WO2021201109A1 - 金属糖質錯体 - Google Patents
金属糖質錯体 Download PDFInfo
- Publication number
- WO2021201109A1 WO2021201109A1 PCT/JP2021/013857 JP2021013857W WO2021201109A1 WO 2021201109 A1 WO2021201109 A1 WO 2021201109A1 JP 2021013857 W JP2021013857 W JP 2021013857W WO 2021201109 A1 WO2021201109 A1 WO 2021201109A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- cells
- lgg
- added
- cell
- Prior art date
Links
- 150000001040 L-glucose derivatives Chemical class 0.000 claims abstract description 27
- 239000003446 ligand Substances 0.000 claims abstract description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 125000000962 organic group Chemical group 0.000 claims abstract description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 4
- 229910052731 fluorine Inorganic materials 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 89
- 150000001875 compounds Chemical class 0.000 description 83
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 206010028980 Neoplasm Diseases 0.000 description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 201000011510 cancer Diseases 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 230000015572 biosynthetic process Effects 0.000 description 26
- 238000003786 synthesis reaction Methods 0.000 description 26
- 238000000034 method Methods 0.000 description 24
- 230000000694 effects Effects 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- 235000002597 Solanum melongena Nutrition 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical group [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 229910052737 gold Inorganic materials 0.000 description 14
- 239000007788 liquid Substances 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- 238000000926 separation method Methods 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 239000010931 gold Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- WQZGKKKJIJFFOK-ZZWDRFIYSA-N L-glucose Chemical compound OC[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@H]1O WQZGKKKJIJFFOK-ZZWDRFIYSA-N 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 229940126062 Compound A Drugs 0.000 description 9
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 206010020843 Hyperthermia Diseases 0.000 description 8
- 230000036031 hyperthermia Effects 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 230000030833 cell death Effects 0.000 description 6
- 239000003623 enhancer Substances 0.000 description 6
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 6
- 230000001235 sensitizing effect Effects 0.000 description 6
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000012267 brine Substances 0.000 description 5
- DEGAKNSWVGKMLS-UHFFFAOYSA-N calcein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(O)=O)CC(O)=O)=C(O)C=C1OC1=C2C=C(CN(CC(O)=O)CC(=O)O)C(O)=C1 DEGAKNSWVGKMLS-UHFFFAOYSA-N 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 229960002378 oftasceine Drugs 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 229960001031 glucose Drugs 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- 108091052347 Glucose transporter family Proteins 0.000 description 3
- 102000003939 Membrane transport proteins Human genes 0.000 description 3
- 108090000301 Membrane transport proteins Proteins 0.000 description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 3
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- LPTITAGPBXDDGR-IBEHDNSVSA-N beta-d-glucose pentaacetate Chemical compound CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O LPTITAGPBXDDGR-IBEHDNSVSA-N 0.000 description 3
- 230000006866 deterioration Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 231100001231 less toxic Toxicity 0.000 description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 description 3
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 102000018711 Facilitative Glucose Transport Proteins Human genes 0.000 description 2
- -1 L-form glucose derivative Chemical class 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002303 glucose derivatives Chemical class 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 238000009217 hyperthermia therapy Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 230000001678 irradiating effect Effects 0.000 description 2
- 210000004153 islets of langerhan Anatomy 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000000879 optical micrograph Methods 0.000 description 2
- VGEREEWJJVICBM-UHFFFAOYSA-N phloretin Chemical compound C1=CC(O)=CC=C1CCC(=O)C1=C(O)C=C(O)C=C1O VGEREEWJJVICBM-UHFFFAOYSA-N 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 2
- 206010046766 uterine cancer Diseases 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- HEVMDQBCAHEHDY-UHFFFAOYSA-N (Dimethoxymethyl)benzene Chemical compound COC(OC)C1=CC=CC=C1 HEVMDQBCAHEHDY-UHFFFAOYSA-N 0.000 description 1
