无论是预先存在还是由新血管生成而形成,并因此到达血流(Ray JM.,Stetler-Stevenson WG;Eur.Respir.J.,7(11):2062-72,1994;Stetler-Stevenson WG,Liotta LA,Kleiner DE Jr;FASEB J.,7(15):1434-41,1993 Dec.)。
在肿瘤的血管区在淋巴管和血管之间存在交通使赘生细胞能够在这两种血管系统中移动。
最近研究已显示了血管生成和关节炎疾病之间的直接关系(KochAE;Arthritis and Rheumatism 41:951-962,1998)。具体地说,已证实关节软骨的新-血管形成在关节翳形成和关节炎进展中起着至关重要的作用。正常的软骨没有血管,而关节炎患者的滑液含有一种由内皮细胞产生的血管生成刺激因子(EASF)。
这种因子的存在与血管形成和软骨降解有关。
其它疾病也与异常的血管生成有关。
已发现在糖尿病性视网膜病[Histol Histopathol 1999 Oct;14(4):1287-94]、牛皮癣[Br.J.Dermatol.1999 Dec;141(6):1054-60]、慢性炎症和动脉粥样硬化[Planta Med.1998 Dec;64(8):686-95]中,受影响的组织的新血管形成是一种促进因子。
因此控制新血管形成是控制和治愈这些疾病的一个基本要素。
已经了解到可用于治疗癌症或具有抗血管生成活性的类维生素A。
一种属于最近一代类维生素A的化合物,CD437(Cancer Research,2002;62(8),2430-6;Blood,2000;95,2672-82;Leukemia,1999,13,739-49;Cancer Letters,1999,137,217-2)对RARγ具有选择性,在乳房癌、黑素瘤和宫颈癌细胞系中抑制细胞生长并诱导凋亡,这些细胞系包括那些对ATRA耐药的,其作用机理不依赖于受体结合(WO9703682;J.Med.Chem.1995,38,4993-5006)。CD437和其它衍生物如顺式-TTNPB衍生物(即四甲基-四氢-萘基-丙烯基苯甲酸酯),在开发新的凋亡诱导剂方面起着引导作用。
并列地,一些通过合成获得的类维生素A,诸如TAC-101[Clin.Cancer Res.1999,5,2304-10]或衍生物如RE-80、AM-580或Am-80[Eur.J.Pharmacol.1993,249,113-6]已显示抗血管生成性能。
尽管近年来有所进展,涉及发现用于治疗肿瘤疾病和特征为异常血管生成的疾病的新药的药理学研究仍被许多医药专家认为是最有希望的领域之一。
事实上,迄今为止仍然强烈地意识到需要能够阻断或干扰肿瘤疾病和因异常血管生成引起的疾病的新化合物。如上所述,这些疾病包括肿瘤、肿瘤转移、慢性炎症、关节炎疾病、糖尿病性视网膜病、牛皮癣、慢性炎症和动脉粥样硬化。
现已出人意料地发现,通式(I)的化合物被赋予抗肿瘤、促凋亡和抗血管生成的活性。
本发明的式(I)的化合物在以前从未描述过。
因此通式(I)的化合物是本文所述的本发明的目的。
本文所述的本发明的另一目的是通式(I)的化合物及其在医学领域的用途。
本文所述的本发明的另一目的是通式(I)的化合物及其制备方法。
本文所述的本发明的另一目的是一种含有式(I)化合物作为活性组分以及至少一种药用可接受的赋形剂和/或稀释剂的药物组合物。
本发明的另一目的涉及式(I)的化合物用于制备治疗与变化的血管生成有关的病理情况的药物的用途,其中该病理情况选自关节炎病理情况、肿瘤、转移、糖尿病性视网膜病、牛皮癣、慢性炎症疾病和动脉粥样硬化。
本发明的另一目的涉及式(I)的化合物用于制备治疗肿瘤的药物的用途,其中抗肿瘤活性为细胞毒性性质、和/或凋亡性质、和/或抗血管生成性质;其中肿瘤选自肉瘤、癌、类癌、骨肿瘤、神经内分泌肿瘤、淋巴细胞白血病、髓细胞白血病、单核细胞白血病、巨核细胞白血病、急性早幼粒细胞白血病或霍奇金病。
本发明的另一目的涉及式(I)的化合物用于制备可用于预防和治疗肿瘤转移的药物的用途。
如上所述,原发肿瘤的生长受到肿瘤组织的良好血管形成促进,并且新血管生成的程度可能是赘生物预后方面的高度负面因子。事实上,在肿瘤部位充足供应氧和营养物质促进肿瘤本身快速生长。
众所周知,可以为医师利用来治疗肿瘤的抗肿瘤药仍然不能阻止许多患者死于这些疾病。还公知大多数肿瘤患者不用单一抗癌药物治疗,而是用几种抗癌药物的组合治疗。需要联合施用抗癌药源于以下事实:通过在不同代谢水平起作用,在某些情况下它们有利于肿瘤完全缓解,而在其它情况下它们延长了患者的寿命和/或改善了所治疗患者的生活质量。
迄今仍然强烈意识到需要新的化合物与已知抗肿瘤化合物联合使用。
本文所述的本发明的化合物可以与一种或多种抗肿瘤药联合使用。
本文所述的本发明的另一目的是一种或多种式(I)的化合物与一种或多种已知的抗癌药的组合,其中抗癌药选自烷化剂、拓扑异构酶抑制剂、抗微管蛋白药、嵌入化合物、抗代谢物、天然产物诸如长春花属生物碱、表鬼臼毒素、抗生素、酶、taxans、细胞分化化合物、磷酸酪氨酸激酶抑制剂诸如Iressa或Glivec、TRAIL(与肿瘤坏死因子相关的凋亡诱导配体)、DR4或DR5受体的激动剂(TRAIL的位点)、免疫学抗肿瘤治疗用的化合物、抗肿瘤疫苗、或干扰素α、β、γ。
本文所述的本发明的另一目的是一种药物组合物,包括一种或多种式(I)的化合物与一种或多种已知的抗癌药的组合,和一种或多种药用可接受的赋形剂或载体。
本文所述的本发明的另一目的是一种或多种式(I)的化合物与一种或多种已知的抗癌药用于制备治疗肿瘤的药物的用途。
本文所述的本发明的另一目的是一种或多种式(I)的化合物与一种或多种已知的抗癌药用于制备治疗肿瘤的药物的用途,特征在于式(I)的化合物作为抗癌药的辅助物存在。
下面的实施例描述本发明。
一般合成步骤
式(I)的化合物是通过以下反应制得:将式(II)的化合物
其中R、R′和D具有式(I)中所述的含义,X代表卤素;与4-甲酰基硼酸在Miyaura-Suzuki反应中反应(Chem.Rev.1995,95,2457-83),得到式(III)的醛。
使式(III)的化合物(其中R、R′和D具有前面所述的含义)按照文献[例如Wittig(Org.Reactions,Vol.14)、Wadsworth-Horner-Emmons(Org.Reactions,Vol.25)、Knoevenagel(Org.Reactions,Vol.15)、Henry(Houben-Weyl,Methoden der organischen Chemie,Vol.10/1,p.250)、Darzens(Org.Reactions,Vol.5)等的反应]所述的熟知步骤反应,得到通式(I)的化合物,其中[A]代表C(RV,RVI)=C(RVII,RVIII)并且RV、RVI、RVII、RVIII代表H、烷基、卤素、OH、OR、NO2、NH2、芳基、-O-,或者其中[A]代表C≡C。
或者,通式(I)的化合物可以由通式(II)的化合物通过根据Miyaura-Suzuki(Chem.Rev.1995.95,2457-83)与通式(IV)的硼酸的反应制得
其中A和R″具有前面所述的含义。
或者,通式(I)的化合物,其中[A]代表C(RV,RVI)=C(RVII,RVIII)或C≡C,可以如下制得:从通式(V)的化合物开始
其中R、R′和D具有前面所述的含义,X代表卤素;通过已知方法,例如通过Heck(Org.Reactions,Vol.27)所述的在有金属或有机金属催化剂存在的情况下与取代的烯或炔反应。
或者,通式(I)的化合物,其中[A]代表C(RV,RVI)=C(RVII,RVIII)或C≡C可以从通式(I)的化合物开始,其中R和D是H并且R′具有前面所述的含义,通过与醇,例如金刚烷-1-醇、1-甲基-1-环己醇、叔丁醇等,在有硫酸或其它酸作为催化剂存在的情况下的烷基化反应制得,例如Charpentier等人(J.Med.Chem.1995,38,4993-5006)所述。用类似反应和合适醇可以从通式(I)的化合物(其中D是H而R,R′具有前面所述的含义)开始制备通式(I)的化合物。
通式(I)的化合物,其中[A]代表C(RV,H)-C(H,RVIII)并且RV、RVIII代表-CH2-,可以由通式(I)的化合物(其中[A]代表C(RV,RVI)=C(RVII,RVIII))通过文献中已知的环丙烷化反应制得,例如Simmons-Smith所述的反应和类似反应,例如J.Am.Chem.Soc.1959,81,4256或J.Am.Chem.Soc.1981,103,5813中所述,或者由通式(I)的化合物(其中A是CH=CH2,并且R″是H)通过与重氮基乙酸乙酯的反应制得。通式(I)的化合物,其中[A]代表C(RV,H)-C(H,RVIII)并且RV、RVIII代表-O,可以由通式(I)的化合物(其中[A]代表C(RV,RVI)=C(RVII,RVIII))通过文献中已知的环氧化反应,例如与二氧杂环丙烷或类似物反应制得,如Yang和同事在J.Org.Chem.,1995,60,3887-9中所述。
通式(I)的化合物,其中[A]代表C-C,可以由通式(I)的化合物(其中[A]代表C(RV,RVI)=C(RVII,RVIII)或C≡C)通过已知的对双键或三键的还原反应例如催化氢化反应制得。
通式(I)的化合物,其中R″代表CONHOH,可以从通式(I)的化合物(其中R″代表COOH)开始,通过用于合成异羟肟酸的文献中已知的步骤制得,例如通过与O-苄基羟基胺和缩合剂反应[De Luca等人J.Org.Chem.,2001,66,2534],接着催化氢化,或者与O-三甲基甲硅烷基羟基胺反应,接着去甲硅烷基。
通式(I)的化合物,其中R″代表CONH芳基,可以由通式(I)的化合物(其中R″代表COOH)通过用于合成酰胺类的文献中已知的步骤制得,例如Sangmam等人(Synth.Commun.,1998,28,2945-58)用于维生素A酸酰胺所述。
通式(I)的化合物,其中R″代表CH2OH,可以从通式(I)的化合物(其中R″代表COOH)或者由其酯或衍生物通过用于合成醇的文献中已知的步骤例如用LiAlH4还原制得。
