JPWO2019172210A1 - がん特異的酵素活性を利用したプロドラッグ型抗がん剤 - Google Patents
がん特異的酵素活性を利用したプロドラッグ型抗がん剤 Download PDFInfo
- Publication number
- JPWO2019172210A1 JPWO2019172210A1 JP2020505030A JP2020505030A JPWO2019172210A1 JP WO2019172210 A1 JPWO2019172210 A1 JP WO2019172210A1 JP 2020505030 A JP2020505030 A JP 2020505030A JP 2020505030 A JP2020505030 A JP 2020505030A JP WO2019172210 A1 JPWO2019172210 A1 JP WO2019172210A1
- Authority
- JP
- Japan
- Prior art keywords
- group
- compound
- mmol
- salt
- ethyl acetate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 38
- 102000004190 Enzymes Human genes 0.000 title claims description 27
- 108090000790 Enzymes Proteins 0.000 title claims description 27
- 206010028980 Neoplasm Diseases 0.000 title claims description 24
- 201000011510 cancer Diseases 0.000 title claims description 21
- 230000000694 effects Effects 0.000 title claims description 17
- 229940041181 antineoplastic drug Drugs 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 74
- 150000003839 salts Chemical class 0.000 claims abstract description 44
- 125000001424 substituent group Chemical group 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 150000001413 amino acids Chemical class 0.000 claims description 27
- 150000001720 carbohydrates Chemical class 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000004185 ester group Chemical group 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 125000003277 amino group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000000539 amino acid group Chemical group 0.000 claims description 6
- 108010031186 Glycoside Hydrolases Proteins 0.000 claims description 5
- 102000005744 Glycoside Hydrolases Human genes 0.000 claims description 5
- 102000035195 Peptidases Human genes 0.000 claims description 5
- 108091005804 Peptidases Proteins 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 235000019833 protease Nutrition 0.000 claims description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 3
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 125000000707 boryl group Chemical group B* 0.000 claims description 3
- 125000005587 carbonate group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 229940002612 prodrug Drugs 0.000 abstract description 15
- 239000000651 prodrug Substances 0.000 abstract description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 252
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 84
- -1 n-octyl Chemical group 0.000 description 82
- 210000004027 cell Anatomy 0.000 description 76
- 238000006243 chemical reaction Methods 0.000 description 70
- 230000015572 biosynthetic process Effects 0.000 description 52
- 239000000243 solution Substances 0.000 description 52
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 51
- 238000003786 synthesis reaction Methods 0.000 description 51
- 239000000047 product Substances 0.000 description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 42
- 239000000203 mixture Substances 0.000 description 42
- 229920006395 saturated elastomer Polymers 0.000 description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical class ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- 239000000741 silica gel Substances 0.000 description 29
- 229910002027 silica gel Inorganic materials 0.000 description 29
- 238000010898 silica gel chromatography Methods 0.000 description 29
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 28
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 26
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
- 238000000605 extraction Methods 0.000 description 26
- 229910052938 sodium sulfate Inorganic materials 0.000 description 26
- 235000011152 sodium sulphate Nutrition 0.000 description 26
- 229940024606 amino acid Drugs 0.000 description 25
- 239000007787 solid Substances 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 235000001014 amino acid Nutrition 0.000 description 24
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
- 239000007788 liquid Substances 0.000 description 22
- 235000017557 sodium bicarbonate Nutrition 0.000 description 21
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 21
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 16
- 239000008194 pharmaceutical composition Substances 0.000 description 16
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 15
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 14
- 239000004480 active ingredient Substances 0.000 description 14
- 235000019270 ammonium chloride Nutrition 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- 238000010609 cell counting kit-8 assay Methods 0.000 description 14
- LGRLWUINFJPLSH-UHFFFAOYSA-N methanide Chemical compound [CH3-] LGRLWUINFJPLSH-UHFFFAOYSA-N 0.000 description 14
- 238000004007 reversed phase HPLC Methods 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 108010005774 beta-Galactosidase Proteins 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- 229940126214 compound 3 Drugs 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 229940079593 drug Drugs 0.000 description 11
- 238000006911 enzymatic reaction Methods 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 230000030833 cell death Effects 0.000 description 10
- WQZGKKKJIJFFOK-FPRJBGLDSA-N beta-D-galactose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-FPRJBGLDSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 8
- 125000002252 acyl group Chemical group 0.000 description 8
- 238000003501 co-culture Methods 0.000 description 8
- 229940125797 compound 12 Drugs 0.000 description 8
- 238000011156 evaluation Methods 0.000 description 8
- 239000008187 granular material Substances 0.000 description 8
- 238000003384 imaging method Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical compound [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- 239000007821 HATU Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 6
- 102000005936 beta-Galactosidase Human genes 0.000 description 6
- 125000005647 linker group Chemical group 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000000684 flow cytometry Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- YMOYURYWGUWMFM-VIFPVBQESA-N (4s)-5-[(2-methylpropan-2-yl)oxy]-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxopentanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](CCC(O)=O)C(=O)OC(C)(C)C YMOYURYWGUWMFM-VIFPVBQESA-N 0.000 description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 125000005336 allyloxy group Chemical group 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229910052735 hafnium Inorganic materials 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- NTFPDEDRMYYPAC-UHFFFAOYSA-N 2-amino-4-[[3-(carboxymethyl)phenoxy]-methoxyphosphoryl]butanoic acid Chemical compound OC(=O)C(N)CCP(=O)(OC)OC1=CC=CC(CC(O)=O)=C1 NTFPDEDRMYYPAC-UHFFFAOYSA-N 0.000 description 3
- APOYTRAZFJURPB-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)-n-(trifluoro-$l^{4}-sulfanyl)ethanamine Chemical compound COCCN(S(F)(F)F)CCOC APOYTRAZFJURPB-UHFFFAOYSA-N 0.000 description 3