- ZWTDXYUDJYDHJR-UHFFFAOYSA-N (E)-1-(2,4-dihydroxyphenyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one Natural products OC1=CC(O)=CC=C1C=CC(=O)C1=CC=C(O)C=C1O ZWTDXYUDJYDHJR-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- 102000010637 Aquaporins Human genes 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 150000000780 D-glucose derivatives Chemical class 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 102000042092 Glucose transporter family Human genes 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-DHVFOXMCSA-N L-galactose Chemical compound OC[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O WQZGKKKJIJFFOK-DHVFOXMCSA-N 0.000 description 1
- WQZGKKKJIJFFOK-JFNONXLTSA-N L-mannopyranose Chemical compound OC[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O WQZGKKKJIJFFOK-JFNONXLTSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- YQHMWTPYORBCMF-UHFFFAOYSA-N Naringenin chalcone Natural products C1=CC(O)=CC=C1C=CC(=O)C1=C(O)C=C(O)C=C1O YQHMWTPYORBCMF-UHFFFAOYSA-N 0.000 description 1
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 1
- ULUHFIOTVAJJBF-UHFFFAOYSA-N [Au+].ClCCP(CC)CC Chemical compound [Au+].ClCCP(CC)CC ULUHFIOTVAJJBF-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- AUJRCFUBUPVWSZ-XTZHGVARSA-M auranofin Chemical compound CCP(CC)(CC)=[Au]S[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O AUJRCFUBUPVWSZ-XTZHGVARSA-M 0.000 description 1
- 229960005207 auranofin Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000002771 cell marker Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 206010022498 insulinoma Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000006249 magnetic particle Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000013307 optical fiber Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 208000021255 pancreatic insulinoma Diseases 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- AFNBMGLGYSGFEZ-UHFFFAOYSA-M potassium;ethanethioate Chemical compound [K+].CC([S-])=O AFNBMGLGYSGFEZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000007944 thiolates Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 230000007723 transport mechanism Effects 0.000 description 1
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
Images
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7135—Compounds containing heavy metals
-
- 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
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/12—Gold compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/5004—Acyclic saturated phosphines
Definitions
- the present invention relates to a metal sugar complex.
- Hyperthermia uses the fact that cancer cells (malignant tumor cells) are more sensitive to heat than normal cells, and by heating the affected area, it kills the cancer cells, changes the environment around the cancer cells, or cancer. This is a method for improving the patient survival rate by enhancing the effect of treatment (see, for example, Non-Patent Document 1).
- Examples of the heating method in hyperthermia include a method of irradiating the affected area with radio waves (RF waves). This is called high frequency hyperthermia therapy.
- RF waves radio waves
- Patent Document 1 proposes a method of inducing magnetic particles or the like as an RF absorption enhancer (sensitizing drug) to a tumor (affected portion) to improve the heating efficiency by RF waves.
- a method of inducing the RF absorption enhancer into the tumor for example, a method of directly introducing the RF absorption enhancer into the tumor by injection or the like as a part of a fluid, a method of inducing the RF absorption enhancer into the affected part by using MRI, and the like have been proposed.
- one of the objects of the present invention is to provide a sensitizing drug that can be selectively taken up by cancer cells and can selectively generate heat at a target site during high-frequency hyperthermia treatment.
- anticancer drugs act not only on cancer cells but also on normal cells, resulting in strong side effects. How to reduce this side effect has become an issue in the treatment of cancer.
- molecular-targeted drugs that suppress the growth and metastasis of cancer cells by grasping the molecules that are specifically expressed by cancer cells are attracting attention.
- Molecular-targeted drugs are expected to suppress the side effects of classic anticancer drugs.
- molecules that are said to be specifically expressed by cancer cells are also expressed in normal cells, and molecular-targeted drugs also act on molecules that are different from those expected, and side effects occur to some extent.
- the human body is a collection of cells. As long as it is a cell, it needs an energy source for its activity and a carbon source for its growth. Therefore, in recent years, a method of identifying cancer by labeling the molecule on the side of being taken up by cells, instead of targeting a specific protein or molecule in our body, has been attracting attention again (OnoK). .Et al., Cancers 2020).