实施例1
4-(3-(1-金刚烷基)-4-叔丁基二甲基-甲硅烷氧基苯基)苯甲醛的制备按照如下报道的合成图1制备标题化合物。
合成图1
将1.56g(3.70mmol)4-叔丁基二甲基甲硅烷氧基-3-(1-金刚烷基)-溴苯[Charpentier等人J.Med.Chem.,1995,38,4993-5006]溶解在7.5ml甲苯中。加入3.7ml的2M Na2CO3水溶液、0.128g(0.11mmol)四-三苯膦-钯,并加入610mg(4.07mmol)4-甲酰基苯硼酸的1.73ml乙醇溶液。在氮气流下将由此获得的溶液回流2小时。然后将溶液冷却,用乙酸乙酯吸收,并用NaCl饱和溶液洗涤。
将各相分离,将有机相过滤,在Na2SO4上干燥,再次过滤,将溶剂蒸发,并将残余物在硅胶(Merck)上使用己烷∶乙酸乙酯3∶1作为洗脱剂进行闪蒸色谱。
获得1.09g标题化合物。
熔点158℃。
1HNMR(CDCl3)δ:0.37(6H,s,-Si(CH3)2);1.05(9H,s,-t-Bu);1.78(6H,s,6Ad.);2.09(3H,s,3Ad.);2.15(6H,s,6Ad.);6.88(1H,d,1Ar,J=8.54Hz);7.35(1H,dd,1Ar,J=2.24Hz,J=8.54Hz);7.51(1H,d,1Ar,J=2.24Hz);7.70(2H,d,2Ar,J=8.14Hz);7.90(2H,d,2Ar,J=8.14Hz);10.01(1H,s,-CHO)。
实施例2
E-4(3-(1-金刚烷基)-4-叔丁基二甲基-甲硅烷氧基苯基)肉桂酸甲酯的制备
按照下面的合成图2制备标题化合物。
合成图2
将386mg(0.864mmol)4-(1-叔丁基二甲基甲硅烷氧基-2-(1-金刚烷基)苯基))-苯甲醛溶解在4.5ml氯仿中,加入298mg(0.864mmol)三苯基亚正膦基乙酸甲酯(methyl triphenylphosphoranylidenacetate),并将由此获得的溶液回流3小时。将溶液冷却,蒸发掉溶剂,然后在硅胶(Merck)上,使用己烷∶CH2Cl2 1∶1作洗脱剂经受闪蒸色谱。获得350mg标题化合物。
熔点148℃。
1HNMR(CDCl3)δ:0.36(6H,s,-Si(CH3)2);1.05(9H,s,-t-Bu);1.77(6H,s,6Ad.);2.08(3H,s,3Ad.);2.15(6H,s,6Ad.);3.80(3H,s,-OCH3);6.44(1H,d,-CH=,J=16.07Hz);6.86(1H,d,1Ar,J=8.54 Hz);7.30(1H,dd,1Ar,J=2.24Hz,J=8.54Hz);7.47(1H,d,1Ar,J=2.24Hz);7.50-7.70(4H,m,4Ar);7.71(1H,d,CH=,J=16.07Hz)。
实施例3
E-4-(3-(1-金刚烷基)-4-羟基苯基)肉桂酸甲酯的制备
按照下面的合成图3制备标题化合物。
合成图3
将1g(2.6mmol)2-(1-金刚烷基)-4-(4-溴苯基)苯酚、358mg(4.16mmol)丙烯酸甲酯、5.8mg(0.02mmol)乙酸钯和30mg(0.1mmol)三-(邻甲苯基)-膦在1.2ml三乙胺中的混合物回流4小时。将三乙胺蒸发,用2N HCl和乙酸乙酯吸收,分离有机相,用水洗涤,在Na2SO4上干燥并将溶剂蒸发。得到640mg产物。
熔点>240℃。
1HNMR(DMSO-d6)δ:1.75(6H),2.1(9H),3.72(s,3H,OCH3),6.63(d,1H,J=16Hz),6.85(dd,1H,J=8.8,1.8Hz),7.3-7.4(2H arom.),7.55-7.85(5H),9.55(s,1H,OH)。
实施例4
E-4-(3-(1-金刚烷基)-4-羟基苯基)肉桂酸的制备(ST 1926)按照下面的合成图4制备标题化合物。
合成图4
将42mg(1mmol)LiOH.H2O溶解在8.2ml THF(四氢呋喃)∶H2O 1∶1中,加入100mg(0.2mmol)E-4(3-(1-金刚烷基)-4-叔丁基二甲基甲硅烷氧基苯基)肉桂酸甲酯,并将由此获得的溶液在室温下搅拌3小时。将THF蒸发,用2N HCl酸化,用乙酸乙酯萃取并在Na2SO4上干燥。
过滤并蒸发,然后在硅胶(Merck)上用己烷∶乙酸乙酯2∶3,接着1∶1作洗脱剂经受闪蒸色谱。获得55mg产物。
熔点>240℃。Rf=0.50(Merck硅胶60F254,EtOAc)
1HNMR(DMSO-d6)δ:1.74(6H,s,6Ad.);2.04(3H,s,3Ad.);2.12(6H,s,6Ad.);6.51(1H,d,-CH=,J=16.18Hz);6.85(1H,d,1Ar,J=8.82Hz);7.30-7.40(2H,m,2Ar);7.55-7.63(3H,m,2Ar+CH=);7.70(2H,d,2Ar,J=8.09Hz);9.54(1H,s,-OH);12.34(1H,brs,-COOH)。
MS(m/z):374(M+,100)。
实施例5
4-(3-(1-金刚烷基)-4-甲氧基苯基)丙炔酸甲酯的制备
按照下面的合成图5制备标题化合物。
合成图5
将301mg(1.26mmol)4-溴苯基丙炔酸甲酯溶解在2.5ml甲苯中,加入1.34ml 2M Na2CO3的水溶液,然后加入43.7mg Pd-四三苯膦,最后加入398mg(1.39mmol)3-(1-金刚烷基)-4-甲氧基苯基硼酸,将该混合物回流3小时。粗产物在乙醚中吸收,有机相用饱和NaCl溶液洗涤,在Na2SO4上干燥,蒸发至干,得到570mg粗产物。在硅胶(Merck)上用己烷∶乙酸乙酯2∶1作洗脱剂经过闪蒸色谱,得到15mg纯产物。
熔点175℃。
1H-NMR(CDCl3)δ:3.86(s,3H,OCH3),3.90(s,3H,OCH3),6.96(d,1H,J=8.5),7.43(dd,1H,J=2.2,8.5),7.47(d,1H,J=2.2),7.55.7.70(4Harom.)。
实施例6
4-(3-(1-金刚烷基)-4-甲氧基苯基)丙炔酸的制备(ST 1879)
按照下面的合成图6制备标题化合物。
合成图6
将15mg(0.0374mmol)E-4-(3-(1-金刚烷基)-4-甲氧基苯基)丙炔酸甲酯溶解在2.14ml 0.7N NaOH的甲醇溶液中,并将该混合物回流1小时。蒸发掉甲醇,在水中吸收,并用6N HCl酸化,用乙醚萃取。在Na2SO4上干燥并蒸发掉溶剂之后,残余物用己烷洗涤,过滤之后获得10mg产物。
熔点156℃。Rf=0.41(Merck硅胶60F254,EtOAc/MeOH 2/1)
1H-NMR(DMSO-d6)δ:1.70(s,6H),2.10(s,9H),3.85(s,3H,OCH3),7.05(d,1H,J=8.4,H-6′),7.40(d,1H,J=2,H-2′),7.45-7.60(3H arom.),7.65(2H arom.)
实施例7
E-4-(3-(1-金刚烷基)-4-甲氧基苯基)肉桂醇的制备
按照下面的合成图7制备标题化合物。
合成图7
将375μl的1M LiAlH4的四氢呋喃溶液(0.365mmol)加入到5ml无水四氢呋喃中,在冰浴中冷却,加入151mg(0.375mmol)E-4-(3-(1-金刚烷基)-4-甲氧基苯基)肉桂酸甲酯(参见实施例19),冷却下搅拌1小时,然后在室温下搅拌过夜。在冰浴中冷却之后,加入5ml 10%NH4Cl的水溶液,将四氢呋喃蒸发,然后用乙酸乙酯吸收。分离有机相并在Na2SO4上干燥。蒸发掉溶剂,获得126mg粗产物,在硅胶(Merck)上用二氯甲烷∶己烷3∶1,然后再用己烷∶乙酸乙酯28∶72作洗脱剂色谱,得到11mg产物。
熔点148℃。
1H-NMR(CDCl3)δ:1.75(s,6H),2.15(9H),3.90,s,3H,OCH3),4.38(dd,2H,J=6,1.6),6.41(dt,1H,J=6,16,=CHCH2OH),6.67(dd,1H,J=1.6,16,芳基CH=),6.96(d,1H,J=8.3,H-6′),7.42(dd,1H,J=2.2,8.3,H-5′),7.45(m,2H,H-2 e H-6),7.48(d,1H,J=2.2,H-3′),7.55(m,2H,H-3e H-5)
MS m/z 374(M+)。
实施例8
E-4-(4-羟基苯基)肉桂酸甲酯的制备
按照下面的合成图8制备标题化合物。
合成图8
将2g(8.03mmol)4-(4-溴苯基)苯酚、1.1g(12.8mmol)丙烯酸甲酯、18mg(0.08mmol)乙酸钯和94mg(0.31mmol)三-(邻甲苯基)膦在3.7ml三乙胺中的混合物回流6小时。加入另外6mg乙酸钯和30mg三-(邻甲苯基)膦并加热1小时,然后加入另外30mg乙酸钯和94mg二三-(邻甲苯基)膦并加热3.5小时。然后将反应物用6M HCl酸化,加入乙酸乙酯,并搅拌一段时间以溶解沉淀物,将各相分离,有机相在Na2SO4上干燥并将溶剂蒸发。粗产物(934mg)通过在己烷/乙醚中吸收纯化并过滤出得到1.7g标题产物。
熔点233-235℃
1HNMR(CDCl3)δ:3.70(s,3H,OCH3),6.13(d,1H,CH=,J=16),6.82(d,2H,H-3′e H-5′),7.48,d,2H,H-2′e H-6′),7.6-7.75(5H)。
实施例9
E-4-(3-(1-甲基环己基)-4-羟基苯基)肉桂酸甲酯的制备
按照下面的合成图9制备标题化合物。
合成图9
将150mg(0.6mmol)E-4-(4-羟基苯基)肉桂酸甲酯和68.5mg 1-甲基-1-环己醇溶解在1.2ml CH2Cl2中,用0.032ml浓H2SO4处理并将该混合物回流1天。加入水并用饱和碳酸氢钠溶液将混合物中和。水相用乙酸乙酯萃取几次,在Na2SO4上干燥,过滤并蒸发。所得粗产物在硅胶(Merck)上用己烷∶乙酸乙酯9∶1作洗脱剂闪蒸色谱。获得20mg产物。