- UCBSXTTUNYWOCC-UHFFFAOYSA-N 6-(cyclooctylamino)quinoline-5,8-dione Chemical compound O=C1C2=CC=CN=C2C(=O)C=C1NC1CCCCCCC1 UCBSXTTUNYWOCC-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 229940127007 Compound 39 Drugs 0.000 description 3
- 108010016626 Dipeptides Proteins 0.000 description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 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 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 208000003445 Mouth Neoplasms Diseases 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Substances CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 3
- 201000004101 esophageal cancer Diseases 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 201000010536 head and neck cancer Diseases 0.000 description 3
- 208000014829 head and neck neoplasm Diseases 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 241000239290 Araneae Species 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 206010034972 Photosensitivity reaction Diseases 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 235000008206 alpha-amino acids Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- 150000001576 beta-amino acids Chemical class 0.000 description 2
- 239000003560 cancer drug Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940125851 compound 27 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 229940125878 compound 36 Drugs 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 239000007902 hard capsule Substances 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 2
- 210000003292 kidney cell Anatomy 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 101150066555 lacZ gene Proteins 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 201000005243 lung squamous cell carcinoma Diseases 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 210000000713 mesentery Anatomy 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 210000004303 peritoneum Anatomy 0.000 description 2
- 208000007578 phototoxic dermatitis Diseases 0.000 description 2
- 231100000018 phototoxicity Toxicity 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- CQRYARSYNCAZFO-UHFFFAOYSA-N salicyl alcohol Chemical compound OCC1=CC=CC=C1O CQRYARSYNCAZFO-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 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
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- PFWFFEYVRFHDBS-JINQPTGOSA-N (2s)-2-amino-5-[(6'-aminospiro[1h-2-benzofuran-3,9'-xanthene]-3'-yl)amino]-5-oxopentanoic acid Chemical compound O1CC2=CC=CC=C2C21C1=CC=C(N)C=C1OC1=CC(NC(=O)CC[C@H](N)C(O)=O)=CC=C21 PFWFFEYVRFHDBS-JINQPTGOSA-N 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000004564 2,3-dihydrobenzofuran-2-yl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- JSNNPYJILIFBES-UHFFFAOYSA-N 2-[[tert-butyl(dimethyl)silyl]oxymethyl]phenol Chemical compound CC(C)(C)[Si](C)(C)OCC1=CC=CC=C1O JSNNPYJILIFBES-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- BWWHTIHDQBHTHP-UHFFFAOYSA-N 2-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1C(Cl)=O BWWHTIHDQBHTHP-UHFFFAOYSA-N 0.000 description 1
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- NXTNASSYJUXJDV-UHFFFAOYSA-N 3-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=CC(C(Cl)=O)=C1 NXTNASSYJUXJDV-UHFFFAOYSA-N 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- ASNHGEVAWNWCRQ-UHFFFAOYSA-N 4-(hydroxymethyl)oxolane-2,3,4-triol Chemical compound OCC1(O)COC(O)C1O ASNHGEVAWNWCRQ-UHFFFAOYSA-N 0.000 description 1
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 1
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 102000004400 Aminopeptidases Human genes 0.000 description 1
- 108090000915 Aminopeptidases Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CXKLIELNANLEIH-UHFFFAOYSA-N CC(=C)C(O)=O.CC=C(C)C(O)=O Chemical compound CC(=C)C(O)=O.CC=C(C)C(O)=O CXKLIELNANLEIH-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000007590 Calpain Human genes 0.000 description 1
- 108010032088 Calpain Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 101710107035 Gamma-glutamyltranspeptidase Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 101710173228 Glutathione hydrolase proenzyme Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-L L-glutamate group Chemical group N[C@@H](CCC(=O)[O-])C(=O)[O-] WHUUTDBJXJRKMK-VKHMYHEASA-L 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical class C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000002521 alkyl halide group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- WQZGKKKJIJFFOK-PQMKYFCFSA-N alpha-D-mannose Chemical compound OC[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-PQMKYFCFSA-N 0.000 description 1
- 102000012086 alpha-L-Fucosidase Human genes 0.000 description 1
- 108010061314 alpha-L-Fucosidase Proteins 0.000 description 1
- SHZGCJCMOBCMKK-SXUWKVJYSA-N alpha-L-fucose Chemical compound C[C@@H]1O[C@@H](O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-SXUWKVJYSA-N 0.000 description 1
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 1
- 125000000748 anthracen-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C([H])=C([*])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-SQOUGZDYSA-N beta-D-arabinopyranose Chemical compound O[C@@H]1CO[C@@H](O)[C@@H](O)[C@@H]1O SRBFZHDQGSBBOR-SQOUGZDYSA-N 0.000 description 1
- SHZGCJCMOBCMKK-FPRJBGLDSA-N beta-D-fucose Chemical compound C[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O SHZGCJCMOBCMKK-FPRJBGLDSA-N 0.000 description 1
- SRBFZHDQGSBBOR-KKQCNMDGSA-N beta-D-xylose Chemical compound O[C@@H]1CO[C@@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-KKQCNMDGSA-N 0.000 description 1
- 108010047754 beta-Glucosidase Proteins 0.000 description 1
- 102000006995 beta-Glucosidase Human genes 0.000 description 1
- SRBFZHDQGSBBOR-KLVWXMOXSA-N beta-L-arabinopyranose Chemical compound O[C@H]1CO[C@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-KLVWXMOXSA-N 0.000 description 1
- WQZGKKKJIJFFOK-KGJVWPDLSA-N beta-L-galactose Chemical compound OC[C@@H]1O[C@H](O)[C@@H](O)[C@H](O)[C@@H]1O WQZGKKKJIJFFOK-KGJVWPDLSA-N 0.000 description 1
- 108010008753 beta-N-Acetyl-Galactosaminidase Proteins 0.000 description 1
- 108010085377 beta-N-Acetylhexosaminidases Proteins 0.000 description 1
- 102000007478 beta-N-Acetylhexosaminidases Human genes 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
- 239000001527 calcium lactate Substances 0.000 description 1
- 235000011086 calcium lactate Nutrition 0.000 description 1
- 229960002401 calcium lactate Drugs 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000010226 confocal imaging Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000001352 cyclobutyloxy group Chemical group C1(CCC1)O* 0.000 description 1
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 description 1
- 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 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
- 230000034994 death Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- JAUGGEIKQIHSMF-UHFFFAOYSA-N dialuminum;dimagnesium;dioxido(oxo)silane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O JAUGGEIKQIHSMF-UHFFFAOYSA-N 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 102000006640 gamma-Glutamyltransferase Human genes 0.000 description 1