- Another object of the present invention is to provide a compound that is less toxic to normal cells and is selectively taken up by cancer cells to exhibit toxicity.
- L-glucose derivative represented by the following general formula (1).
- X 1 represents 1 -SAuR group
- X 2 , X 3 , X 4 and X 5 independently represent -OR 2 groups, -NH 2 groups or fluorine atoms, respectively.
- R 1 represents a ligand and R 2 represents a hydrogen atom or an organic group.
- an L-glucose derivative it can be selectively taken up by cancer cells as shown in Examples.
- the heating efficiency by RF waves is improved, so that it can function as a sensitizing drug.
- the L-glucose derivative is expected to have a low toxicity to normal cells and an effect of enhancing selectivity for cancer cells.
- L-glucose is an optical isomer of D-glucose, which is a naturally occurring glucose, although it is a molecule that is rarely seen in nature. It is considered that D-glucose is taken up into cells via a glucose transporter (GLUT or SGLT) existing in the cell membrane and becomes an energy source or a carbon source, while L-glucose cannot pass through the glucose transporter. It is said that it is hardly taken up by normal cells.
- GLUT or SGLT glucose transporter
- At least a part of the L-glucose derivative of the present invention may be selectively taken up by cancer cells.
- the L-glucose derivative of the present invention contains a gold atom (Au) in the molecule, it is considered that a heating effect may be obtained. Furthermore, since the L-glucose derivative of the present invention contains a gold atom (Au) in the molecule, the gold atom may exhibit significant toxicity to the cancer cell when taken up into the cancer cell. There is.
- the present invention it is possible to provide a sensitizing drug that can be selectively taken up by cancer cells and can selectively generate heat at a target site during high-frequency hyperthermia treatment. Furthermore, according to the present invention, it is possible to provide a compound that has low toxicity to normal cells and is selectively taken up by cancer cells to exhibit toxicity.
- FIG. 1 It is a schematic diagram which shows the RF wave irradiation unit. It is a figure which shows the ratio of the number of dead cells at the time of administration of LGG to MIN6 of culture days 4DIV (Days In Vitro).
- A is cells after administration of LGG to MIN6 having 5 DIV culture days
- B is MIN6 having 5 DIV culture days
- C is pre-administered PHT to MIN 6 having 5 DIV culture days.
- the L-glucose derivative of the present embodiment has a structure represented by the following general formula (1).
- X 1 represents 1 -SAuR group
- X 2 , X 3 , X 4 and X 5 independently represent -OR 2 groups, -NH 2 groups or fluorine atoms, respectively.
- R 1 represents a ligand and R 2 represents a hydrogen atom or an organic group.
- Glucose derivatives include D-form and L-form, but the structure represented by the general formula (1) is an L-form glucose derivative.
- the glucose derivative, anomeric isomers, i.e. X 1 is but anomer and X 1 facing the equatorial direction may exist anomeric facing the axial direction, L- glucose derivative of the embodiment of It may be a mixture.
- Examples of the ligand in R 1 include a phosphine ligand, a thiolate ligand, an olefin ligand and the like.
- R 1 is preferably a phosphine ligand, more preferably a trialkylphosphine ligand, and even more preferably a triethylphosphine ligand.
- the organic group in R 2 for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an acyl group, and the like. These groups may have yet another substituent.
- the number of carbon atoms of the organic group can be, for example, 1 to 10, preferably 1 to 5, and more preferably 1 to 3.
- R 2 is a hydrogen atom and is an alkyl group or an acyl group, more preferably the are hydrogen atom or an acyl group, more preferably a hydrogen atom or an acetyl group.
- the L-glucose derivative represented by the general formula (1) can be synthesized from, for example, an L-form sugar or a derivative thereof.
- Specific examples of the L-form sugar or its derivative include L-glucose, L-mannose, L-galactose, 1,2: 5,6-di-O-isopropylidene- ⁇ -L-glucofuranose and the like. ..
- Examples of the method for synthesizing the L-glucose derivative represented by the general formula (1) from the L-form sugar or its derivative include the methods described in Examples.