1HNMR(丙酮-d6)δ:1.43(3H,s,-CH3);1.4-1.9(8H,m,cyclohex.);2.3-2.45(2H,m,cyclohex.);3.80(3H,s,-OCH3);6.60(1H,d,CH=,J=16.18Hz);7.0(1H,d,1Ar,J=8.2Hz);7.44(1H,dd,1Ar,J=8.2Hz,2.2Hz);7.65(1H,d,1Ar,J=2.2Hz);7.7-7.85(5H,m,4Ar+CH=);8.65(1H,s,-OH)。
实施例10
2-(1-金刚烷基)-4-溴-6-N-邻苯二甲酰亚氨基甲基)苯酚的制备按照下面的合成图10制备标题化合物。
合成图10
向500mg(1.63mmol)2-金刚烷基-4-溴苯酚的7ml二氯甲烷溶液中加入289mg(1.63mmol)N-羟基甲基邻苯二甲酰亚胺和2滴浓H2SO4。将该混合物回流3小时,用水稀释,并用二氯甲烷萃取。将溶剂蒸发并在硅胶上用己烷∶乙酸乙酯80∶20作洗脱剂色谱,得到348mg(46%)产物。
熔点253℃。
1HNMR(CDCl3)δ:1.78(6H,s,6Ad.);2.09(3H,s,3Ad.9;2.12(6H,s,6Ad.);4.76(2H,s,-CH2-);7.28(1H,d,1Ar,J=2.94Hz),7.45(1H,d,1Ar,J=2.94Hz);7.76(2H,dd,2Ar,J=2.94Hz,J=5.52Hz);7.88(2h,dd,2Ar,J=2.94Hz,J=5.52Hz);8.13(1H,s,-OH)。
实施例11
E-4-(3-(1-金刚烷基)-5-(N-邻苯二甲酰亚氨基甲基)-4-羟基苯基)肉桂酸甲酯的制备
按照下面的合成图11制备标题化合物。
合成图11
将100mg 2-(1-金刚烷基)-4-溴-6-N-邻苯二甲酰亚氨基甲基)苯酚悬浮于1.6ml二烷中并在氮气流下;加入59.7mg(双频哪酸)硼(boro(bispinacolate))、63mg无水乙酸钾、5mg二氯(二苯膦二茂铁)钯和103mg 4-溴肉桂酸甲酯。将其回流2小时,重悬于乙酸乙酯中,用1ml的2M HCl酸化,有机相用饱和NaCl溶液洗涤,在Na2SO4上干燥,蒸发掉溶剂并在硅胶上用己烷∶乙酸乙酯65∶35色谱。得到32mg(27%)产物。
熔点216℃。
1HNMR(CDCl3)δ:1.78(6H,s,6Ad.);2.09(3H,s,3Ad.);2.12(6H,s,6Ad.);3.83(3H,s,-OCH3);4.90(2H,s,-CH2-);6.44(1H,d,CH=,J=16.18 Hz);7.45-7.90(11H,m,10Ar+CH=);8.22(1H,s,OH)。
MS(m/z):547(M+,100);400(30);160(30)。
实施例12
E-4-(3-(1-金刚烷基)-5-(N-邻苯二甲酰亚氨基甲基)-4-羟基苯基)肉桂酸的制备
按照下面的合成图12制备标题化合物。
合成图12
将30mg E-4-(3-(1-金刚烷基)-5-(N-邻苯二甲酰亚氨基甲基)-4-羟基苯基)肉桂酸甲酯加入到1ml的乙酸和37%盐酸的3∶1混合物中,将该混合物回流30小时。将乙酸蒸发,然后用水吸收,将固体残余物过滤,并用水洗涤。得到24mg产物。
熔点216℃。
1HNMR(DMSO-d6)δ:1.73(6H,s,6Ad.);2.04(3H,s,3Ad.);2.12(6H,s,6Ad.);4.81(2H,s,-CH2-);6.45(1H,d,-CH=,J=16.18Hz);7.07(1H,d,1Ar,J=1.84Hz);7.30(1H,d,1Ar,J=1.84Hz);7.46(2H,dd,2Ar,J=8.82Hz,J=1.84Hz);7.53(1H,d,-CH=,J=16.18Hz);7.64(2H,dd,2Ar,J=8.82Hz,J=1.84Hz);7.78-7.94(4H,m,4Ar);8.60(1H,s,-OH);12.5(1H,brs,COOH)。
MS(m/z):533(M+,100);386(40);160(60)130(50)。
实施例13
E-4-(3-(1-金刚烷基)-5-(氨基甲基)-4-羟基苯基)肉桂酸的制备按照下面的合成图13制备标题化合物。
合成图13
将20mg E-4-(3-(1-金刚烷基)-5-(N-邻苯二甲酰亚氨基甲基)-4-羟基苯基)肉桂酸悬浮于0.15ml甲醇中,加入0.013ml水合肼,在50℃下将该混合物加热5小时。将溶剂蒸发,重悬于水中,用2M HCl酸化并在真空下将沉淀物过滤。将粗产物干燥,用四氢呋喃处理以溶解邻苯二甲酰肼,并过滤。
熔点195℃
1HNMR(DMSO-d6)δ:1.73(6H,s,6Ad.);2.04(3H,s,3Ad.);2.12(6H,s,6Ad.);4.00(2H,s,-CH2-);6.45(1H,d,-CH=,J=16.18Hz);7.07-8.00(5H,m,5Ar)。
实施例14
4-(7-金刚烷-1-基-苯并(1,3)二氧戊环-5-基)-苯甲醛的制备按照下面的合成图14制备标题化合物。
合成图14
将0.875g(2.61mmol)4-金刚烷-1-基-6-溴-苯并(1,3)二氧戊环溶解在5.2ml甲苯中,并加入2.6ml 2M Na2CO3水溶液、0.090g(0.08mmol)四-三苯膦-钯、和0.430 g(2.87mmol)4-甲酰基苯硼酸的1.2ml乙醇溶液。在氮气流下将其回流7小时。将其冷却,在乙酸乙酯中吸收,并用饱和NaCl溶液洗涤。有机相在Na2SO4上干燥,过滤并将溶剂蒸发。在硅胶(Merck)上用己烷∶乙酸乙酯9∶1作洗脱剂闪蒸色谱之后,得到0.66g产物(70%)。
1HNMR(CDCl3)δ:1.80(6H,s,6Ad.);2.09(3H,s,3Ad.);2.12(6H,s,6Ad.);6.02(2H,s,-CH2-);7.01(1H,d,1Ar,J=1.86Hz);7.04(1H,d,1Ar,J=1.86Hz);7.68(2H,d,2Ar,J=8.19Hz,);7.92(2H,d,2Ar,J=8.19Hz,);10.02(1H,s,-CHO)。
实施例15
E-4-(7-金刚烷-1-基-苯并(1,3)二氧戊环-5-基)-肉桂酸甲酯的制备按照下面的合成图15制备标题化合物。
合成图15
在氮气下将300mg的4-(7-金刚烷-1-基-苯并(1,3)二氧戊环-5-基)苯甲醛的4.5ml CHCl3溶液用278mg三苯基亚正膦基乙酸甲酯处理并回流5小时,3小时之后再加入叶立德(20%)。在该段时间结束时将溶剂蒸发,并且残余物在硅胶上用己烷∶二氯甲烷45∶55作洗脱剂色谱。得到298mg产物。
熔点205℃。
1HNMR(CDCl3)δ:1.72(6H,s,6Ad.);2.06(3H,s,3Ad.);2.12(6H,s,6Ad.);3.80(3H,s,-OCH3);5.97(2H,s,-CH2-);6.44(1H,d,-CH=,J=16Hz);6.95(1H,d,1Ar,J=1.86Hz);6.98(1H,d,1Ar,J=1.86Hz);7.52-7.58(4H,m,4Ar);7.71(1H,d,-CH=,J=16Hz,)。
实施例16
E-4-(7-金刚烷-1-基-苯并(1,3)二氧戊环-5-基)-肉桂酸的制备按照下面的合成图16制备标题化合物。
合成图16
将200mg(0.48)E-4-(7-金刚烷-1-基-苯并(1,3)二氧戊环-5-基)-肉桂酸甲酯悬浮于LIOH.H2O的25ml THF/H2O 3∶2溶液中并在室温下搅拌过夜。将THF蒸发,羧酸酯悬液用己烷洗涤,然后用2N HCl酸化,并在冰浴中冷却。过滤之后得到150mg(78%)产物。
熔点>300℃。Rf=0.59(Merck硅胶60F254,EtOAc/己烷9/1)
1HNMR(DMSO-d6)δ:1.72(6H,s,6Ad.);2.01(3H,s,3Ad.);2.12(6H,s,6Ad.);6.01(2H,s,-CH2-);6.52(1H,d,-CH=,J=16.18Hz);6.99(1H,d,1Ar,J=1.84Hz);7.14(1H,d,1Ar,J=1.84Hz);7.60(1H,d,-CH=,J=16.18Hz);7.62(2H,dd,2Ar,J=8.46Hz,1.84Hz);7.68(2H,dd,2Ar,J=8.46Hz,1.84Hz)。
实施例17
2-[4-(3-(1-金刚烷基)-4-羟基苯基)]环丙烷甲酸甲酯的制备按照下面的合成图17制备标题化合物。
合成图17
将0.5mg四乙酸铑二水合物和36μl重氮基乙酸乙酯加入到150mg(3-金刚烷-1-基-4′-乙烯基联苯基-4-氧基)叔丁基二甲基甲硅烷(由相应的醛通过Wittig反应制得)的2ml二氯甲烷溶液中。室温下将反应物静置5天,加入总共5mg催化剂和10μl重氮基乙酸乙酯。经硅藻土将催化剂过滤,在硫酸钠上干燥,蒸发,在硅胶上用65∶35己烷∶乙酸乙酯的混合物色谱。
获得43mg两种非对映异构体顺式和反式的混合物。
1HNMR(CDCl3)δ:0.45(6H,s,-Si(CH3);0.95(3H,t,-CH3,J=7 Hz);1.1(9H,s,tBu);1.25(3H,t,-CH3,J=7 Hz);1.35-1.55(1H,m,1-CH2);1.55-1.74(1H,m,1-CH2);1.79(6H,s,6Ad.);1.95(1H,m,-CH-COOEt)2.07(3H,s,3Ad.);2.12(6H,s,6Ad.);2.48-2.65(1H,m,-CH-Ar);3.85(2H,q,-OCH2,J=7Hz);4.18(2H,q,-OCH2,J=7Hz);6.82(1H,dd,1Ar,J=1.84Hz,8.46Hz);7.15(1H,d,1Ar,J=8.46Hz);7.25(2H,dd,2Ar,J=8.0Hz,1.84Hz);7.45-7.50(3H,m,3Ar)。
实施例18
顺式和反式2-(4-(3-(1-金刚烷基)-4-羟基苯基)]环丙烷甲酸的制备按照下面的合成图18制备标题化合物。
合成图18
将113mg担载在细碎Al2O3上的KF(40%)加入到2-[4-(3-(1-金刚烷基)-4-羟基苯基)]环丙烷甲酸甲酯(110mg)的4.4ml二甲氧基乙烷溶液中,并在室温下搅拌2天。过滤之后,将溶剂蒸发,将该粗产物加入到63mgLiOH.H2O在12.4ml 50%四氢呋喃水溶液中的溶液中。室温下将其搅拌3天,蒸发掉溶剂,用乙醚萃取,用2M HCl酸化,并用乙酸乙酯萃取。蒸发之后,产物(58mg)在硅胶上用己烷∶乙酸乙酯40∶60进行色谱。获得6mg反式-2-4-(3-(1-金刚烷基)-4-羟基苯基)]环丙烷甲酸(熔点190℃)、10mg非对映异构体的混合物和20mg顺式-2-[4-(3-(1-金刚烷基)4-羟基苯基)]环丙烷甲酸。