- 125000002642 gamma-glutamyl group Chemical group 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 108010025899 gelatin film Proteins 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 125000005639 glycero group Chemical group 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 238000006241 metabolic reaction Methods 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
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000004492 methyl ester group Chemical group 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 230000029115 microtubule polymerization Effects 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- VSIVTUIKYVGDCX-UHFFFAOYSA-M sodium;4-[2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].COC1=CC([N+]([O-])=O)=CC=C1[N+]1=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=NN1C1=CC=C([N+]([O-])=O)C=C1 VSIVTUIKYVGDCX-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000001954 time-lapse fluorescence microscopy Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
-
- 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
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Pyrrole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
ここで、本発明者らが本プローブの生細胞適用実験を行っている際に、プローブを高濃度で用いると顕著な細胞毒性が見られることが明らかとなった。毒性のメカニズムは明らかとなっていないが、細胞内グルタチオンといったチオール類が酵素反応に伴って生成するキノンメチド中間体によって消費され、細胞に酸化ストレスが与えられたためと考えている。
[1]以下の一般式(I)で表される化合物又はその塩。
(式中、
Xは、フッ素原子、エステル基(−OC(=O)−R’)、カーボネート基(−OCO2−R’)、カーバメート基(−OCONH−R’)、リン酸およびそのエステル基(−OP(=O)(−OR’)(―OR’’)、及び硫酸およびそのエステル基(―OSO2―OR’)からなる群から選択され、
ここで、R’、R’’は、各々独立に、置換又は無置換のアルキル基、又は、置換又は無置換のアリール基から選択され;
Yは、−NH−CO−L、−NH−L’又は−OL’であり、
ここで、Lは、アミノ酸の部分構造であり、
L’は、糖類又は糖類の部分構造、自己開裂型のリンカーを有する糖類、自己開裂型のリンカーを有するアミノ酸類又はペプチドであり;
R1及びR2は、各々独立に、水素原子又は一価の置換基から選択され;
R3は、水素原子、又はベンゼン環上に存在する1〜4個の同一又は異なる一価の置換基を示す。)
[2]Lのアミノ酸の部分構造は、それが結合しているC=Oと一緒になって、アミノ酸、アミノ酸残基、ペプチド、アミノ酸の一部を構成している、[1]に記載の化合物又はその塩。
[3]L’の糖類の部分構造は、それが結合しているOと一緒になって、糖類、糖類の一部を構成している、[1]に記載の化合物又はその塩。
[4]一般式(I)中の−Yが、−C(R1)(R2)Xに対してベンゼン環のオルト位又はパラ位上で結合している、[1]〜[3]のいずれか1項に記載の化合物又はその塩。
[5]Yが、以下から選択される構造を有する、[1]〜[4]のいずれか1項に記載の化合物又はその塩。
[6]Xは、フッ素原子又はエステル基(−OCO−R’)である、[1]〜[5]のいずれか1項に記載の化合物又はその塩。
[7]R1及びR2は、各々独立に、水素原子又はフッ素原子から選択される、[1]〜[6]のいずれか1項に記載の化合物又はその塩。
[8]R3の一価の置換基が、アルキル基、アルコキシカルボニル基、ニトロ基、アミノ基、水酸基、アルキルアミノ基(−NHR’、−NHCOR’)、アルコキシ基(−OR’、−OCOR’)、ハロゲン原子、ボリル基、シアノ基からなる群から選択される(R’は、置換又は無置換のアルキル基、又は、置換又は無置換のアリール基である)、[1]〜[7]のいずれか1項に記載の化合物又はその塩。
[9]R3の一価の置換基が、アルキル基(例えば、メチル基)又はアルコキシカルボニル基(例えば、メトキシカルボニル基)である、[8]に記載の化合物又はその塩。
[10][1]〜[9]のいずれか1項に記載の化合物又はその医薬的に許容可能な塩を含む、プロドラッグ型抗がん剤。
[11][1]〜[9]のいずれか1項に記載の化合物又はその医薬的に許容可能な塩を含む、がん細胞特異的な酵素活性により細胞選択的に作用するプロドラッグ型抗がん剤。
[12]前記酵素が、ペプチダーゼ又はグリコシダーゼである、[11]に記載のプロドラッグ型抗がん剤。
を提供するものである。
本発明の1つの実施態様は、以下の一般式(I)で表される化合物又はその塩である。
Yは酵素の種類に応じて選択することができる。プロドラッグ型抗がん剤の標的酵素がグリコシダーゼである場合は、Yは糖類に由来する基から選択され、標的酵素がペプチダーゼである場合は、Yはアミノ酸類に由来する基、アミノ酸類を含む基から選択される。
ここで、Lは、アミノ酸の部分構造である。Lのアミノ酸の部分構造とは、Lが結合しているC=Oと一緒になって、アミノ酸、アミノ酸残基、ペプチド、アミノ酸の一部を構成していることを意味する
アミノ酸残基には、αアミノ酸の残基、βアミノ酸の残基、γアミノ酸の残基が含まれる。好ましいアミノ酸残基としては、GGT基質の「γ―グルタミル基」やDPP4基質のジペプチド「アミノ酸―プロリンからなるジペプチド」などが挙げられる。
L’の糖類の部分構造は、L’が結合しているOと一緒になって、糖類、糖類の一部を構成している。
ここで、R’、R’’は、各々独立に、置換又は無置換のアルキル基、又は、置換又は無置換のアリール基から選択さる。
Xとしては、フッ素原子又はエステル基(−OCO−R’)が好ましい。理論に拘束されることを意図するものではないが、Xがフッ素原子又はエステル基(−OCO−R’)である場合は、Yが切断されると速やかにキノンメチドが形成される。
R1及びR2は、好ましくは、各々独立に、水素原子又はフッ素原子から選択される。
R3の一価の置換基としては、炭素数1以上のアルキル基(例えば、炭素数1〜6程度のアルキル基)、アルコキシカルボニル基、ニトロ基、アミノ基、水酸基、アルキルアミノ基(−NHR’、−NHCOR’)、アルコキシ基(−OR’、−OCOR’)、ハロゲン原子、ボリル基、シアノ基からなる群から選択される。ここで、R’は、置換又は無置換のアルキル基、又は、置換又は無置換のアリール基である。
R3の一価の置換基としては、好ましくは、炭素数1以上のアルキル基(例えば、炭素数1〜6程度のアルキル基(例えば、メチル基))である。理論に拘束されることを意図するものではにが、アルキル基は電子供与性を向上させ殺細胞活性を向上させることができる。
本発明のもう1つの実施態様は、一般式(I)の化合物又はその医薬的に許容可能な塩を含む、プロドラッグ型抗がん剤である(以下「本発明のプロドラッグ型抗がん剤」ともいう)。
また、本発明のもう1つの実施態様は、一般式(I)の化合物又はその医薬的に許容可能な塩を含む、がん細胞特異的な酵素活性により細胞選択的に作用するプロドラッグ型抗がん剤である。
ペプチダーゼとしては、ペプチダーゼが、γ-グルタミルトランスペプチダーゼ(GGT)、ジペプチジルペプチダーゼIV(DPP−IV)、カルパインが挙げられる。
グリコシダーゼとしては、β-ガラクトシダーゼ、β-グルコシダーゼ、α-マンノシダーゼ、α−L−フコシダーゼ、β−ヘキソサミニダーゼ、β−N−アセチルガラクトサミニダーゼ等が挙げられる。
まず図3に示すように、3種類の酵素(β−Gal、DPP−IV、GGT)の酵素認識部位、脱離基にフッ素を有した単環式の化合物を以下の手順で合成した。
本発明の化合物1(β−Gal−FMP)を以下のスキーム1により合成した。
1H NMR(CD2Cl2,400MHz):δ7.50(d,1H,J=8.0Hz),7.20(dd,1H,J=8.0Hz,J=7.3Hz),7.08(dd,1H,J=7.8Hz,J=7.3Hz),7.00(d,1H,J=7.8Hz),5.47−5.43(m,2H),5.13(dd,1H,J=11Hz,J=3.7Hz),5.08(d,1H,J=8.2Hz),4.75(d,1H,Jgem=15Hz),4.62(d,1H,Jgem=15Hz),4.22−4.09(m,3H),2.16(s,3H,OCOCH3),2.04(s,3H,OCOCH3),2.03(s3H,OCOCH3),1.98(s,3H,OCOCH3),0.96(s,9H,Si(CH3)3),0.12(s,6H,Si(CH3)2).
1H NMR(CDCl3,400MHz):δ7.38(d,1H,J=7.8Hz), 7.32(dd,1H,J=7.8Hz,J=7.8Hz),7.10(dd,1H,J=8.2Hz,J=7.8Hz),7.07(d,1H,J=8.2Hz),5.54(dd,1H,J=11Hz,J=7.8Hz),5.47(dd,1H,JHBn−F=48Hz,Jgem=11Hz),5.46(d,1H,J=2.7Hz),5.23(dd,1H,JHBn−F=48Hz,Jgem=11Hz),5.11(dd,1H,J=11Hz,J=3.7Hz),5.03(d,1H,J=7.8Hz),4.25(dd, 1H,J=11Hz,J=6.9Hz),4.15(dd,1H,J=11Hz,J=6.0Hz),4.08(dd,1H,J=6.9Hz,J=6.0Hz),2.18(s,3H,OCOCH3),2.06(s,3H,OCOCH3),2.06(s,3H,OCOCH3),2.01(s,3H,OCOCH3).
1H NMR(CD3OD,400MHz):δ7.35(d,1H,Ha,JHa−Hb=7.3Hz),7.29(dd,1H,Hc,JHc−Hd=8.2Hz,JHc−Hb=7.3Hz),7.21(d,1H,Hd,JHd−Hc=8.2Hz),7.03(dd,1H,Hb,JHb−Ha=JHb−Hc=7.3Hz),5.51(d,2H,HBn,JHBn−F=48Hz),4.85(d,1H,H1,JH1−H2=7.8Hz),3.88(d,1H,H4,JH4−H3=3.7Hz),3.79(dd,1H,H2,JH2−H3=9.6Hz,JH2−H1=7.8Hz),3.78−3.70(m,2H,H6,6‘),3.65(dd,1H,H5,JH5−H6=6.9Hz,JH5−H6’=5.0Hz),3.55(dd,1H,H3,JH3−H2=9.6Hz,JH3−H4=3.7Hz);HRMS 311.08976(M+Na+).
本発明の化合物2(GP−FMA)を以下のスキーム2により合成した。
1H NMR(CD3OD,400MHz):δ7.44−7.41(m,2H),7.28−7.18(m,2H),4.75(d,1H,HBn,Jgem=14Hz),4.70(d,1H,HBn‘,Jgem=14Hz),4.53(dd,1H,J=8.5Hz,J=2.7Hz),3.95(d,1H,Jgem=17Hz),3.88(d,1H,Jgem=17Hz),3.71−3.56(m,2H),2.17−1.91(m,3H),1.41(s,9H,NHCOO(CH3)3),0.91(s,9H,Si(CH3)3),0.09(s,6H,Si(CH3)2).
1H NMR(CD3OD,400MHz):δ7.70(d,1H,J=7.8Hz),7.30(d,1H,J=7.8Hz),7.25(ddd,1H,J=7.8Hz,J=7.8Hz,J=1.4Hz),7.13(ddd,1H,J=7.8Hz,J=7.8Hz,J=1.4Hz),4.61(dd,1H,HBn,Jgem=14Hz,J=4.1Hz),4.57(dd,1H,HBn,Jgem=14Hz,J=4.1Hz),4.55(dd,1H,J=8.5Hz,J=3.7Hz),3.94(s,2H),3.73−3.55(m,2H),2.30−2.12(m,2H),2.10−2.03(m,2H),1.43(s,9H,NHCOO(CH3)3).
1H NMR(CDCl3,400MHz):δ8.93(brs,1H,−CONH−),7.95(d,1H,J=7.8Hz),7.36(dd,1H,J=7.8Hz,J=7.8Hz),7.29(d,1H,J=7.3Hz),7.13(dd,1H,J=7.8Hz,J=7.3Hz),5.41(brs,1H,−OCONH−),5.39(d,2H,HBn,JHBn−F=48Hz),4.76(d,1H,J=6.9Hz),4.03(dd,1H,Jgem=17Hz,J=5.0Hz),3.93(dd,1H,Jgem=17Hz,J=4.6Hz),3.60−3.54(m,1H),3.49−3.40(m,1H),2.22−2.11(m,1H),2.11−2.02(m,1H),2.01−1.90(m,1H),1.44(s,9H,NHCOO(CH3)3).
1H NMR(CD3OD,400MHz):δ7.46(d,1H,Ha,JHa−Hb=7.3Hz),7.41−7.27(m,3H,Hb,Hc,Hd),5.38(ddd,2H,HBn,JHBn−F=48Hz,JHBn‘−F=34Hz,Jgem=11Hz),4.61(dd,1H,Hα2,Jα2-β2=8.2Hz,Jα2-β2’=3.7Hz),3.88(d,2H,Hα1,Jgem=4.1Hz),3.68−3.52(m,2H,Hδ),2.39−2.28(m,1H,Hβ2),2.17−1.97(m,3H,Hβ2,Hγ2);13C NMR(CD3OD,100MHz):δ172.1,164.8,128.9,128.1,126.6,125.9,60.6,46.4,40.2,29.5,24.5; HRMS 280.14657(M+H+).
本発明の化合物3(gGlu−FMA)を以下のスキーム3により合成した。
1H NMR(CDCl3,400MHz):δ8.88(brs,1H,−CONH−),8.15(d,1H,J=8.2Hz),7.29(dd,1H,J=8.2Hz,J=7.3Hz),7.10(d,1H,J=6.9Hz),7.13(dd,1H,J=7.3Hz,J=6.9Hz),5.20(brd,1H,−OCONH−,J=7.8Hz),4.75(d,1H,HBn,Jgem=13Hz),4.71(d,1H,HBn‘,Jgem=13Hz),4.27−4.15(m,1H),2.52−2.34(m,2H),2.32−2.20(m,1H),2.07−1.95(m,1H),1.46(s,9H,COO(CH3)3),1.42(s,9H,NHCOO(CH3)3),0.90(s,9H,Si(CH3)3),0.07(s,6H,Si(CH3)2).