- Various derivatives can be synthesized by appropriately combining the steps of the methods described in the examples or by introducing a substituent by a conventionally known method.
- the L-glucose derivative represented by the general formula (1) can be suitably used as a sensitizing drug used during high-frequency hyperthermia treatment.
- Conventionally known devices can be used for high-frequency hyperthermia treatment.
- the L-glucose derivative represented by the general formula (1) can be administered before or during irradiation of RF waves in high-frequency hyperthermia therapy.
- High-frequency hyperthermia treatment using the L-glucose derivative represented by the general formula (1) as a sensitizing drug is for cancer treatment, especially for various cancers such as pancreatic cancer, brain tumor, breast cancer, and uterine cancer. Can be effective for.
- L-glucose derivative represented by the general formula (1) it can be effective in the treatment of cancer, particularly in the treatment of various cancers such as pancreatic cancer, brain tumor, breast cancer and uterine cancer.
- the L-glucose derivative represented by the general formula (1) is, for example, an oral preparation (tablet, granule, powder, capsule, syrup, etc.), sublingual tablet, injection (for intravenous administration, intramuscular administration). , Sublingual administration, intraperitoneal administration, intramuscular administration, epidural administration), or can be administered in the form of direct application directly to the cervix, oral cavity, skin, etc.
- KSAc S-potassium thioacetate NaOMe: sodium methoxide Et 3
- PAuCl chloro (triethylphosphine) gold
- DMF N, N-dimethylformiamide
- HOBt 1-Hydroxybenzotriazole
- WSC HCl 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
- TMSOTf Trifluoromethanesulfonic acid trimethylsilylTH F: tetrahydrofuran
- Example 2 Synthesis of Compound C Using Compound 4B of Example 1 as a starting material, Compound C was synthesized according to the following reaction formula.
- RF wave irradiation test In order to confirm the temperature rise effect of the L-glucose derivative of the present invention, a radio wave (RF wave) irradiation test was conducted using the RF wave irradiation unit 10 shown in FIG.
- the RF wave irradiation unit 10 is an electromagnetic wave for shielding electromagnetic waves generated between the high frequency generator 1, the upper electrode 3 and the lower electrode 5 connected to the high frequency generator 1, and the upper electrode 3 and the lower electrode 5. It is provided with a shield 7.
- RF wave electromagnetic wave
- the conditions for RF wave irradiation were frequency (13.56 MHz).
- An optical fiber thermometer FL-2000 (manufactured by Anritsu Meter Co., Ltd.) was used to accurately measure the temperature of sample S while performing RF irradiation.
- the tip of the temperature center FS100 (manufactured by Anritsu Meter Co., Ltd.) was inserted into the center of the sample S to measure the temperature.
- compound D ((2,3,6-tri-O-acetyl-1-thio- ⁇ -L-glucopyranosato) (S-triethylphosphine) gold (I)) is used as a predetermined gold atomic concentration (gold).
- gold gold
- the water-containing gel is a model of biological tissue, and compound D is an L-glucose derivative containing a gold atom.
- sample S a sample in which a gel containing compound D was sealed in a polystyrene container was used as sample S.
- the sample was prepared by the following procedure. A water-containing gel containing a predetermined concentration of compound D was sealed in a polystyrene container having a distance between the electrodes of 28 mm when sandwiched between the upper electrode 3 and the lower electrode 5.
- the rate of temperature rise (° C./min) is determined from the time required for the temperature to rise from 30 ° C. to 35 ° C. I asked.
- the rate of temperature rise was 2.5 (° C./min) on average, and the standard error SE was 0.06 ° C.
- the rate of temperature rise was 2.9 (° C./min) on average, and the standard error SE was 0.12 ° C. From these results, it was confirmed that the rate of temperature rise increased when the compound D was contained as compared with the case where the compound D was not contained.
- MIN6 cells derived from mouse pancreas are a heterogeneous cell population (Yamato, E. et al., PLoS One 8: e61211, 2013) and produce normal cells, that is, insulin, up to about 4-5 DIV after the start of culture.