熔点204℃
Rf=0.23顺式;0.44反式(Merck硅胶60F254,EtOAc/己烷6/4)
1H NMR(MeOD)δ反式:1.45-1.50(1H,m,1-CH2);1.60-1.65(1H,m,1-CH2);1.95-2.0(7H,m,-CH-COOEt+6Ad)2.2(3H,s,3Ad.);2.35(6H,s,6Ad.);2.50-2.58(1H,m,-CH-Ar);6.84(1H,d,1Ar,J=8.46Hz);7.24(2H,dd,2Ar,J=7.35Hz,J=1.84Hz);7.31(1H,dd,1Ar,J=8.46Hz,2.57Hz);7.42(1H,d,1Ar,J=2.57Hz);7.52(2H,dd,2Ar,J=7.35Hz,J=1.84Hz)。
1H NMR(MeOD)δ顺式:1.40-1.50(1H,m,1-CH2);1.70-1.75(1H,m,1-CH2);1.95-2.0(6H,s,6Ad);2.10-2.15(4H,m,3Ad+-CH-COOH);2.30(6H,s,6Ad.);2.70-2.78(1H,m,-CH-Ar);6.83(1H,d,1Ar,J=8.46Hz);7.30(1H,dd,1Ar,J=8.46Hz,2.57Hz);7.38(2H,dd,2Ar,J=7.30Hz,J=1.84Hz);7.42(1H,d,1Ar,J=2.57Hz);7.49(2H,dd,2Ar,J=7.30Hz,J=1.84Hz)。
MS(m/z):388(M+,100);135(50)。
实施例19
E-4-(3-(1-金刚烷基)-4-甲氧基苯基)肉桂酸甲酯的制备按照下面的合成图19制备标题化合物。
合成图19
向NaH(60%在矿物油中,66mg,2.74mmol)的3.3mL DMF悬浮液中,于N2下加入969mg(2.49mmol)E-4(3-(1-金刚烷基)-4-羟基肉桂酸甲酯。室温下将该混合物搅拌1小时,然后滴186μL(2.99mmol)CH3I。
室温下将反应静置过夜;在加入80ml冷水之后,水相用CH2Cl2(4x60ml)萃取。有机层用水洗涤,在Na2SO4上干燥并将溶剂蒸发。获得972mg产物(97%)。
1H-NMR(CDCl3)δ:1.75(6H),2.1(9H),3.75(s,3H,OCH3),3.80(s,3H,-COOCH3);6.40(d,1H,CH=,J=16Hz),6.90(d,1H,1Ar,J=8.8Hz),7.35(dd,1H,1Ar,J=8.8,1.8Hz);7.42(d,1H,1Ar,J=1.8Hz);7-48-7.53(m,4H,4Ar);7.65(d,1H,CH=,J=16Hz)。
实施例20
E-4-(3-(1-金刚烷基)-4-甲氧基苯基)肉桂酸的制备(ST 1898)按照下面的合成图20制备标题化合物。
合成图20
将455mg(10.8mmol)LiOH.H2O溶解在90ml THF∶H2O 1∶1中;加入873mg(2.17mmol)E-4(3-(1-金刚烷基)-4-甲氧基苯基)肉桂酸甲酯,并在室温下将由此获得的溶液搅拌2天。将THF蒸发,用2N HCl酸化并将白色沉淀过滤出来。固体用AcOEt和Et2O洗涤,获得792mg(94%)标题化合物。
Rf=0.28(Merck硅胶60F254,EtOAc/己烷9/1)
1HNMR(DMSO-d6)δ:1.74(6H,s,6Ad.);2.04(3H,s,3Ad.);2.12(6H,s,6Ad.);3.75(3H,s,-OCH3);6.50(1H,d,-CH=,J=16Hz);6.98(1H,d,1Ar,J=8.8Hz);7.40-7.70(7H,m,6Ar+CH=);12.3(1H,brs,-COOH)。
ST1926对肿瘤细胞系的细胞毒性
为了进行细胞毒性试验,使用两种急性早幼粒细胞白血病(APL)细胞系。
1.细胞系NB4,带有染色体易位t(15;17),它产生融合蛋白PML/RARα。该细胞系对药用剂量的ATRA(10-7-10-6M)的分化作用极其敏感;
2.细胞系HL60,相对于细胞系NB4,其响应ATRA的敏感性较差。该细胞系不携带上述的染色体易位。
将这些细胞系保持在含有10%胎牛血清(FCS)和1%谷氨酰胺的RPMI 1640中。
还使用源自实体肿瘤的不同细胞系。
1.人前列腺癌PC3和DU145。将这些细胞系保持在含有10%FCS、1%丙酮酸钠和1%谷氨酰胺的RPMI1640培养基中;
2.人结肠腺癌LoVo。将该细胞系保持在含有10%FCS和1%谷氨酰胺的HAM′s F-12培养基中。
3.人卵巢癌,诸如A2780和A2780/Dx,分别对药物(阿霉素、紫杉醇、依托泊苷、长春新碱)敏感和耐药;IGROV-1和IGROV-1/Pt,分别对基于铂的化学疗法敏感和耐药,将它们保持在含有10%FCS、1%丙酮酸钠和1%谷氨酰胺的RPMI 1640培养基中;
4.人黑素瘤MeWo和MeS 2.21,成胶质细胞瘤GBM,非小细胞肺癌A431,NCI-H460,骨肉瘤SAOS和U20S,将它们保持在含有10%FCS、1%丙酮酸钠和1%谷氨酰胺的RPMI 1640培养基中。
该细胞毒性试验是使用NB4或HL-60细胞悬液(10000/孔)进行的。将这些细胞以250μl的体积接种在96孔板中并在37℃下培养24小时。次日以增加的浓度加入测试化合物ST1926[(2E)-3-[3′-(l-金刚烷基)-4′-羟基[l,1′-联苯基]-4-基]-2-丙烯酸酯/丙烯酸],并在37℃下在含有5%CO2的潮湿环境中将这些细胞再培养24小时。在第3天,将平板在1600xg下离心10分钟除去培养基并倾析掉上清液。加入250μl PBS;然后再在1600xg下将平板离心10分钟并将上清液倾析掉。加入200μl/孔的含10%FCS的RPMI1640培养基,并在37℃下将这些平板再培养48小时。在第5天,再在1600xg下将这些平板离心10分钟,并将这些平板翻转除去培养基,加入200μl PBS和50μl冷的80%TCA。然后将这些平板在冰上静置培养至少1小时。翻转除去TCA;将这些平板在蒸馏水中浸泡洗涤3次并首先在纸上干燥,然后通过喷射热空气干燥。向所有孔中加入200μl在1%乙酸中的0.4%sulphorodamine B。在室温下将这些平板再培养30分钟。
翻转除去sulphorodamine B,通过在1%乙酸中浸泡3次清洗这些平板,然后首先用吸水纸干燥,然后喷射热空气干燥。将200μl的10mM Tris碱加入到所有孔中并将这些平板搅拌至少20分钟。使用Multiskan分光光度计于540nm下测定光密度。
就粘附的细胞而言,采用的步骤相同,只是在第3天的平板洗涤是通过翻转然后加入PBS3次进行的,而不在1600xg下离心。同样在第5天,通过翻转平板将上清液除去。
通过与ST1926培养24小时,在除去化合物之后48小时来测定细胞存活率。与产品培养24小时能够以浓度依赖性方式抑制细胞增殖。表1显示了对研究的每一肿瘤细胞系计算得到的IC50值(抑制细胞存活率50%的产品浓度)。证实ST1926表现出对人早幼粒细胞白血病肿瘤细胞系NB4(IC50=0.022μM)的细胞毒性比对其它肿瘤系计算的大10倍左右。
表1
ST1926的细胞毒性
细胞系 | IC50(μM) |
前髓细胞白血病 | |
NB4 | 0.02 |
HL-60 | 0.2 |
前列腺癌 | |
PC3 | 0.21 |
DU145 | 0.10 |
结肠癌 | |
LoVo | 0.24 |
卵巢癌 | |
A2780 | 0.10 |
A2780/Dx | 0.20 |
IGROV-1 | 0.23 |
IGROV-1/Pt | 0.33 |
黑素瘤 | |
MeWo | 0.23 |
MeS 2.21 | 0.23 |
成胶质细胞瘤 | |
GBM | 0.18 |
肺癌 | |
A431 | 0.25 |
NCI-H460 | 0.19 |
骨肉瘤 | |
SAOS | 0.25 |
U2OS | 0.26 |
实施例9
评价ST1926对肿瘤细胞周期的影响
为了评价本发明的化合物对细胞周期的不同阶段的影响,进行细胞荧光测定细胞周期分析。
将HL60或NB4以150000个细胞/ml含10%FCS的RPMI1640培养基的密度接种到平板上,加入以0.01-0.1μM的浓度溶解在0.1%DMSO中的测试化合物(ST1926),在有或者没有亚适剂量的ATRA(5-10nM(对NB4)和0.5μM(对HL60))的情况下在暗处并在恒温箱中放置3天,不更换培养基。
在处理的第3天,抽取500000个细胞,在180xg下离心5分钟,在没有钙和镁的PBS中洗涤2次。在由保持在-20℃下的丙酮/甲醇1∶4v/v和50%无钙和镁的PBS组成的固定混合物中将这些细胞(1×106/ml固定剂)固定至少1小时;然后将这些细胞离心,在无钙和镁的PBS中洗涤,再次离心和洗涤。在暗处于室温下将该细胞沉淀物与200μl碘化丙锭(100μg/ml)和200μl RNAse(150KU/mg)培养30分钟。
样品通过尼龙过滤器(60-80μm直径)过滤并经细胞荧光计FACScan(Becton Dickinson)分析,获取20000事件/样品,在488nm的激发波长和620nm的发射波长下。使用专用软件包Modfit v.2.0(BectonDickinson)进行细胞周期阶段的百分比的分析。
就前列腺癌细胞PC3的细胞周期分析而言,将这些细胞以500000个细胞/ml接种到平板的RPMI培养基中。用化合物ST1926处理24小时之后,如上所述分析细胞。
实施例9/1
评价ST1926对人早幼粒细胞白血病NB4细胞的细胞周期的影响
对用ST1926处理(3天)对NB4的细胞周期的影响的分析显示,本发明的化合物在0.08和0.1μM的浓度诱导生长停滞在周期的复制S阶段和凋亡。所得结果报道于表2。
表2.