1H NMR(CD2Cl2,400MHz):δ 8.69(brs,1H,−CONH−),7.91(d,1H,J=7.3Hz),7.29(dd,1H,J=7.8Hz,J=7.3Hz),7.23(d,1H,J=7.3Hz),7.09(dd,1H,J=7.8Hz,J=6.3Hz),4.66(m,2H,HBn),4.22−4.11(m,1H),2.80(brs,1H,−CH2OH),2.51−2.35(m,2H),2.29−2.16(m,1H),1.97−1.85(m,1H),1.44(s,9H,COO(CH3)3),1.40(s,9H,NHCOO(CH3)3).
1H NMR(CD2Cl2,40MHz):δ8.04(brs,1H,−CONH−),7.84(d,1H,J=8.2Hz),7.37(dd,1H,J=8.2Hz,J=7.3Hz),7.33(d,1H,J=6.9Hz),7.17(dd,1H,J=7.3Hz,J=6.9Hz),5.43(d,2H,HBn,JHBn−F=48Hz,Jgem=11Hz),4.22−4.11(m,1H),2.80(brs,1H,−CH2OH),2.51−2.35(m,2H),2.29−2.16(m,1H),1.97−1.85(m,1H),1.44(s,9H,COO(CH3)3),1.40(s,9H,NHCOO(CH3)3).
1H NMR(CD2Cl2,400MHz):δ7.49(d,1H,Ha,JHa−Hb=7.8Hz),7.43(dd,1H,Hc,JHc−Hb=JHc−Hd=7.8Hz),7.36(dd,1H,Hb,JHb−Ha=JHb−Hc=7.8Hz),7.29(d,1H,Hd,JHd−Hc=7.8Hz),5.35(d,2H,HBn,JHBn−F=48Hz),3.80−3.77(m,1H,Hα),2.67−2.56(m,2H,Hγ),2.20−2.15(m,2H,Hβ);13C NMR(D2O,100MHz):δ174.7,173.8,134.3,132.0,130.4,130.0,128.1,127.5,82.9,81.3,54.1,31.6,26.3;HRMS 255.11370(M+H+).
次に、合成した3種の化合物と精製酵素を用いて酵素反応を以下の条件で行った。
化合物終濃度:100μM
酵素終濃度:4nM(β−Gal)、8.5μg/mL(DPP−IV)、10U/mL(GGT)
反応温度:37℃
機種:ACQUITY UPLC(Waters社製)
カラム:Poroshell 120、4.6×100mm(Agilent社製)
移動相A:水(0.01Mギ酸アンモニウム)
移動相B:80%アセトニトリル/水(0.01Mギ酸アンモニウム)
グラジエント:A/B:95/5→5/95、5分
機種:1260 Infinity(Agilent社製)
カラム:Poroshell 120、4.6×100mm(Agilent社製)
移動相A:水(0.01Mギ酸アンモニウム)
移動相B:80%アセトニトリル/水(0.01Mギ酸アンモニウム)
グラジエント:A/B:95/5→50/50、20分
化合物1〜3は、β−Gal、DPP−IV、GGTによってそれぞれ切断され、キノンメチドがH2Oと反応した2−ヒドロキシベンジルアルコール(β−Gal)あるいは2−アミノベンジルアルコール(DPP−IV、GGT)が反応生成物として確認された。
GGTについては、阻害剤を入れた実験も行ったが、GGT阻害剤であるGGsTop(登録商標)を100μMの濃度で添加するとモデル化合物の酵素反応が阻害されることを確認した。
酵素高発現/低発現細胞を用いたin vitro薬効試験
次に、化合物1〜3を酵素高発現/低発現細胞に投与した時、それらがプロドラッグとして機能することで細胞生存率を変化させることが可能であるか検証した。薬効試験は、一般的な比色定量法であるCCK−8アッセイ(生細胞内の脱水素酵素活性を、無色のWST−8から橙色のホルマザンへの還元という形で定量する方法)を用いて生細胞数を定量することで行った。以下にCCK−8アッセイの評価方法を記載する。
β−ガラクトシダーゼ活性化プロドラッグの評価は、HEK/lacZ細胞(ヒト腎細胞由来細胞、β−Gal高発現)とHEK293細胞(ヒト腎細胞由来細胞、β−Gal低発現)を用いて行った。DPP−IV活性化プロドラッグの評価は、H226細胞(ヒト肺扁平上皮がん細胞、DPP−IV高発現)とH460細胞(ヒト非小細胞性上皮性肺がん細胞、DPP−IV低発現)を用いて行った。GGT活性化プロドラッグの評価は、SHIN3細胞(ヒト卵巣がん細胞、GGT高発現)とH226細胞(ヒト肺扁平上皮がん細胞、GGT低発現)を用いて行った。
各種細胞を96ウェルプレートに播種し(細胞密度:1.0×104/well)、一晩インキュベーションした。新鮮な培地に交換し、合成した誘導体を添加した(最終濃度1〜50μM、0.5%DMSO、n=3)。さらに細胞を24時間培養した後、Cell counting Kit−8(10μL/well、プロメガ社製)を添加し、2.5時間後、プレートリーダーにより450nmの吸光度を測定し、生存細胞数の定量を行った。
まず、β−galactosidase用の化合物1(β−Gal−FMP)を高発現細胞(HEK/lacZ)および低発現細胞(HEK293)に投与し、24時間後に生存率を算出した。その結果、50μMという高濃度で投与しても両細胞の生存率は全く低下せず、有意な差も観測されなかった(図5)。β−galactosidaseでの結果とは対照的に、アミノペプチダーゼであるDPP−IVおよびGGTの化合物2、3(GP−FMA、gGlu−FMA)を用いた場合には、酵素高発現/低発現細胞間で細胞生存率の変化が観測された(図6、7)。この結果から、(i)DPP−IVやGGT(細胞膜)とβ−galactosidase(細胞質)の局在の差、(ii)キノンメチド種の差(DPP−IVとGGTはアザキノンメチドを放出)が重要であることが示唆されたが、現段階では不明である。特にGGTプロドラッグは細胞種選択性が高く、GGT阻害剤のGGsTop(登録商標)で完全に生存率が回復したことから、薬効発現の大部分がGGT活性に依存していることが予想された。
共培養条件下での細胞死観察に関する検討
細胞種の変更を行い、培地をRPMI−1640に統一することで共培養が可能となったため、続いて共培養条件下での細胞死観察および定量法の構築を目指した。これまでの結果を受け、GGT用化合物3(gGlu−FMA)を用いてこれらの検討を行うこととし、まずは初期検討として1種類の細胞を用い、蛍光観察によって細胞死を視覚的に観察可能か調べた(図8)。実験は以下のプロトコル1にて行った。
レンズ63x/1.4Oil。
スキャンモード:xyzt、x=512、y=512、z=4、t=24。スケールバー、50μm。
図9は、化合物3及びEthD−1を用いた共培養細胞の微速度撮影蛍光イメージングを示す(死細胞染色、Ex/Em=525nm/511−564nm)(上)。
24時間イメージング後の他の3つの視野における細胞の共焦点イメージング(下)。
レンズ63x/1.4Oil。
スキャンモード:xyzt、x=512、y=512、z=4、t=24。スケールバー、50μm。
Flow Cytometry(フローサイトメトリー)による薬効評価
蛍光色素を用いたイメージングにより共培養条件下での細胞死がリアルタイムで観測可能であることが示された。一方で、高発現/低発現細胞の生存率がどの程度変化したのかという定量的な議論はできないため、これらがフローサイトメトリーを用いて評価可能であるか検討した(図10)。実験は以下プロトコル3にて行った。
次に、GGTを標的としたベンジル位変換誘導体の合成の検討を行った。EvansのpKa表(D.H. Ripin; D.A. Evans, http://evans.rc.fas.harvard.edu/pdf/evans_pKa_table.pdfを参照)を参考にして、図11に示すようなアシル系脱離基を有する誘導体が合成可能か検証した。
以下のスキーム4により、本発明の化合物を合成した。
1H NMR(CDCl3,400MHz):δ8.91(brs,1H,−CONH−),8.16(d,1H,J=7.8Hz),7.29(dd,1H,J=7.8Hz,J=7.3Hz),7.08(d,1H,J=7.3Hz),7.02(dd,1H,J=7.3Hz,J=7.3Hz,5.95−5.82(m,2H),5.61(brd,1H,−OCONH−,J=7.8Hz),5.32(d,1H,J=17Hz),5.28(d,1H,J=17Hz),5.24(d,1H,J=11Hz),5.18(d,1H,J=11Hz),4.73(s,2H,HBn),4.64(d,1H,J=5.5Hz),4.56−4.52(m,2H),4.47−4.37(m,1H),2.56−2.39(m,2H),2.38−2.27(m,1H),2.18−2.05(m,1H),0.90(s,9H,Si(CH3)3),0.08(s,6H,Si(CH3)2).