- Pancreatic islet Langerhans ⁇ -cells occupy the main proportion, and although there are some cells that exhibit the properties of malignant cells in pathology, the proportion is small.
- the proportion of malignant cells increases relatively (Sasaki, A. et al., Human Cell 2016, 29, 37). -45).
- LGG was administered to MIN6 having 4 DIV (Days In Vitro) culture days under in vitro.
- LGG is an L-glucose derivative in which the 1-position OH group of L-glucose is replaced with 3 -SAuP (C 2 H 5 ) groups.
- DGG is a D-glucose derivative in which the 1-position OH group of D-glucose is replaced with 3 -SAuP (C 2 H 5 ) groups.
- a dead cell marker PI Propidium Iodide
- the percentage of dead cells evaluated was measured. The result is shown in FIG. In FIG. 2, the horizontal axis shows the concentration of DGG to LGG, and the vertical axis shows the total average intensity of PI fluorescence for each cell. However, the vertical axis is a value (%) when the number of dead cells having a concentration of 1000 ⁇ M is assumed to be the total number of cells in each well and standardized by the fluorescence intensity of the total number of cells.
- the polygonal line is the Eye guide.
- DGG is a known compound, and its cytotoxicity is thought to be due to the gold atom (Au) that has entered the cell (Sutton BM et al., J. Med. Chem. 15: 1095-98, 1972; Wu , B. et al., J. Med. Chem. 62: 7751-68, 2019).
- Au gold atom
- LGG when LGG is administered, it is estimated that if the concentration exceeds 10 ⁇ M, cell death evaluated by PI becomes detectable. Under the experimental conditions, the concentration of DGG exhibiting 50% effective dose is observed to be between 10 ⁇ M and 100 ⁇ M. Therefore, LGG is compared with normal cells represented by pancreatic Langerhans islet ⁇ cell line. It is estimated that the safety is about 10 times (about 1 digit) higher than that of.
- LGG phloretin
- PHT functions as an inhibitor of various membrane transport proteins such as water channels and glucose transporters (Ono K. et al., Cancers 12: 850, 2020).
- the fact that the effect of a substance (here LGG) is "inhibited by PHT” means that the substance (ie, LGG) is at least partially transported intracellularly via the membrane transport protein described above. It suggests that the transport was inhibited by PHT (Ono K. et al., Cancers 12: 850, 2020).
- FIG. 3B and FIG. 4e which is an enlarged view thereof, a characteristic morphology in which a part of the cytoplasm protrudes outside the cell is observed in some cells (see the arrow). Such a morphology was not observed in FIGS. 3A and 4a to 4d, which are enlarged views thereof, suggesting deterioration of the cellular state. On the other hand, in FIG. 3C and FIGS. 4f to 4i, which are enlarged views thereof, almost no cells showing deterioration of the cell state are observed.
- the fluorescence intensity of Calcein reflects the activity of the intracellular hydrolase esterase, and a decrease in the fluorescence intensity of Calcein indicates deterioration of the cellular state.
- the vertical axis of the figure shows the average fluorescence intensity (arbitrary unit, A.U.) of Calcein per region of interest (ROI) set in the cell.
- the Bonferroni-Dunn test was used for statistical analysis.