ST1926对NB4的细胞周期的影响
处理 | G0/G1 | S | G2+M | 凋亡 |
对照 | 53.4 | 35.5 | 11.1 | 26.6 |
ST1926 0.01μM | 48.4 | 38.8 | 12.8 | 19.9 |
ST1926 0.02μM | 48.2 | 39.4 | 12.4 | 28.4 |
ST1926 0.04μM | 51.3 | 35.7 | 13.0 | 33.9 |
ST1926 0.08μM | 41.4 | 53.6 | 5.0 | 45.0 |
ST1926 0.1μM | 50.6 | 46.1 | 3.3 | 53.6 |
实施例9/2
评价ST1926对人早幼粒细胞白血病HL-60细胞的细胞周期的影响
对用ST1926处理3天对HL-60细胞的细胞周期的影响的分析显示,在0.5和1μM的浓度下,细胞周期不可测定,但是,该化合物已显示强的促凋亡效果。
所得结果报道于表3。
表3.
ST1926对人早幼粒细胞白血病HL-60细胞的细胞周期的影响
处理 | G0/G1 | S | G2+M | 凋亡 |
对照 | 57.9 | 30.9 | 11.2 | 10.5 |
ST1926 0.0025μM | 54.9 | 33.4 | 11.7 | 8 |
ST1926 0.005μM | 53.4 | 34.4 | 12.2 | 14.0 |
ST1926 0.01μM | 52.0 | 35.4 | 12.6 | 12.5 |
ST1926 0.05μM | 45.0 | 42.0 | 13.0 | 13.0 |
ST1926 0.1μM | 39.9 | 46.8 | 13.3 | 27.5 |
ST1926 0.5μM | n.e. | n.e. | n.e. | 82 |
ST1926 1μM | n.e. | n.e. | n.e. | 86.5 |
实施例9/3
ST1926对前列腺癌PC3细胞的细胞周期的影响
对用ST1926处理24小时对PC3细胞周期的影响的分析显示,在处理结束时即刻,测试的化合物在测定的最高浓度(0.4μM)下诱导凋亡;在细胞恢复24小时之后,这些细胞在S阶段积聚,而在0.4μM的浓度下,诱导细胞凋亡。
所得结果报道于表4。
表4
ST1926对人前列腺癌PC3细胞的细胞周期的影响
处理 | G0/G1 | S | G2+M | 凋亡 |
处理24小时和恢复0小时 | ||||
对照 | 54.8 | 24.6 | 20.6 | 8 |
ST1926 0.02μM | 54.0 | 24.2 | 21.9 | 9 |
ST1926 0.05μM | 55.8 | 23.6 | 20.6 | 11 |
ST1926 0.1μM | 52.0 | 35.4 | 28.0 | 10 |
ST1926 0.2μM | n.v. | n.v. | n.v. | 13.5 |
ST1926 0.4μM | n.v. | n.v. | n.v. | 25 |
处理24小时和恢复24小时 | ||||
对照 | 49.9 | 31.8 | 22.3 | 10.5 |
ST1926 0.02μM | 44.6 | 30.4 | 25.0 | 13 |
ST1926 0.05μM | 44.9 | 29.5 | 25.6 | 15 |
ST1926 0.1μM | 45.8 | 25.8 | 28.4 | 10 |
ST1926 0.2μM | 31.8 | 43.2 | 25.0 | 13 |
ST1926 0.4μM | n.e. | n.e. | n.e. | 26 |
ST1926与TRAIL(与肿瘤坏死因子相关的凋亡诱导配体)联合的体外细胞毒性活性
淋巴细胞以及自然杀伤细胞负责TRAIL产生(与肿瘤坏死因子相关的凋亡诱导配体),它是TNF细胞因子家族(肿瘤坏死因子)的成员。该膜蛋白诱导多种转化细胞凋亡,并且与该家族的其它成员不同,它在体外对正常细胞似乎没有细胞毒性。TRAIL通过与两个含有死亡域的死亡受体DR4和DR5相互作用诱导凋亡。因此,认为TRAIL是一种肿瘤选择性、凋亡诱导性细胞因子和一种预防和治疗癌症的有希望的新候选物(Neoplasia,6:535-546,2001)。
对两种不同肿瘤细胞系如M109鼠肺癌和A2780/Dx多重耐药的人卵巢癌进行ST1926与TRAIL组合的细胞毒性的研究。将细胞保持在含有10%FCS、1%丙酮酸钠和1%谷氨酰胺的RPMI1640培养基中。
将这些细胞以250μl的体积接种在96孔平板中并在37℃下培养24小时。次日,以递增的浓度加入测定化合物ST 1926[(2E)-3-[3′-(1-金刚烷基)-4′-羟基[1,1′-联苯基]-4-基]-2-丙烯酸酯/丙烯酸]或TRAIL,并在37℃、含有5%CO2的潮湿环境下将这些细胞再培养72小时。在第5天,将这些平板翻转除去上清液。加入200μlPBS和50μl冷的80%TCA。然后将这些平板在冰上静置培养至少1小时。翻转除去TCA;将这些平板在蒸馏水中浸泡洗涤3次并首先在纸上干燥,然后通过喷射热空气干燥。向所有孔中加入200μl在1%乙酸中的0.4%sulphorodamine B。在室温下将这些平板再培养30分钟。翻转除去sulphorodamine B,通过在1%乙酸中浸泡3次洗涤这些平板,然后首先用吸水纸干燥,然后喷射热空气干燥。将200μl的10mM Tris碱加入到所有孔中并将这些平板搅拌至少20分钟。使用Multiskan分光光度计于540nm下测定光密度。
使用Drewinko等人的分析(Cancer Biochem.Biophys.1:187-195,1976)测定ST1926和TRAIL之间的相互作用。
如下进行分析:
(SFaxSFb/Sfa+SFb)/100,其中SFa是ST1926的存活分数,SFb是TRAIL的存活分数。
数值说明以下效果:
值>1协同作用,<1拮抗作用 ,=1没有影响。
在两种细胞系中,ST1926显示出与TRAIL的协同活性(图1和2)。
ST1926在鼠肺癌模型M109和3LL中的抗肿瘤活性
通过s.c.传代肿瘤片段保持鼠肺腺癌Madison109细胞(M109)。接种之日,将细胞悬液以3×105个细胞/小鼠的密度肌内注射到20g雌性BALB/c小鼠的左后肢中。通过将1×105个细胞/小鼠在C57BL/6J小鼠内i.m.传代(每10-14天)常规保持3LL鼠Lewis肺癌。为了测定抗肿瘤活性,从供体小鼠切除肿瘤并在机械分离和酶消化之后通过台盼蓝染料排除试验评价肿瘤细胞活力。然后,将1×105细胞/100μl/小鼠肌内注射到C57BL/6J小鼠的右后腿肌肉内。
从肿块能够测定之日起使用数字测径器(Vernier Caliper)每周两次测定肿瘤维度。从两个主要维度(长和宽)的大小(以mm计),采用公式(长×宽2)/2,即肿瘤体积mm3,评价肿瘤块。就每一试验组而言,相对于对照即(100-(T/C%)计算肿瘤体积抑制的百分比(TVI%)。在最后给予ST1926之后两天评价TVI。
还测定平均存活时间(MST),平均寿命的增加以ILS%(寿命增加)表示,以(MSTT/MSTc)×100-100计算。
用对非成对数据的非参数Mann Whitney检验,使用得自GraphPadinc的Instat软件,进行每一组获得的TVI和存活时间值之间的比较。
在使用之前即刻制备ST1926溶液,将其溶解在cremophor∶乙醇1∶1中,接着以1∶4稀释到缓冲盐水溶液中。以10ml/kg的体积处理动物。在不同剂量下的ST1926的处理方案为连续5天(qdx5),在接种肿瘤细胞后1天开始并重复3个循环。
首先,在每次处理之前将小鼠(每个组8只)称重,以便以在整个给药期间观察到的重量的可能变化为基础,能够给予正确量的物质,并且还能够登记整个处理期间的最大失重(BWL%Max)。
将结果报道于下表5。ST1926证实,在患鼠肺肿瘤M109的动物中,以10mg/kg口服和15mg/kg腹膜内的剂量,按照处理方案qdx5x3w,存活率增加,并且抑制了肿瘤质量。
而且,ST1926以10mg/kg口服的剂量延长了携带3LL-肿瘤的小鼠的寿命,并且使肿瘤体积减少65%。
表5.
ST1926(qdx5x3w)对鼠肺M109肿瘤的抗肿瘤活性
处理 | 剂量(mg/kg) | BWL%Max | MST(范围天数) | ILS% | TVI% |
M109 | |||||
对照 | / | 9 | 22(13-34) | / | / |
ST1926 | 10,腹膜内 | 9 | *28(25-35) | 27 | 18 |
ST1926 | 15,腹膜内 | 10 | **36(30-42) | 64 | *46 |
ST1926 | 10口服 | 10 | **35(27-42) | 59 | *49 |
3LL | |||||
对照 | / | 3 | 21(15-33) | / | / |
ST1926 | 10,口服 | 7 | *32(24-42) | 52 | ***65 |
*P<0.05,**P<0.01,***P<0.001相对于对照(Mann-Whitney)。
ST1926在人卵巢癌模型A2780和A2780/Dx以及人非小细胞肺癌NCI-H460中的抗肿瘤活性
在37℃、含有5%CO2的潮湿环境中,将人卵巢癌细胞A2780、A2780/Dx和NCI-H460保持在含有10%FCS、2mM谷氨酰胺、50μg/ml庆大霉素的RPMI-1640中。将细胞用胰蛋白酶消化,收集在完全培养基中,并在约1100rpm下离心10分钟,将沉淀物重悬在Hank′s 199培养基中;将该操作进行2次。细胞以20×106/ml的密度重悬在Hank′s 199培养基中并将0.1ml(相当于2×106个细胞/小鼠)s.c.注射到CD1 nu/nu 6周龄的雌性小鼠的右胁腹内。
在使用之前即刻制备ST1926溶液,溶解在cremophor∶乙醇1∶1中,接着以1∶4稀释到缓冲盐水溶液中。动物处理以10ml/kg的体积给药。不同剂量的ST 1926的处理方案持续5天(qdx5),在肿瘤细胞接种后1天开始并重复3个循环。
从肿块能够测定之日起使用数字测径器(Vernier Caliper)每周两次测定肿瘤维度。从两个主要维度(长和宽)的大小(以mm计),采用公式(长×宽2)/2,即肿瘤体积mm3,评价肿瘤块。就每一试验组而言,相对于对照(即(100-(T/C%))计算肿瘤体积抑制的百分比(TVI%)。在最后给予ST1926之后两天评价TVI。
对小鼠进行测定,直到对照组肿瘤重量达到2g,然后通过颈脱位将小鼠处死。
用对非成对数据的非参数Mann Whitney检验,使用得自GraphPadinc的Instat软件,在每一组获得的TVI值之间进行比较。
首先,在每次处理之前将小鼠称重,以便以在整个给药期间观察到的重量的可能变化为基础,能够给予正确量的物质,并且还能够记录整个处理期间的最大失重(BWL%max)。
将结果报道于表6。同样,在这种情况下ST1926以15-5mg/kg口服的剂量,按照处理方案qdx5x3w,抑制了患人卵巢腺癌A2780、多重耐药的A2780/Dx和人非小细胞肺癌NCI-H460的小鼠的肿瘤质量。
表6.