1H NMR(CDCl3,400MHz):δ8.73(brs,1H,−CONH−),7.97(d,1H,J=8.2Hz),7.30(dd,1H,J=8.2Hz,J=7.8Hz),7.18(d,1H,J=7.3Hz),7.07(dd,1H,J=7.8Hz,J=7.3Hz),5.95−5.79(m,2H,5.67(brd,1H,−OCONH−,J=7.8Hz),5.32(d,1H,J=17Hz),5.27(d,1H,J=17Hz),5.24(d,1H,J=10Hz),5.19(d,1H,J=10Hz),4.74−4.61(m,2H,HBn),4.63(d,1H,J=6.0Hz),4.57−4.45(m,2H),4.45−4.35(m,1H),2.97(brs,1H,CH2OH),2.55−2.40(m,2H),2.39−2.26(m,1H),2.12−1.96(m,1H).
1H NMR(CDCl3,400MHz):δ8.86(brs,1H,−CONH−),7.96(d,1H,J=7.8Hz),7.35(dd,1H,J=7.8Hz,J=7.3Hz),7.34(d,1H,J=7.3Hz),7.13(dd,1H,J=7.8Hz,J=7.3Hz),5.95−5.81(m,2H),5.68(brd,1H,−OCONH−,J=7.3Hz),5.32(d,1H,J=17Hz),5.27(d,1H,J=17Hz),5.24(d,1H,J=11Hz),5.18(d,1H,J=11Hz),5.13(d,1H,HBn,Jgem=12Hz),5.08(d,1H,HBn‘,Jgem=12Hz),4.63(d,1H,J=5.5Hz),4.58−4.48(m,2H),4.48−4.39(m,1H),2.62−2.46(m,2H),2.41−2.27(m,1H),2.19−2.05(m,1H),2.08(s,3H,OCOCH3).
1H NMR(CD3OD,400MHz):δ7.40(d,1H,Ha,JHa−Hb=7.3Hz),7.38(d,1H,Hd,JHd−Hc=7.3Hz),7.32(dd,1H,Hc,JHc−Hb=JHc−Hd=7.3Hz),7.24(dd,1H,Hb,JHb−Ha=JHb−Hc=7.3Hz),5.09(s,2H,HBn),3.63(t,1H,Hα,JHα-Hβ=6.2Hz),2.65(t,2H,Hγ,JHγ-Hα=JHγ-Hβ=7.3Hz),2.18(td, 2H,Hβ,JHβ-Hγ=7.3Hz,JHβ-Hα=6.2Hz),2.05(s,3H,CH3COO−);13C NMR(CD3OD,100MHz):δ172.3,172.4,171.4,135.3,131.1,129.4,128.6,126.3,126.1,62.6,54.3,32.0,26.5,19.5;HRMS 317.11124(M+Na+).
1H NMR(CDCl3,400MHz):δ9.20(brs,1H,−CONH−),8.00(d,2H,J=9.2Hz),8.00(d,1H,J=7.3Hz),7.43(d,1H,J=7.8Hz),7.37(dd,1H,J=7.8Hz,J=7.3Hz),7.14(dd,1H,J=7.3Hz,J=7.3Hz),6.90(d,2H,J=9.2Hz),5.95−5.82(m,2H),5.71(brd,1H,−OCONH−,J=6.9Hz),5.35(d,1H,HBn,Jgem=12Hz),5.34(d,1H,J=19Hz),5.31(d,1H,HBn‘,Jgem=12Hz),5.27(d,1H,J=19Hz),5.23(d,1H,J=11Hz),5.17(d,1H,J=11Hz),4.63(d,1H,J=6.0Hz),4.58−4.50(m,2H),4.50−4.41(m,1H),3.85(s,3H,ArOCH3),2.67−2.52(m,2H),2.42−2.30(m,1H),2.24−2.07(m,1H).
1H NMR(CD3OD,400MHz):δ7.96(d,2H,He,Hf,JHe−Hh=JHf−Hg=9.2Hz),7.50(d,1H,Ha,JHa−Hb=7.3Hz),7.41(d,1H,Hd,JHd−Hc=6.9Hz),7.34(dd,1H,Hc,JHc−Hb=7.8Hz,JHc−Hd=6.9Hz),7.26(dd,1H,Hb,JHb−Hc=7.8Hz,JHb−Ha=7.3Hz),6.97(d,2H,Hg,Hh,JHg−Hf=JHh−He=9.2Hz),5.32(s,2H,HBn),3.83(s,3H,−OCH3),3.62(t,1H,Hα,JHα-Hβ=6.0Hz),2.66(t,2H,Hγ,JHγ-Hα=JHγ-Hβ=7.3Hz),2.17(td,2H,Hβ,JHβ-Hγ=7.3Hz,JHβ-Hα =6.0Hz);13C NMR(CD3OD,100MHz):δ172.9,166.5,164.0,135.3,131.4,131.3,129.4,128.6,126.4,126.0,122.0,113.6,62.8,54.7,54.4,32.0,26.5;HRMS 409.13271(M+Na+).
1H NMR(CDCl3,400MHz):δ9.02(brs,1H,−CONH−),7.97(d,2H,J=8.7Hz),7.95(d,1H,J=7.3Hz),7.43(d,1H,J=7.8Hz),7.43(d,2H,J=8.7Hz),7.37(dd,1H,J=7.8Hz,J=7.3Hz),7.16(dd,1H,J=7.3Hz,J=7.3Hz),5.95−5.79(m,2H),5.69(brd,1H,−OCONH−,J=7.8Hz),5.38(d,1H,HBn,Jgem=12Hz),5.35(d,1H,J=17Hz),5.33(d,1H,HBn‘,Jgem=12Hz),5.26(d,1H,J=17Hz),5.23(d,1H,J=9.6Hz),5.16(d,1H,J=9.6Hz),4.63(d,1H,J=6.0Hz),4.56−4.48(m,2H),4.49−4.40(m,1H),2.66−2.51(m,2H),2.43−2.30(m,1H),2.20−2.05(m,1H).
1H NMR(CD3OD,400MHz):δ7.99(d,2H,He,Hf,JHe−Hh=JHf−Hg=7.8Hz),7.51(d,1H,Ha,JHa−Hb=7.8Hz),7.48(d,2H,Hg,Hh,JHg−Hf=JHh−He=7.8Hz),7.40(d,1H,Hd,JHd−Hc=7.8Hz),7.34(dd,1H,Hc,JHc−Hd=7.8Hz,JHc−Hb=7.3Hz),7.27(dd,1H,Hb,JHb−Ha=7.8Hz,JHb−Hc=7.3Hz),5.36(s,2H,HBn),3.62(t,1H,Hα,JHα-Hβ=6.0 Hz),2.66(t,2H,Hγ,JHγ-Hα=JHγ-Hβ=7.3Hz),2.16(td,2H,Hβ,JHβ-Hγ=7.3Hz,JHβ-Hα=6.0 Hz);13C NMR(CD3OD,100MHz):δ172.9,172.5,165.6,139.4,135.4,131.1,130.9,129.5,128.8,128.6,126.5,126.2,63.3,54.3,32.0,26.5;HRMS 413.08817(M+Na+).
1H NMR (CDCl3, 400 MHz): δ 8.86 (brs, 1H, -CONH-), 8.27 (d, 2H, J = 8.7 Hz), 8.21 (d, 2H, J = 8.7 Hz), 7.91 (d, 1H, J = 7.8 Hz), 7.45 (d, 1H, J = 7.3 Hz), 7.38 (dd, 1H, J = 7.8 Hz, J = 7.3 Hz), 7.18 (dd, 1H, J = 7.3 Hz, J = 7.3 Hz), 5.95-5.78 (m, 2H), 5.67 (brd, 1H, -OCONH-, J = 7.8 Hz), 5.44 (d, 1H, HBn, Jgem = 12 Hz), 5.39 (d, 1H, HBn’, Jgem = 12 Hz), 5.31 (d, 1H, J = 17 Hz), 5.25 (d, 1H, J = 17 Hz), 5.23 (d, 1H, J = 11 Hz), 5.16 (d, 1H, J = 11 Hz), 4.63 (d, 1H, J = 6.0 Hz), 4.56-4.39 (m, 3H), 2.65-2.51 (m, 2H), 2.43-2.29 (m, 1H), 2.20-2.03 (m, 1H).