- LGG which is much less toxic to normal cells than DGG, has at least a part of it selectively taken up inside cancer cells, and probably after taking up gold atoms (Au). It suggests that it is extremely toxic to cancer cells.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
Description
KSAc: チオ酢酸 S-カリウム
NaOMe: ナトリウムメトキシド
Et3PAuCl: クロロ(トリエチルホスフィン)金(I)
DMF: N,N-ジメチルホルミアミド
HOBt: 1-ヒドロキシベンゾトリアゾール
WSC HCl: 1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩
TMSOTf: トリフルオロメタンスルホン酸 トリメチルシリル
THF: テトラヒドロフラン
化合物3A(500mg,1.2mmol)から出発し、同様の方法で得た化合物Aと合わせて、無色アモルファスの化合物Aを1.7g(収率63%(2工程))得た。
化合物A50.7mgをメタノールに溶かし、5.00mLとした。セル長100mmのセルを用いて、比旋光度を10回測定し、最大値と最小値を外した平均値をとったところ、その平均値は+7.28度であった。
化合物B50.5mgをメタノールに溶かし、5.00mLとした。セル長100mmのセルで、20℃で、比旋光度を10回測定し、最大値と最小値を外した平均値をとったところ-8.73度であった。なお、既知のD体である化合物Aの比旋光度(+7.28度)と比較して、化合物BがL体であることが確認された。
化合物C101.2mgをメタノール10.0mLに溶かし、濃度1.01mg/mLのサンプル溶液を調製した。セル長100mmのセルを用いて、20℃で、比旋光度を10回測定し、最大値と最小値を外した平均値をとったところ+56.1度であった。なお、化合物CのD体であるオーラノフィンの比旋光度は-52度であり(Green Chemistry, 2015, 17, 4, 2545-2551参考)、化合物CがL体であることが確認できた。
実施例で得られた化合物について、以下に示す試験を行った。
本発明のL-グルコース誘導体による温度上昇効果を確認するために、図1に示すRF波照射ユニット10を用いて、ラジオ波(RF波)照射試験を行った。RF波照射ユニット10は、高周波発生器1と、高周波発生器1に接続された上部電極3及び下部電極5と、上部電極3と下部電極5との間で発生する電磁波を遮蔽するための電磁シールド7とを備える。上部電極3と下部電極5との間に試料Sを設置して、上部電極3と下部電極5の間で電磁波(RF波)を照射すると電気力線LEFが発生し、RF波照射試験を行うことができる。RF波照射の条件は、周波数(13.56MHz)とした。
マウスの膵β細胞の腫瘍化(インスリノーマ)細胞株MIN6(Miyazaki J. et al., Endocrinology 127: 126-132, 1990)を用いて、以下の実験を行なった。ここで、すべての実験は、96穴のウェルのなかに約1000個のMIN6細胞を前もって入れ、上記化合物B(以下LGGと呼ぶ)を投与する実験と、上記化合物A(以下DGGと呼ぶ)を投与する対照実験について、外的擾乱が極力ないように配慮して行なった。
Claims (3)
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2021538243A JP6982358B1 (ja) | 2020-04-01 | 2021-03-31 | 金属糖質錯体 |
CN202180025320.0A CN115427423A (zh) | 2020-04-01 | 2021-03-31 | 金属糖类络合物 |
EP21777929.7A EP4130019A4 (en) | 2020-04-01 | 2021-03-31 | METAL-CARBON HYDRATE COMPLEX |
AU2021245687A AU2021245687A1 (en) | 2020-04-01 | 2021-03-31 | Metal-carbohydrate complex |
US17/915,822 US20230151051A1 (en) | 2020-04-01 | 2021-03-31 | Metal-carbohydrate complex |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2020-066177 | 2020-04-01 | ||
JP2020066177 | 2020-04-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2021201109A1 true WO2021201109A1 (ja) | 2021-10-07 |
Family
ID=77928111
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2021/013857 WO2021201109A1 (ja) | 2020-04-01 | 2021-03-31 | 金属糖質錯体 |
Country Status (7)
Country | Link |
---|---|
US (1) | US20230151051A1 (ja) |
EP (1) | EP4130019A4 (ja) |
JP (1) | JP6982358B1 (ja) |
CN (1) | CN115427423A (ja) |
AU (1) | AU2021245687A1 (ja) |
TW (1) | TW202203944A (ja) |