ST1926(qdx5x3w)对人卵巢癌A2780、A2780/Dx和非小细胞肺癌NCI-H460的抗肿瘤活性
处理 | 剂量(mg/kg) | BWL%Max | 致死率 | TVI%±SE |
A2780 | ||||
对照 | / | 0 | 0/8 | / |
ST1926 | 5,口服 | 3 | 0/8 | *34±8 |
ST1926 | 10,口服 | 5 | 0/8 | *39±5 |
A2780/Dx | ||||
对照 | / | 0 | 0/8 | / |
ST1926 | 10,口服 | 0 | 0/8 | *34±3 |
ST1926 | 15,口服 | 6 | 0/8 | *54±9 |
NCI-H460 | ||||
对照 | / | |||
ST1926 | 15,口服 | 4 | 0/8 | *40±2 |
*P<0.05相对于对照。
ST1926显示出以15mg/kg口服的剂量按照方案qdx4x3w在有和没有紫杉醇(15mg/kg,腹膜内,按照方案q7dx3)的情况下在NCI-H460非小细胞肺癌内有效(表7)。
表7.
ST1926(qdx4x3w)对非小细胞肺癌NCI-H460在有和没有紫杉醇(q7dx3)的情况下的抗肿瘤活性
处理 | 剂量(mg/kg) | BWL%max | 致死率 | TVI%±SE |
对照 | / | 3 | / | / |
ST1926 | 15,口服 | 14 | 0/8 | **38±8 |
紫杉醇 | 15,腹膜内 | 4 | 0/8 | 0 |
1926+Tax | 15,口服15,腹膜内 | 16 | 0/8 | **°56±6 |
**P<0.01相对于对照;°P<0.05相对于ST1926(Mann-Whitney)。
ST1926当以15mg/kg口服剂量按照方案qdx3x3w给药时显示显著的抗肿瘤活性(表8)。
表8.
ST1926(qdx3x3w)对非小细胞肺癌NCI-H460的抗肿瘤活性
处理 | 剂量(mg/kg) | BWL%max | 致死率 | TVI%±SE |
对照 | / | 3 | / | / |
ST1926 | 15,口服 | 4 | 0/8 | *52±7 |
*P<0.05相对于对照(Mann-Whitney)。
ST1879对牛肾上腺微循环(microcircle)内皮(BMEC)细胞系的细胞
毒性
使用内皮细胞系BMEC,预先以如下方式从新鲜牛肾上腺制备。在处死之后即刻从动物取下腺并贮藏在冰中直到到达实验室。在无菌条件(Bio-Hazard层流通风橱)下,将这些腺在Betadine溶液中洗涤5分钟,接着用2升无菌PBS洗涤。然后用无菌一次性解剖刀将这些腺切成小段,约2mm,并转移到含有PBS(30ml/腺)的聚苯乙烯Falcon管中。在冷却离心机中在4℃下以600rpm离心之后,倾析上清液。将沉淀重悬在等体积(相对沉淀物的体积)的0.12%的胶原酶A(Boehringer Mannheim)中并在振荡下于37℃下培养2小时。通过过滤器(Sigma)(首先200目,然后100目)连续过滤之后,将上清液加入到15%DMEM FBS溶液中以抑制胶原酶A的作用。将该溶液在1000rpm、室温下离心,将沉淀物重悬在含有20%FBS、50μg/ml牛脑提取物(BBE)、50μg/ml肝素(Sigma)、0.5%v/v庆大霉素(Sigma)、1%v/v L-谷氨酰胺的DMEM培养基中并接种到用1%明胶(猪明胶Sigma)凝胶化的培养皿上。在达到融合时,将这些细胞用内皮标记物,例如因子VIII表征。
使用BMEC细胞进行细胞毒性测定。将这些细胞以200μl的体积接种到96孔平板中并在37℃下培养24小时。次日,以从200μM到1.56μM减少的浓度加入测定化合物ST 1879,并在37℃下在含有5%CO2的潮湿环境中将这些细胞再培养24小时。在第3天,将该平板翻转除去培养基并在第3天通过翻转和加入300μl PBS 4次洗涤该平板。洗涤之后,加入200μl/孔的前面所述的用于平板接种在明胶上的培养基。在第5天,通过翻转平板除去培养基,并将这些细胞用冷15%TCA的溶液处理1小时。用水浸泡平板并通过翻转除去将这些孔洗涤3次。向每一孔中加入200μl在1%乙酸中的0.4%sulphorodamine B。在室温下将这些平板再培养30分钟。翻转除去sulphorodamine B,通过在1%乙酸中浸泡3洗涤这些平板,然后首先用吸水纸干燥,然后喷射热空气干燥。向每一孔中加入200μl的10mM Tris碱并将这些平板振荡至少20分钟。使用Multiskan分光光度计于540nm下测定光密度。
通过与ST1879培养24小时在除去化合物之后48小时来测定细胞存活率。与产品培养24小时能够以浓度依赖性方式抑制细胞增殖。表5显示了计算的IC50值(抑制50%细胞存活率的产品浓度),ST1879已证实等于105μM的差的细胞毒性和等于25μM的非毒性浓度,随后将其用于研究ST1879对内皮细胞迁移的影响(参见表9)。
表9
ST1879对内皮细胞的细胞毒性
细胞系 | IC50±SD(μM) | IC0 |
BMEC | 105±14 | 25μM |
内皮BMEC细胞趋化性
为了评价ST1879对内皮细胞趋化性的影响,使用Boyden室,它由带2个孔的室组成,1个在下面,另一个在上面,它们通过8μm的确定孔径的聚碳酸酯过滤器分开。在下面孔中加入化学引诱因子1%FBS在DMEM中,在上面孔中加入牛肾下微循环内皮细胞(BMEC)(悬浮在含有1%无脂肪酸的猪血清白蛋白的DMEM中)。ST1879抑制细胞向化学引诱因子方向穿过聚碳酸酯过滤器迁移的能力,是通过计数过滤器下侧存在的细胞数来定量评价的。表8中报道的移动百分比是按照公式:(处理-对照/对照)×100计算的。ST1926在等于50和25μM的浓度下显示抑制BMEC细胞向化学引诱剂刺激物FCS的趋化性(表10)。
表10.
ST1879诱导的对BMEC细胞的迁移的抑制
细胞系 | %对迁移的抑制 | |
50μM | 25μM | |
BMEC | 91%(6.1个细胞±2.4相对于对照中72.1±7.4细胞) | 42.7%(41.3个细胞±10.2相对于对照中72.1±7.4个细胞) |
ST1879对HUVEC细胞在matrigel上分化的影响
内皮细胞在matrigel上的分化试验,是一种常用于评价产品抗血管生成活性的试验。Matrigel是一种得自肿瘤的重组基底膜提取物,主要由层粘连蛋白和胶原IV组成,在其上内皮细胞以类似毛细血管的三维结构组织起来。通过显微镜计数″结″可以测定其网络密度,该″结″定义为两个以上的管状结构离开的交叉点,或者可以通过计算机化成象系统(能够计算毛细血管结构所占面积的百分比)测定。
将4℃下的Matrigel(Becton-Dickinson)接种到24孔平板中并使其在37℃下的恒温箱中胶凝30分钟。在有或者没有25μM无毒浓度的ST1879情况下将人脐带内皮细胞HUVEC(Clonetics)重悬在500μl培养基中,并接种在该matrigel上。培养5小时之后,用4%低聚甲醛的PBS溶液固定这些细胞。通过显微镜计数3个独立视野的结的数目/视野将结果定量化,并以相对于阳性对照的百分比计。
ST1879以25μM的浓度显示61%抑制这些内皮细胞在matrigel上的分化(表11)。
表11.
ST1879诱导的对HUVEC细胞分化的抑制
细胞系 | %对在matrigel上分化的抑制 |
HUVEC | ST1879(25μM)=61%(8.2个结相对于对照中21.2个结) |
ST1879和ST1898对人肿瘤细胞系的细胞毒性
使用人急性早幼粒细胞白血病细胞系NB4进行该细胞毒性测定,将它们保持在含有10%胎牛血清(FCS)和1%谷氨酰胺的RPMI1640中。
还使用另外两种实体肿瘤细胞系:
1.人前列腺癌PC3。将该细胞系保持在含有10%FCS、1%丙酮酸钠和1%谷氨酰胺的RPMI1640培养基中。
2.人结肠腺癌LoVo。将该细胞系保持在含有10%FCS和1%谷氨酰胺的HAM′s F-12培养基中。
使用10000个NB4细胞/孔进行细胞毒性测定。将这些细胞以250μl的体积接种到96孔平板中并在37℃下培养24小时。次日,以增加的浓度加入测定化合物ST1879,并在37℃下在含有5%CO2的潮湿环境中将这些细胞再培养24小时。在第3天,将该平板在1600xg下离心10分钟除去培养基并倾析掉上清液。加入250μl PBS;然后再在1600xg下将平板离心10分钟并将上清液倾析掉。加入200μl/孔的含10%FCS的RPMI1640培养基,并在37℃下将这些平板再培养48小时。在第5天,再在1600xg下将这些平板离心10分钟,并将这些平板翻转除去培养基,加入200μl PBS和50μl的80%冷TCA。然后将这些平板在冰上静置培养至少1小时。翻转除去TCA;将这些平板在蒸馏水中浸泡洗涤3次并首先在纸上干燥,然后通过喷射热空气干燥。向每个孔中加入200μl在1%乙酸中的0.4%sulphorodamine B。在室温下将这些平板再培养30分钟。翻转除去sulphorodamine B,通过在1%乙酸中浸泡3次洗涤这些平板,然后首先用吸水纸干燥,然后喷射热空气干燥。将200μl的10mM Tris碱加入到每一孔中并将这些平板搅拌至少20分钟。使用Multiskan分光光度计于540nm下测定光密度。
就粘附的细胞系PC3和LoVo而言,采用的步骤相同,只是在第3天的平板洗涤,是通过翻转,然后加入PBS 3次进行的,而不在1600xg下离心。同样在第5天,通过翻转平板将上清液除去。
通过与ST1879或ST1898培养24小时,在除去化合物后48小时来测定细胞存活率。与产品培养48小时足以以浓度依赖性方式抑制细胞增殖。表10显示了对研究的每一肿瘤细胞系计算的IC50值(抑制50%细胞存活率的产品浓度)。ST1879已证实对LoVo细胞的细胞毒性(IC50=5.2μM)比对前列腺癌细胞系PC3(IC50=13.6μM)和对人早幼粒细胞NB4细胞系(58.5μM)计算的要大。ST1898也已显示对结肠癌LoVo更具活性(参见表12)。
表12.