1H NMR (CD3OD, 400 MHz): δ 8.31 (d, 2H, He, Hf, JHe-Hh = JHf-Hg = 9.2 Hz), 8.22 (d, 2H, Hg, Hh, JHg-Hf = JHh-He = 9.2 Hz), 7.53 (d, 1H, Ha, JHa-Hb = 7.3 Hz), 7.40-7.34 (m, 2H, Hc, Hd), 7.29 (ddd, 1H, Hb, JHb-Ha = JHb-Hc = 7.3 Hz, JHb-Hd = 1.8 Hz), 5.41 (s, 2H, HBn), 3.62 (t, 1H, Hα, JHα-Hβ =6.0 Hz), 2.66 (t, 2H, Hγ, JHγ-Hα = JHγ-Hβ = 7.3 Hz), 2.16 (td, 2H, Hβ, JHβ-Hγ =7.3 Hz, JHβ-Hα =6.0 Hz); 13C NMR (CD3OD, 100 MHz): δ 173.0, 172.5, 164.7, 150.8, 135.5, 130.9, 130.5, 129.7, 129.0, 128.0, 127.6, 126.5, 125.6, 124.6, 123.3, 63.9, 54.3, 32.0, 26.6; HRMS 413.11126 (M+Na+).
1H NMR (CDCl3, 400 MHz): δ 8.74 (brs, 1H, -CONH-), 7.94 (d, 1H, J = 8.2 Hz), 7.83 (d, 1H, J = 7.6 Hz), 7.47-7.41 (m, 3H), 7.37 (ddd, 1H, J = 7.8 Hz, J = 7.8 Hz, J = 1.4 Hz), 7.30 (ddd, 1H, J = 7.3 Hz, J = 6.9 Hz, J = 1.8 Hz), 7.16 (dd, 1H, J = 7.3 Hz, J = 7.3 Hz), 5.95-5.80 (m, 2H), 5.66 (brd, 1H, -OCONH-, J = 7.8 Hz), 5.40 (d, 1H, HBn, Jgem = 12 Hz), 5.36 (d, 1H, HBn’, Jgem = 12 Hz), 5.31 (d, 1H, J = 17 Hz), 5.26 (d, 1H, J = 17 Hz), 5.22 (d, 1H, J = 11 Hz), 5.16 (d, 1H, J = 11 Hz), 4.63 (d, 1H, J = 6.0 Hz), 4.58-4.49 (m, 2H), 4.49-4.39 (m, 1H), 2.67-2.50 (m, 2H), 2.44-2.30 (m, 1H), 2.18-2.04 (m, 1H).
1H NMR (CD3OD, 400 MHz): δ 7.81 (d, 1H, He, JHe-Hf = 7.3 Hz), 7.53 (d, 1H, Ha, JHa-Hb = 7.3 Hz), 7.49-7.48 (m, 2H, Hc, Hd), 7.41-7.34 (m, 3H, Hb, Hg, Hh), 7.29 (dd, 1H, Hb, JHb-Ha = JHb-Hc = 7.3 Hz), 5.37 (s, 2H, HBn), 3.63 (t, 1H, Hα, JHα-Hβ =6.0 Hz), 2.67 (t, 2H, Hγ, JHγ-Hα = JHγ-Hβ = 7.3 Hz), 2.18 (td, 2H, Hβ, JHβ-Hγ = 7.3 Hz, JHβ-Hα = 6.0 Hz); 13C NMR (CD3OD, 100 MHz): δ 172.9, 172.7, 135.4, 133.1, 132.7, 131.1, 130.8, 130.7, 130.1, 129.6, 128.8, 126.7, 126.4, 126.1, 63.6, 54.4, 32.0, 26.6; HRMS 413.08882 (M+Na+).
1H NMR (CDCl3, 400 MHz): δ 8.90 (brs, 1H, -CONH-), 8.85 (s, 1H), 8.41 (dd, 1H, J = 8.0 Hz, J = 2.3 Hz), 8.36 (d, 1H, J = 7.8 Hz), 7.91 (d, 1H, J = 7.8Hz), 7.65 (dd, 1H, J = 8.2 Hz, J = 7.8 Hz), 7.47 (d, 1H, J = 7.8 Hz), 7.38 (dd, 1H, J = 7.8 Hz, J = 7.3 Hz), 7.18 (dd, 1H, J = 7.3 Hz, J = 7.3 Hz), 5.95-5.78 (m, 2H), 5.68 (brd, 1H, -OCONH-, J = 7.8 Hz), 5.45 (d, 1H, HBn, Jgem = 12 Hz), 5.40 (d, 1H, HBn’, Jgem = 12 Hz), 5.31 (d, 1H, J = 17 Hz), 5.25 (d, 1H, J = 17 Hz), 5.23 (d, 1H, J = 11 Hz), 5.15 (d, 1H, J = 11 Hz), 4.63 (d, 1H, J = 6.0 Hz), 4.56-4.40 (m, 2H), 2.67-2.51 (m, 2H), 2.44-2.30 (m, 1H), 2.22-2.05 (m, 1H).
1H NMR (CD3OD, 400 MHz): δ 8.78 (s, 1H, He), 8.45 (d, 1H, Hh, JHh-Hg = 8.2 Hz), 8.39 (d, 1H, Hf, JHf-Hg = 7.6 Hz), 7.75 (dd, 1H, Hg, JHg-Hh = 8.2 Hz, JHg-Hf = 7.6 Hz), 7.54 (d, 1H, Ha, JHa-Hb = 7.3 Hz), 7.43-7.35 (m, 2H, Hc, Hd), 7.41-7.34 (m, 3H, Hb, Hg, Hh), 7.30 (dd, 1H, Hb, JHb-Ha = JHb-Hc = 7.3 Hz), 5.43 (s, 2H, HBn), 3.60 (t, 1H, Hα, JHα-Hβ =6.0 Hz), 2.66 (t, 2H, Hγ, JHγ-Hα = JHγ-Hβ = 7.3 Hz), 2.16 (td, 2H, Hβ, JHβ-Hγ =7.3 Hz, JHβ-Hα =6.0 Hz); 13C NMR (CD3OD, 100 MHz): no data; HRMS 424.11063(M+Na+).
1H NMR (CDCl3, 400 MHz): δ 8.23 (brs, 1H, -CONH-), 7.91 (d, 1H, J = 7.8 Hz), 7.74 (d, 1H, J = 8.0 Hz),7.71-7.60 (m, 2H), 7.38 (dd, 1H, J = 7.8 Hz, J = 7.3 Hz), 7.37 (d, 1H, J = 7.3 Hz), 7.16 (dd, 1H, J = 7.3 Hz, J = 7.3 Hz), 5.95-5.80 (m, 2H), 5.69 (brd, 1H, -OCONH-, J = 7.8 Hz), 5.38 (d, 1H, HBn, Jgem = 12 Hz), 5.31 (d, 1H, HBn’, Jgem = 12 Hz), 5.31 (d, 1H, J = 17 Hz), 5.26 (d, 1H, J = 17 Hz), 5.22 (d, 1H, J = 11 Hz), 5.15 (d, 1H, J = 11 Hz), 4.63 (d, 1H, J = 6.0 Hz), 4.58-4.40 (m, 2H), 2.68-2.53 (m, 2H), 2.42-2.30 (m, 1H), 2.18-2.20 (m, 1H).
1H NMR (CD3OD, 400 MHz): δ 7.94 (d, 1H, He, JHe-Hf = 7.8 Hz), 7.82-7.69 (m, 3H, Hf, Hg, Hh), 7.46 (d, 1H, Ha, JHa-Hb = 7.3 Hz), 7.42-7.33 (m, 2H, Hc, Hd), 7.27 (dd, 1H, Hb, JHb-Ha = JHb-Hc = 7.3 Hz), 5.34 (s, 2H, HBn), 3.63 (t, 1H, Hα, JHα-Hβ =5.3 Hz), 2.69 (t, 2H, Hγ, JHγ-Hα = JHγ-Hβ = 6.6 Hz), 2.18 (td, 2H, Hβ, JHβ-Hγ =6.6 Hz, JHβ-Hα =5.3 Hz); 13C NMR (CD3OD, 100 MHz): 173.0, 172.6, 165.3, 135.5, 133.0, 132.3, 130.2, 129.8, 129.0, 126.9, 126.4, 126.1, 123.8, 64.4, 54.4, 32.0, 26.5; HRMS 424.11207 (M+Na+).