WO (1) | WO2021201109A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023058608A1 (ja) * | 2021-10-06 | 2023-04-13 | オルバイオ株式会社 | グルコース誘導体及びそれを用いた抗がん剤 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5624908A (en) * | 1993-06-11 | 1997-04-29 | Valley Cancer Institute | Antineoplastic compositions |
JP2007536016A (ja) | 2004-05-07 | 2007-12-13 | サーム メッド エルエルシー | Rf誘導ハイパーサーミアのための機能強化されたシステムおよび方法 |
WO2012133688A1 (ja) * | 2011-03-31 | 2012-10-04 | 国立大学法人弘前大学 | 蛍光標識されたl-グルコース誘導体を用いたがん細胞を検出するための方法及び該誘導体を含むがん細胞のイメージング剤 |
JP2021501832A (ja) * | 2017-11-04 | 2021-01-21 | ソナ ナノテック | 金属ナノ粒子およびその製造方法 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003113194A (ja) * | 2001-08-03 | 2003-04-18 | Fuji Photo Film Co Ltd | 新規金−硫黄化合物及び該化合物の合成法 |
US20080279781A1 (en) * | 2007-05-10 | 2008-11-13 | Brookhaven Science Associates, Llc | Glycosylated Carboranylporphyrins and Uses Thereof |
IT1398263B1 (it) * | 2010-03-04 | 2013-02-22 | Monzani | Nanoparticelle magnetiche di ossido di ferro a dimensione controllata per la diagnosi ed il trattamento di neoplasie avanzate e metastatiche |
WO2015056960A1 (ko) * | 2013-10-16 | 2015-04-23 | 주식회사 지니스 | 전자기파를 이용한 암 온열치료용 감작제 조성물 및 이를 이용한 암 치료 방법 |
CN108727451B (zh) * | 2017-04-18 | 2020-10-16 | 广州医科大学 | 新的磷化烃金化合物及其制备方法和应用 |
-
2021
- 2021-03-31 JP JP2021538243A patent/JP6982358B1/ja active Active
- 2021-03-31 WO PCT/JP2021/013857 patent/WO2021201109A1/ja unknown
- 2021-03-31 TW TW110111917A patent/TW202203944A/zh unknown
- 2021-03-31 AU AU2021245687A patent/AU2021245687A1/en active Pending
- 2021-03-31 EP EP21777929.7A patent/EP4130019A4/en active Pending
- 2021-03-31 CN CN202180025320.0A patent/CN115427423A/zh active Pending
- 2021-03-31 US US17/915,822 patent/US20230151051A1/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5624908A (en) * | 1993-06-11 | 1997-04-29 | Valley Cancer Institute | Antineoplastic compositions |
JP2007536016A (ja) | 2004-05-07 | 2007-12-13 | サーム メッド エルエルシー | Rf誘導ハイパーサーミアのための機能強化されたシステムおよび方法 |
WO2012133688A1 (ja) * | 2011-03-31 | 2012-10-04 | 国立大学法人弘前大学 | 蛍光標識されたl-グルコース誘導体を用いたがん細胞を検出するための方法及び該誘導体を含むがん細胞のイメージング剤 |
JP2021501832A (ja) * | 2017-11-04 | 2021-01-21 | ソナ ナノテック | 金属ナノ粒子およびその製造方法 |
Non-Patent Citations (10)
Title |
---|
GREEN CHEMISTRY, vol. 17, no. 4, 2015, pages 2545 - 2551 |
KILLOCK, D, NATURE REVIEWS CLINICAL ONCOLOGY, vol. 15, 2018, pages 266 |
MIYAZAKI J. ET AL., ENDOCRINOLOGY, vol. 127, 1990, pages 126 - 132 |
NAVARRO, M. ET AL.: "Metal-chloroquine derivatives as possible anti-malarial drugs: evaluation of anti-malarial activity and mode of action", MALARIA JOURNAL, vol. 13, no. 471, 3 December 2014 (2014-12-03), pages 1 - 8, XP021204957, DOI: 10.1186/1475-2875-13-471 * |
ONO K. ET AL., CANCERS, vol. 12, 2020, pages 850 |
SASAKI, A. ET AL., HUMAN CELL, vol. 29, 2016, pages 37 - 45 |
See also references of EP4130019A4 |
SUTTON B.M. ET AL., J. MED. CHEM., vol. 15, 1972, pages 1095 - 98 |