ST1879和ST1898的细胞毒性
测定的化合物 | 细胞系 | IC50±SD(μM) |
ST1879 | NB4 | 58.5±3.2 |
ST1879 | PC3 | 13.6±2.1 |
ST1879 | LoVo | 5,2±0.9 |
ST1898 | NB4 | 8.8±0.6 |
ST1898 | PC3 | 1.7±0.2 |
ST1898 | LoVo | 0.38±0.02 |
ST1879和ST1898对NB4细胞的促分化效应
将NB4细胞以150000个细胞/ml的密度接种在含有10%胎牛血清的RPMI1640培养基中。然后将这些细胞用ST1879或ST1898以从0.4μM开始到0.01μM的递减的浓度处理并在恒温箱中放置3天,不更换培养基。为了测定该分化影响,从每一样品中收集500000个细胞,离心并重悬在1ml含有10%血清、1mg/ml氮蓝四唑(NBT)和100ng PMA(乙酸肉豆蔻佛波醇)的RPMI 1640培养基中。将这些如上所述重悬的细胞在37℃下培养60分钟。在培养结束时将这些细胞离心并将沉淀物重悬在1ml含有10%Triton x100的PBS中。将这些样品进行超声处理直到溶解,然后在540nm的波长下通过分光光度计读数。含有分化细胞的样品变成略带紫色,而对照样品和/或未分化细胞的这些样品保持白色或者着色浅得多。根据如下报道的AC50(对50%细胞分化的活化浓度)评价ST1879或ST1898的促分化作用。ST1898证实具有良好的促分化能力,可通过AC50值等于19nM来衡量(见表13)。
表13.
ST1879和ST1898对NB4细胞的促分化作用
产品 | AC50(nM±SD) |
ST1879 | 55±9 |
ST1898 | 19±0.8 |
ST1879、ST1926和ST1898在鸡尿囊绒膜(CAM)模型中的抑血管(angiostatic)活性
鸡尿囊绒膜是非常血管化的薄膜,其中血管在发育的第4天出现,到发育的第8天发展出动静脉系统,并且积极增殖直到第11天。
本研究的目的是在基本条件下和在有血管增殖的诱导剂bFGF(碱性成纤维细胞生长因子)的情况下追踪CAM中的血管发育。本研究使用在其发育的最初阶段的鸡胚胎蛋。在发育的第3天,打开壳使CAM的血管可以看见。在发育的第9天通过连续3天施加约1mm3片段的无菌明胶(GELFOAM Pharmacia-Upjohn)到CAM表面,在其上给予bFGF(50ng/胚胎)或讨论的产品来进行处理。
通过将0处理时的血管与后面时间(第12天)的血管比较而获得该分子对血管增殖的影响的评价。
如下将结果报道于表14。3个产品证实在鸡尿囊绒膜模型中以0.25-0.5μg/胚胎的浓度具有抑血管活性(表14)。
表14.
ST1879、ST1926、ST1898的抑血管活性
处理 | 浓度(μg/胚胎) | n | 第9天(T0) | 第12天(72小时) | Δ血管 |
bFGF | 0.05 | 7 | 5±1 | 19±1 | 15±1 |
bFGF+1879 | 0.05+0.5 | 6 | 4±1 | 8±1 | 4±1(-73%) |
bFGF | 0.05 | 6 | 3±1 | 22±1 | 19±1 |
bFGF+1926 | 0.05+0.25 | 8 | 3±1 | 12±2 | 9±2(-53%) |
bFGF | 0.05 | 4 | 3±1 | 28±2 | 24±1 |
bFGF+1898 | 0.05+0.25 | 6 | 3±1 | 10±1 | 7±1(-71%) |
结果是每个海绵中的血管数的平均值±SE。
Claims (20)
2、一种药物组合物,包含权利要求1的化合物作为活性组分以及至少一种药用可接受的赋形剂和/或稀释剂。
3、权利要求1的化合物用于制备治疗与变化的血管生成有关的病理情况的药物的用途。
4、如权利要求3的用途,其中该病理情况选自关节炎病理情况、肿瘤、转移、糖尿病性视网膜病、牛皮癣、慢性炎症和动脉粥样硬化。
5、如权利要求3或4的用途,其中该病理情况是糖尿病性视网膜病。
6、如权利要求3或4的用途,其中该病理情况是牛皮癣。
7、如权利要求3或4的用途,其中该病理情况是慢性炎症疾病。
8、如权利要求3或4的用途,其中该病理情况是动脉粥样硬化。
9、如权利要求3或4的用途,所述药物用于治疗关节炎病理情况。
10、权利要求1的化合物用于制备具有抗肿瘤活性的药物的用途。
11、如权利要求10的用途,其中抗肿瘤活性为细胞毒性性质。
12、如权利要求10的用途,其中抗肿瘤活性为凋亡性质。
13、如权利要求10的用途,其中抗肿瘤活性为抗血管生成性质。
14、权利要求1的化合物用于制备可用于预防和治疗肿瘤转移的药物的用途。
15、如权利要求10-14中任一项的用途,其中肿瘤选自肉瘤、癌、类癌、骨肿瘤、神经内分泌肿瘤、淋巴细胞白血病、髓细胞白血病、单核细胞白血病、巨核细胞白血病或霍奇金病。
16、如权利要求15的用途,其中肿瘤是急性早幼粒细胞白血病。
17、由一种或多种权利要求1的化合物与一种或多种已知的抗癌药组成的组合。
18、一种药物组合物,包括权利要求17的组合和一种或多种药用可接受的赋形剂或载体。
19、一种或多种权利要求1的化合物与一种或多种已知的抗癌药用于制备治疗肿瘤的药物的用途。
20、一种或多种权利要求1的化合物与一种或多种已知的抗癌药用于制备治疗肿瘤的药物的用途,特征在于权利要求1的化合物作为抗癌药的辅助物存在。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITRM2001A000464 | 2001-07-31 | ||
IT2001RM000464A ITRM20010464A1 (it) | 2001-07-31 | 2001-07-31 | Derivati retinoidi ad attivita' antiangiogenica, antitumorale e pro-apoptotica. |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1537094A CN1537094A (zh) | 2004-10-13 |
CN1279014C true CN1279014C (zh) | 2006-10-11 |
Family
ID=11455702
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB028150082A Expired - Fee Related CN1279014C (zh) | 2001-07-31 | 2002-07-18 | 具有抗血管生成、抗肿瘤和促凋亡活性的类维生素a衍生物 |
Country Status (20)
Country | Link |
---|---|
US (2) | US8101793B2 (zh) |
EP (1) | EP1412317B1 (zh) |
JP (1) | JP4463550B2 (zh) |
KR (1) | KR100888466B1 (zh) |
CN (1) | CN1279014C (zh) |
AT (1) | ATE492526T1 (zh) |
AU (1) | AU2002326144B2 (zh) |
BR (1) | BR0211521A (zh) |
CA (1) | CA2454532C (zh) |
CY (1) | CY1114535T1 (zh) |
DE (1) | DE60238683D1 (zh) |
DK (1) | DK1412317T3 (zh) |
ES (1) | ES2358097T3 (zh) |
HK (1) | HK1068868A1 (zh) |
HU (1) | HU229308B1 (zh) |
IT (1) | ITRM20010464A1 (zh) |
MX (1) | MXPA04000877A (zh) |
PL (1) | PL207530B1 (zh) |
PT (1) | PT1412317E (zh) |
WO (1) | WO2003011808A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104496839A (zh) * | 2014-12-03 | 2015-04-08 | 广东东阳光药业有限公司 | 取代环丁烷类神经氨酸酶抑制剂及其使用方法和用途 |
Families Citing this family (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060062786A1 (en) * | 2000-11-08 | 2006-03-23 | Human Genome Sciences, Inc. | Antibodies that immunospecifically bind to TRAIL receptors |
US20030228309A1 (en) * | 2000-11-08 | 2003-12-11 | Theodora Salcedo | Antibodies that immunospecifically bind to TRAIL receptors |
US20050214209A1 (en) * | 2001-05-25 | 2005-09-29 | Human Genome Sciences, Inc. | Antibodies that immunospecifically bind to TRAIL receptors |
US20050129616A1 (en) * | 2001-05-25 | 2005-06-16 | Human Genome Sciences, Inc. | Antibodies that immunospecifically bind to TRAIL receptors |
US20090226429A1 (en) * | 2001-05-25 | 2009-09-10 | Human Genome Sciences, Inc. | Antibodies That Immunospecifically Bind to TRAIL Receptors |
US7361341B2 (en) * | 2001-05-25 | 2008-04-22 | Human Genome Sciences, Inc. | Methods of treating cancer using antibodies that immunospecifically bind to trail receptors |
US7348003B2 (en) | 2001-05-25 | 2008-03-25 | Human Genome Sciences, Inc. | Methods of treating cancer using antibodies that immunospecifically bind to TRAIL receptors |
ITRM20010464A1 (it) * | 2001-07-31 | 2003-01-31 | Sigma Tau Ind Farmaceuti | Derivati retinoidi ad attivita' antiangiogenica, antitumorale e pro-apoptotica. |
CA2468745A1 (en) | 2001-11-30 | 2003-06-12 | The Burnham Institute | Induction of apoptosis in cancer cells |
CA2471140A1 (en) * | 2001-12-20 | 2003-07-03 | Human Genome Sciences, Inc. | Antibodies that immunospecifically bind to trail receptors |
MX2007010185A (es) | 2005-02-22 | 2007-12-06 | Ranbaxy Lab Ltd | Derivados de acido 5-fenil-pentanoico como inhibidores de metaloproteinasa de matriz para el tratamiento de asma y otras enfermedades. |
FR2884248B1 (fr) * | 2005-04-08 | 2007-05-18 | Galderma Res & Dev | Nouveau procede de preparation de l'acide 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtoique |
MX2007012492A (es) | 2005-04-08 | 2007-12-06 | Galderma Res & Dev | Nuevo metodo para la preparacion del acido 6-[3-(1-adamantil)-4- metoxifenil]-2-naftoico. |
ITRM20050248A1 (it) * | 2005-05-20 | 2006-11-21 | Sigma Tau Ind Farmaceuti | Uso acido adamantil metossidifenil propenoico per il trattamento di patologie cutanee. |
EA012729B1 (ru) | 2005-06-28 | 2009-12-30 | Сигма-Тау Индустрие Фармасьютике Риуните С.П.А. | Бифенил- и нафтилфенилпроизводные гидроксамовой кислоты |
CN101316584A (zh) * | 2005-09-27 | 2008-12-03 | 北海道公立大学法人札幌医科大学 | 用于预防及治疗由血管通透性亢进引起的眼病的医药 |
WO2007071605A1 (en) * | 2005-12-19 | 2007-06-28 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | The use of st1898 for the treatment of restenosis |
JP5054006B2 (ja) * | 2006-06-23 | 2012-10-24 | ロート製薬株式会社 | ヒアルロン酸産生促進能を有する組成物 |
WO2008077772A2 (en) * | 2006-12-22 | 2008-07-03 | Sigma-Tau Industrie Farmaceutiche Riunite Spa | Combination of a retinoid and a platinum anticancer agent |
WO2010000784A1 (en) * | 2008-07-03 | 2010-01-07 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Treatment of restenosis |
TW201031402A (en) * | 2008-12-24 | 2010-09-01 | Sigma Tau Ind Farmaceuti | New retinoid derivatives endowed with cytotoxic and/or antiangiogenic properties |
US9056085B2 (en) | 2009-02-03 | 2015-06-16 | Children's Medical Center Corporation | Methods for enhancing hematopoietic stem/progenitor cell engraftment |