(1)ベンジル位脱離基変換誘導体を用いた酵素認識能の確認
次に、合成したベンジル位脱離基変換誘導体と精製酵素を用いて酵素反応を以下の条件で行った。
化合物終濃度:100μM
酵素終濃度:10U/mL(GGT)
反応温度:37℃
機種:1260 Infinity(Agilent社製)
カラム:Poroshell 120、4.6×100mm(Agilent社製)
移動相A:水(0.01Mギ酸アンモニウム)
移動相B:80%アセトニトリル/水(0.01Mギ酸アンモニウム)
グラジエント:A/B:95/5→50/50、20分
図12の結果から、アシル系脱離基を有する誘導体群は、精製GGTによって速度は違うもののアザキノンメチドを放出することが確認された。
次に、ベンジル位脱離基変換誘導体について、前述したCCK−8アッセイを行った。結果を図13に示す。
図13に示すように、脱離基がフッ素のモデル化合物が薬効を示した25μMの濃度で、アシル系脱離基を有する誘導体はいずれも抗腫瘍活性を示さない結果となった。
更に、GGTプロドラッグ誘導体としてベンゼン環上4、5位に置換基を導入した以下の4種の化合物の合成を行った。メチル基(電子供与基)とメチルエステル基(電子吸引基)を導入することで、ベンゼン環の電子密度が変化し、放出されるアザキノンメチドの反応性が変化するため、細胞死にも影響が出ると予想される。
以下の合成スキーム5により、4位置換体を合成した。
1H NMR (CDCl3, 400 MHz): δ 9.16 (brs, 1H, -CONH-), 8.24 (d, 1H, J = 8.2 Hz), 7.97 (d, 1H, J = 8.2 Hz), 7.85 (s, 1H), 5.31 (brd, 1H, -OCONH-, J = 7.3 Hz), 4.84-4.64 (m, 2H, HBn), 4.27-4.15 (m, 1H), 3.88 (s, 3H, ArCOOCH3), 3.26-3.18 (m, 1H, CH2OH), 2.36-2.22 (m, 1H), 2.03-1.88 (m, 1H), 1.45 (s, 9H, COO(CH3)3), 1.41 (s, 9H, NHCOO(CH3)3).
1H NMR (CDCl3, 400 MHz): δ 8.48 (brs, 1H, -CONH-), 8.23 (d, 1H, J = 8.2 Hz), 8.07 (d, 1H, J = 8.2 Hz), 7.99 (s, 1H), 5.70-5.38 (m, 2H, HBn), 5.30 (brs, 1H, -OCONH-), 4.28-4.18 (m, 1H), 3.91 (s, 3H, ArCOOCH3), 2.62-2.42 (m, 2H), 2.40-2.26 (m, 1H), 2.20-1.82 (m, 1H), 1.46 (s, 9H, COO(CH3)3), 1.44 (s, 9H, NHCOO(CH3)3).
1H NMR (CD3OD, 400 MHz): δ 8.09 (s, 1H, Ha), 7.99 (d, 1H, Hb, JHb-Hc = 8.7 Hz), 7.66 (d, 1H, Hb, JHb-Hc = 8.7 Hz), 5.44 (d, 2H, HBn, JHBn-F = 48 Hz), 4.06 (t, 1H, Hα, JHα-Hβ = 6.4 Hz), 3.89 (s, 3H, ArCOOCH3), 2.76 (t, 2H, Hγ, JHγ-Hα = 6.9 Hz), 2.25 (tt, 2H, Hβ, JHβ-Hγ = 6.9 Hz, JHβ-Hα = 6.4 Hz); 13C NMR (CD3OD, 100 MHz): δ 173.1, 171.4, 167.7, 140.7, 131.9, 131.4, 131.0, 128.7, 126.0, 82.2 (d, CH2F, JC-F = 164 Hz), 53.4, 52.7, 32.7, 26.8; HRMS 335.10105 (M+Na+).
以下の合成スキーム6により、4位置換体を合成した。
1H NMR (CDCl3, 400 MHz): δ 8.78 (brs, 1H, -CONH-), 8.00 (d, 1H, J = 7.8 Hz), 7.09 (d, 1H, J = 7.8 Hz), 6.91 (s, 1H), 5.21 (brd, 1H, -OCONH-, J = 7.8 Hz), 4.70 (d, 1H, HBn, Jgem = 13 Hz), 4.67 (d, 1H, HBn’, Jgem = 13 Hz), 4.28-4.14 (m, 1H), 2.52-2.33 (m, 2H), 2.32-2.18 (m, 1H), 2.29 (s, 3H, ArCH3), 2.06-1.92 (m, 1H), 1.46 (s, 9H, COO(CH3)3), 1.42 (s, 9H, NHCOO(CH3)3), 0.90 (s, 9H, Si(CH3)3), 0.08 (s, 6H, Si(CH3)2).
1H NMR (CDCl3, 400 MHz): δ 8.75 (brs, 1H, -CONH-), 7.68 (d, 1H, J = 7.8 Hz), 7.07 (d, 1H, J = 7.8 Hz), 7.01 (s, 1H), 5.36 (brd, 1H, -OCONH-, J = 8.2 Hz), 4.60 (d, 1H, HBn, Jgem = 13 Hz), 4.54 (d, 1H, HBn’, Jgem = 13 Hz), 4.22-4.10 (m, 1H), 2.48-2.32 (m, 2H), 2.32-2.06 (m, 1H), 2.27 (s, 3H, ArCH3), 2.20-1.82 (m, 1H), 1.44 (s, 9H, COO(CH3)3), 1.40 (s, 9H, NHCOO(CH3)3).
1H NMR (CDCl3, 400 MHz): δ 8.14 (brs, 1H, -CONH-), 7.68 (d, 1H, J = 8.2 Hz), 7.17 (d, 1H, J = 8.2 Hz), 7.12 (s, 1H), 5.38 (d, 2H, HBn, JHBn-F = 48 Hz, Jgem = 11 Hz), 5.30 (brd, 1H, -OCONH-, J = 6.0 Hz), 4.32-4.16 (m, 1H), 2.56-2.36 (m, 2H), 2.36-2.20 (m, 1H), 2.31 (s, 3H, ArCH3), 2.20-1.84 (m, 1H), 1.45 (s, 9H, COO(CH3)3), 1.43 (s, 9H, NHCOO(CH3)3).
1H NMR (CD2Cl2, 400 MHz): δ 7.26 (s, 1H), 7.23 (d, 1H, Hc, JHc-Hb = 7.8 Hz), 7.17 (d, 1H, Hb, JHb-Hc = 7.8 Hz), 5.32 (d, 2H, HBn, JHBn-F = 48 Hz), 3.62 (t, 1H, Hα, JHa-Hβ = 6.0 Hz), 2.63 (t, 2H, Hγ, JHγ-Hβ = 7.3 Hz), 2.33 (s, 3H, ArCH3), 2.22-2.10 (m, 2H, Hβ); 13C NMR (CD3OD, 100 MHz): δ 174.2, 173.6, 137.7, 133.6, 132.8, 130.8, 130.2, 127.2, 82.5 (d, CH2F, JC-F = 163 Hz), 55.4, 33.2, 27.8, 21.0; HRMS 269.13277 (M+H+).
続いて、以下のスキーム7により、5位置換体の合成を行った。
1H NMR (CDCl3, 400 MHz): δ 8.93 (brs, 1H, -CONH-), 8.77 (s, 1H), 7.73 (d, 1H, J = 7.8 Hz), 7.20 (d, 1H, J = 7.8 Hz), 5.20 (brd, 1H, -OCONH-, J = 7.8 Hz), 4.78 (d, 1H, HBn, Jgem = 13 Hz), 4.74 (d, 1H, HBn’, Jgem = 13 Hz), 4.26-4.16 (m, 1H), 3.88 (s, 3H, ArCOOCH3), 2.53-2.34 (m, 2H), 2.34-2.20 (m, 1H), 2.06-1.90 (m, 1H), 1.45 (s, 9H, COO(CH3)3), 1.41 (s, 9H, NHCOO(CH3)3), 0.90 (s, 9H, Si(CH3)3), 0.08 (s, 6H, Si(CH3)2).
1H NMR (CDCl3, 400 MHz): δ 8.96 (brs, 1H, -CONH-), 8.55 (d, 1H, J = 8.2 Hz), 7.75 (d, 1H, J = 7.8 Hz), 7.29 (d, 1H, J = 7.8 Hz), 5.34 (brd, 1H, -OCONH-, J = 7.8 Hz), 4.74 (dd, 1H, HBn, Jgem = 13 Hz, J = 6.0 Hz), 4.67 (dd, 1H, HBn’, Jgem = 13 Hz, J = 5.5 Hz), 4.26-4.12 (m, 1H), 3.88 (s, 3H, ArCOOCH3), 3.51 (dd, 1H, CH2OH, J = 6.0 Hz, J = 5.5 Hz), 2.54-2.38 (m, 2H), 2.34-2.20 (m, 1H), 2.01-1.84 (m, 1H), 1.45 (s, 9H, COO(CH3)3), 1.41 (s, 9H, NHCOO(CH3)3).