WU, B. ET AL., J. MED. CHEM., vol. 62, 2019, pages 7751 - 68 |
YAMATO, E. ET AL., PLOS ONE, vol. 8, 2013, pages e61211 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023058608A1 (ja) * | 2021-10-06 | 2023-04-13 | オルバイオ株式会社 | グルコース誘導体及びそれを用いた抗がん剤 |
Also Published As
Publication number | Publication date |
---|---|
US20230151051A1 (en) | 2023-05-18 |
JP6982358B1 (ja) | 2021-12-17 |
EP4130019A1 (en) | 2023-02-08 |
EP4130019A4 (en) | 2024-04-24 |
AU2021245687A1 (en) | 2022-10-20 |
JPWO2021201109A1 (ja) | 2021-10-07 |
TW202203944A (zh) | 2022-02-01 |
CN115427423A (zh) | 2022-12-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2563638C2 (ru) | Способ получения производных морфолинилантрациклина | |
CN113234116B (zh) | 一种雷公藤红素衍生物及其制备方法和医用用途 | |
WO2021201109A1 (ja) | 金属糖質錯体 | |
CN102898478B (zh) | 一种高效端粒酶抑制剂及其在抗肿瘤药物中的应用 | |
CN104592091B (zh) | 一种含吲哚乙酸核心结构的化合物及其应用 | |
Zhan et al. | Design and synthesis of a gossypol derivative with improved antitumor activities | |
CN106699771A (zh) | 隐丹参酮类化合物、制备方法和用途 | |
RU2099333C1 (ru) | Производное 3-дезоксиманнозамина, способ его получения и фармацевтическая композиция, обладающая ингибирующей активностью к развитию сосудов и метастазов | |
CN113173964A (zh) | 一种抗肿瘤的白桦醇衍生物及其制备方法 | |
CN113149942A (zh) | 一种洛克米兰醇酚羟基衍生物、其制备方法和应用 | |
EP2130834A1 (en) | Novel sulfonated sugar derivative, and use thereof for medicinal agent | |
EP3974437B1 (en) | D-glucopyranoside and salts thereof | |
CN108752404B (zh) | 一种三氮唑糖修饰的小檗碱盐衍生物及其制备方法和用途 | |
JP7003057B2 (ja) | グリコシル化クロリンe6誘導体、または、その薬学的に許容される塩、医薬組成物、標的を破壊する方法、および、グリコシル化クロリンe6誘導体、またはその薬学的に許容される塩の製造方法 | |
Adam et al. | Design, Synthesis, Anticancer Activity and Molecular Docking of New 1, 2, 3-Triazole combined Glucosides with coumarin | |
WO2023058608A1 (ja) | グルコース誘導体及びそれを用いた抗がん剤 | |
JPWO2002020536A1 (ja) | テトラフェニルバクテリオクロリン誘導体およびそれを含む組成物 | |
Qi et al. | Synthesis and evaluation of N-(2-[18 F] fluoro-4-nitrobenzoyl) glucosamine: a preliminary report | |
TWI836652B (zh) | 葡萄糖衍生物及使用其之抗癌劑 | |
CN102702297B (zh) | 胆酸-萘酰亚胺类化合物的制备方法 | |
CN105566304B (zh) | 含硫尿苷抗癌化合物及其中间体和制备方法 | |
CN112812145B (zh) | 一种苯并咪唑衍生物bi293及其制备方法和应用 | |
CN109369634B (zh) | 具有抗肿瘤活性的2-甲氧基烟酰胺衍生物制备方法及用途 | |
CN104610188B (zh) | 含苯基脒结构的腈基苯噻唑羧酸酰胺类化合物、其制备及用途 | |
JP6082643B2 (ja) | 低酸素性細胞放射線増感剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
ENP | Entry into the national phase |
Ref document number: 2021538243 Country of ref document: JP Kind code of ref document: A |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21777929 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2021245687 Country of ref document: AU Date of ref document: 20210331 Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2021777929 Country of ref document: EP Effective date: 20221102 |