US9051548B2 (en) | 2009-02-03 | 2015-06-09 | Children's Medical Center Corporation | Methods for enhancing hematopoietic stem/progenitor cell engraftment |
WO2010106135A1 (en) | 2009-03-20 | 2010-09-23 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Combined use for the treatment of ovarian carcinoma |
EP2516396A1 (en) | 2009-12-23 | 2012-10-31 | Wayne State University | Therapeutic compounds |
EA023171B1 (ru) * | 2011-09-19 | 2016-04-29 | Сигма-Тау Индустрие Фармасьютике Риуните С.П.А. | Тиопроизводные лактамов в качестве высокоактивных ингибиторов hdac и их применение в качестве лекарственных средств |
WO2013168601A1 (ja) * | 2012-05-11 | 2013-11-14 | 国立大学法人 金沢大学 | 不斉選択性の切り替えが可能なクロマトグラフィー用充填剤 |
US11707442B2 (en) | 2015-09-25 | 2023-07-25 | The General Hospital Corporation | Antibacterial and antifungal compounds |
EP3301085A1 (en) | 2016-09-29 | 2018-04-04 | Biogem S.Ca.R.L. | Retinoid derivatives with antitumor activity |
AU2018256890B2 (en) * | 2017-04-27 | 2024-04-11 | Vanderbilt University | Methods for treating atherosclerosis with gamma-ketoaldehyde scavengers |
WO2018213609A1 (en) | 2017-05-17 | 2018-11-22 | Ausubel Frederick M | Antibiotic compounds |
WO2019018185A1 (en) | 2017-07-15 | 2019-01-24 | Arisan Therapeutics Inc. | ENANTIOMERICALLY PURE ADAMATANE DERIVATIVES FOR THE TREATMENT OF FILOVIRUS INFECTIONS |
IT201900003343A1 (it) * | 2019-03-07 | 2020-09-07 | Special Product’S Line S P A | Derivati fenolici per uso come antimicrobici, antibatterici, battericidi |
CN111956806B (zh) * | 2020-09-03 | 2023-04-07 | 四川大学 | 一种药物载体、胶束、药剂及其制备方法和应用 |
IT202000029906A1 (it) * | 2020-12-04 | 2022-06-04 | Special Product’S Line S P A | Derivati fenolici per uso come antimicrobici, antibatterici, battericidi. |
IT202000029882A1 (it) * | 2020-12-04 | 2022-06-04 | Special Product’S Line S P A | Derivati fenolici per uso come antimicrobici, antibatterici, battericidi |
WO2022229017A1 (en) | 2021-04-27 | 2022-11-03 | Biogem S.C.A R.L. | Adamantyl retinoid derivative with anticancer activity |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2676052B1 (fr) * | 1991-05-02 | 1994-04-29 | Cird Galderma | Nouveaux composes polycycliques aromatiques et leur utilisation en medecine humaine ou veterinaire et en cosmetique. |
BR9710255A (pt) * | 1996-07-08 | 1999-08-10 | Galderma Res & Dev | Método para o tratamento de cáncer composto de retinóide de adamantila composição farmacéutica ou cosmética de matéria método de tratamento ou de prevenção e método para controlar |
ITRM20010464A1 (it) * | 2001-07-31 | 2003-01-31 | Sigma Tau Ind Farmaceuti | Derivati retinoidi ad attivita' antiangiogenica, antitumorale e pro-apoptotica. |
CA2468745A1 (en) * | 2001-11-30 | 2003-06-12 | The Burnham Institute | Induction of apoptosis in cancer cells |
-
2001
- 2001-07-31 IT IT2001RM000464A patent/ITRM20010464A1/it unknown
-
2002
- 2002-07-18 ES ES02760553T patent/ES2358097T3/es not_active Expired - Lifetime
- 2002-07-18 HU HU0401604A patent/HU229308B1/hu not_active IP Right Cessation
- 2002-07-18 JP JP2003517002A patent/JP4463550B2/ja not_active Expired - Fee Related
- 2002-07-18 AT AT02760553T patent/ATE492526T1/de active
- 2002-07-18 DE DE60238683T patent/DE60238683D1/de not_active Expired - Lifetime
- 2002-07-18 CN CNB028150082A patent/CN1279014C/zh not_active Expired - Fee Related
- 2002-07-18 PT PT02760553T patent/PT1412317E/pt unknown
- 2002-07-18 PL PL368412A patent/PL207530B1/pl not_active IP Right Cessation
- 2002-07-18 AU AU2002326144A patent/AU2002326144B2/en not_active Ceased
- 2002-07-18 CA CA2454532A patent/CA2454532C/en not_active Expired - Fee Related
- 2002-07-18 KR KR1020047001546A patent/KR100888466B1/ko not_active IP Right Cessation
- 2002-07-18 EP EP02760553A patent/EP1412317B1/en not_active Expired - Lifetime
- 2002-07-18 DK DK02760553.4T patent/DK1412317T3/da active
- 2002-07-18 WO PCT/IT2002/000474 patent/WO2003011808A1/en active Application Filing
- 2002-07-18 BR BR0211521-2A patent/BR0211521A/pt not_active IP Right Cessation
- 2002-07-18 US US10/485,530 patent/US8101793B2/en not_active Expired - Fee Related
- 2002-07-18 MX MXPA04000877A patent/MXPA04000877A/es active IP Right Grant
-
2005
- 2005-02-16 HK HK05101240A patent/HK1068868A1/xx not_active IP Right Cessation
-
2007
- 2007-06-20 US US11/765,737 patent/US7449495B2/en not_active Expired - Fee Related
-
2011
- 2011-03-16 CY CY20111100294T patent/CY1114535T1/el unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104496839A (zh) * | 2014-12-03 | 2015-04-08 | 广东东阳光药业有限公司 | 取代环丁烷类神经氨酸酶抑制剂及其使用方法和用途 |
CN104496839B (zh) * | 2014-12-03 | 2016-04-20 | 广东东阳光药业有限公司 | 取代环丁烷类神经氨酸酶抑制剂及其使用方法和用途 |
Also Published As
Publication number | Publication date |
---|---|
HUP0401604A3 (en) | 2006-01-30 |
HK1068868A1 (en) | 2005-05-06 |
EP1412317B1 (en) | 2010-12-22 |
JP4463550B2 (ja) | 2010-05-19 |
KR100888466B1 (ko) | 2009-03-12 |
US7449495B2 (en) | 2008-11-11 |
JP2004536879A (ja) | 2004-12-09 |
DK1412317T3 (da) | 2011-03-28 |
MXPA04000877A (es) | 2004-06-03 |
AU2002326144B2 (en) | 2008-04-10 |
PL368412A1 (en) | 2005-03-21 |
KR20040028968A (ko) | 2004-04-03 |
WO2003011808A1 (en) | 2003-02-13 |
EP1412317A1 (en) | 2004-04-28 |
PL207530B1 (pl) | 2010-12-31 |
US20040235757A1 (en) | 2004-11-25 |
CY1114535T1 (el) | 2016-10-05 |
BR0211521A (pt) | 2004-09-14 |
CN1537094A (zh) | 2004-10-13 |
ES2358097T3 (es) | 2011-05-05 |
DE60238683D1 (de) | 2011-02-03 |
CA2454532C (en) | 2011-01-25 |
CA2454532A1 (en) | 2003-02-13 |
PT1412317E (pt) | 2011-03-21 |
HU229308B1 (en) | 2013-10-28 |
US20080021088A1 (en) | 2008-01-24 |
ITRM20010464A1 (it) | 2003-01-31 |
US8101793B2 (en) | 2012-01-24 |
ITRM20010464A0 (it) | 2001-07-31 |
HUP0401604A2 (hu) | 2004-12-28 |
ATE492526T1 (de) | 2011-01-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1279014C (zh) | 具有抗血管生成、抗肿瘤和促凋亡活性的类维生素a衍生物 | |
CN1247575C (zh) | 磺酰胺基醚取代的咪唑并喹啉 | |
CN1249062C (zh) | 取代的咪唑并吡啶 | |
CN1031992C (zh) | 苯醌衍生物及其药用 | |
CN1036918C (zh) | 苯并吡喃衍生物及含有此衍生物的k+通道活化剂 | |
CN1179960C (zh) | 吲哚衍生物和其在治疗骨质疏松中的应用以及其它应用 | |
CN1218471A (zh) | 咔啉衍生物 | |
CN1055182A (zh) | N-(吡咯并《2,3-d》嘧啶-3-基酰基)-谷氨酸衍生物 | |
CN1073161A (zh) | Et(endothelin)受体拮抗物 | |
CN1173497A (zh) | 含杂环碳酸衍生物 | |
CN1088581A (zh) | 内皮素受体拮抗剂 | |
CN1560035A (zh) | 5-羟基吲哚-3-羧酸脂类衍生物 | |
CN1194976C (zh) | 作为肿瘤坏死因子抑制剂的噻吩并二苯并薁化合物 | |
CN1612852A (zh) | 脂氧素a4类似物 | |
CN1257152C (zh) | 用于麻醉和镇静的短效镇静催眠剂 | |
CN1031839A (zh) | 抗炎呋喃酮类 | |
CN1230166A (zh) | 隐杯伞素类抗肿瘤剂 | |
CN1067053C (zh) | 单环β-内酰胺类抗生素衍生物的中间体的制备方法 | |
CN1031532A (zh) | 杂环化合物 | |
CN1058494C (zh) | 新的洋芫荽黄素化合物,其制备方法和含它们的药用组合物 | |
CN88101674A (zh) | 色酮衍生物 | |
CN1079465A (zh) | 吲哚类 | |
CN1309655A (zh) | 可用于治疗脂血异常、动脉粥样硬化和糖尿病的环状化合物、药物组合物和制备方法 | |
CN1027064C (zh) | 萘衍生物及制备方法 | |
CN1744892A (zh) | 乳癌耐性蛋白(bcrp)抑制剂 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1068868 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20061011 Termination date: 20140718 |
|
EXPY | Termination of patent right or utility model |