1H NMR (CDCl3, 400 MHz): δ 8.47 (brs, 1H, -CONH-), 8.45 (s, 1H), 7.85 (d, 1H, J = 8.2 Hz), 7.43 (d, 1H, J = 8.2 Hz), 5.48 (d, 2H, HBn, JHBn-F = 48 Hz, Jgem = 12 Hz), 5.33 (brd, 1H, -OCONH-, J = 7.8 Hz), 4.28-4.17 (m, 1H), 3.90 (s, 3H, ArCOOCH3), 2.57-2.40 (m, 2H), 2.35-2.22 (m, 1H), 1.97 -1.82 (m, 1H), 1.45 (s, 9H, COO(CH3)3), 1.43 (s, 9H, NHCOO(CH3)3).
1H NMR (CD3OD, 400 MHz): δ 8.04 (s, 1H, Hc), 7.91 (d, 1H, Hb, JHb-Ha = 7.8 Hz), 7.56 (d, 1H, Ha, JHa-Hb = 7.8 Hz), 5.44 (d, 2H, HBn, JHBn-F = 48 Hz), 4.07 (t, 1H, Hα, JHα-Hβ = 6.4 Hz), 2.75 (t, 2H, Hγ, JHγ-Hα = 7.3 Hz), 2.26 (tt, 2H, Hβ, JHβ-Hγ = 7.3 Hz, JHβ-Hα= 6.4 Hz); 13C NMR (CD3OD, 100 MHz): δ 172.0, 170.2, 166.3, 136.5, 134.6, 130.7, 127.8, 126.9, 126.6, 80.7 (d, CH2F, JC-F = 165 Hz), 52.1, 51.5, 31.1, 25.6; HRMS 313.11879 (M+H+).
更に、以下のスキーム8により、5位置換体の合成を行った。
1H NMR (CDCl3, 400 MHz): δ 8.80 (brs, 1H, -CONH-), 7.93 (s, 1H), 6.89 (d, 1H, J = 7.6 Hz), 6.76 (d, 1H, J = 7.6 Hz), 5.90-5.70 (m, 2H), 5.56 (brd, 1H, -OCONH-, J = 8.0 Hz), 5.28-5.10 (m, 4H), 4.62 (s, 2H, HBn), 4.58-4.40 (m, 4H), 4.40-4.30 (m, 1H), 2.51-2.30 (m, 2H), 2.36-2.21 (m, 1H), 2.26 (s, 3H, ArCH3), 2.13-1.95 (m, 1H), 0.83 (s, 9H, Si(CH3)3), 0.00 (s, 6H, Si(CH3)2).
1H NMR (CDCl3, 400 MHz): δ 8.68 (brs, 1H, -CONH-), 7.80 (s, 1H), 7.06 (d, 1H, J = 7.8 Hz), 6.88 (d, 1H, J = 7.8 Hz), 5.96-5.80 (m, 2H), 5.66 (brd, 1H, -OCONH-, J = 7.8 Hz), 5.36-5.14 (m, 4H), 4.71-4.35 (m, 8H), 2.87 (brs, 1H, CH2OH), 2.55-2.41 (m, 2H), 2.39-2.27 (m, 1H), 2.32 (s, 3H, ArCH3), 2.14-1.97 (m, 1H).
1H NMR (CDCl3, 400 MHz): δ 7.77 (s, 1H), 7.17 (d, 1H, J = 7.3 Hz), 6.96 (d, 1H, J = 7.3 Hz), 5.97-5.82 (m, 2H), 5.57 (brd, 1H, -OCONH-, J = 6.9 Hz), 5.40 (d, 2H, HBn, JHBn-F = 48 Hz, Jgem = 11 Hz), 5.36-5.17 (m, 4H), 4.65 (d, 2H, J = 5.5 Hz), 4.59-4.42 (m, 3H), 2.59-2.42 (m, 2H), 2.45-2.27 (m, 1H), 2.36 (s, 3H, ArCH3), 2.15-2.00 (m, 1H).
1H NMR (CD3OD, 400 MHz): δ 7.31 (d, 1H, Hb, JHb-Ha = 7.8 Hz), 7.22 (s, 1H, Hc), 7.09 (d, 1H, Ha, JHa-Hb = 7.8 Hz), 5.32 (d, 2H, HBn, JHBn-F = 48 Hz), 3.65 (t, 1H, Hα, JHα-Hβ = 6.0 Hz), 2.71-2.59 (m, 2H, Hγ), 2.32 (s, 3H, ArCH3), 2.23-2.10 (m, 2H, Hβ); 13C NMR (CD3OD, 100 MHz): δ 172.0, 170.1, 139.4, 134.8, 130.0, 128.7, 127.0, 126.4, 81.1 (d, CH2F, JC-F = 163 Hz), 52.3, 31.2, 25.7, 19.8; HRMS 291.08980 (M+Na+).
ベンゼン環上置換基変換誘導体のin vitro薬効評価
4位置換誘導体のCCK−8アッセイの結果を図14に示す。電子供与基が置換した誘導体が相対的に強い抗腫瘍活性を示す傾向が見られた。
腹膜播種モデルマウスに対するgGlu−FMA(化合物3)の投与試験
(1)腹膜播種について
腹膜播種とは、腹膜内を覆う腹膜の表面に腫瘍細胞が散布され、生着した状態をさす。臨床では、胃癌・大腸癌、卵巣癌などから転移してくる場合が多く、化学療法を含め画期的な治療法が確立されていない。
腹膜播種のモデルマウスは、腹腔内にPBSに懸濁したSHIN3細胞(卵巣癌由来癌細胞株、高GGT活性)を腹腔内投与することにより作製した。細胞播種後7日目から5mg/kgのgGlu−FMAまたはPBS(コントロール)を腹腔内に連日投与し、細胞播種後21日目にgGlu−HMRGを腹腔内投与し、10分後にマウスをサクリファイス、開腹したのちin vivoイメージング装置maestroにて蛍光画像の取得を行った(図16)。
図17にPBSおよびgGlu−FMA投与マウスの腸間膜のマクロ画像とその蛍光画像2例を示した。マクロ画像と蛍光画像ともにgGlu−FMA投与マウスの方が腫瘍が全体的に減少しているように見える。
本発明のプロドラッグ型抗がん剤は、近接した2細胞間の代謝酵素活性の違いを認識し、酵素活性が亢進しているがん細胞のみを死滅させることが可能であり、重篤な副作用による患者のQOL低下というがん化学療法における大きな問題を改善し得る革新的な臨床薬剤となることが期待される。さらに、既存の抗がん剤を用いないアザキノンメチド放出型の本発明のプロドラッグは簡便に合成可能であることから、開発コストにも大きな寄与をもたらすものと期待される。このように、開発したプロドラッグの医療上、産業上の利用価値、経済価値は極めて大きいと考えられる。
Claims (12)
- 以下の一般式(I)で表される化合物又はその塩。
(式中、
Xは、フッ素原子、エステル基(−OC(=O)−R’)、カーボネート基(−OCO2−R’)、カーバメート基(−OCONH−R’)、リン酸およびそのエステル基(−OP(=O)(−OR’)(―OR’’)、及び硫酸およびそのエステル基(―OSO2―OR’)からなる群から選択され、
ここで、R’、R’’は、各々独立に、置換又は無置換のアルキル基、又は、置換又は無置換のアリール基から選択され;
Yは、−NH−CO−L、−NH−L’又は−OL’であり、
ここで、Lは、アミノ酸の部分構造であり、
L’は、糖類又は糖類の部分構造、自己開裂型のリンカーを有する糖類、自己開裂型のリンカーを有するアミノ酸類又はペプチドであり;
R1及びR2は、各々独立に、水素原子又は一価の置換基から選択され;
R3は、水素原子、又はベンゼン環上に存在する1〜4個の同一又は異なる一価の置換基を示す。) - Lのアミノ酸の部分構造は、それが結合しているC=Oと一緒になって、アミノ酸、アミノ酸残基、ペプチド、アミノ酸の一部を構成している、請求項1に記載の化合物又はその塩。
- L’の糖類の部分構造は、それが結合しているOと一緒になって、糖類、糖類の一部を構成している、請求項1に記載の化合物又はその塩。
- 一般式(I)中の−Yが、−C(R1)(R2)Xに対してベンゼン環のオルト位又はパラ位上で結合している、請求項1〜3のいずれか1項に記載の化合物又はその塩。
- Yが、以下から選択される構造を有する、請求項1〜4のいずれか1項に記載の化合物又はその塩。
- Xは、フッ素原子又はエステル基(−OCO−R’)である、請求項1〜5のいずれか1項に記載の化合物又はその塩。
- R1及びR2は、各々独立に、水素原子又はフッ素原子から選択される、請求項1〜6のいずれか1項に記載の化合物又はその塩。
- R3の一価の置換基が、アルキル基、アルコキシカルボニル基、ニトロ基、アミノ基、水酸基、アルキルアミノ基(−NHR’、−NHCOR’)、アルコキシ基(−OR’、−OCOR’)、ハロゲン原子、ボリル基、シアノ基からなる群から選択される(R’は、置換又は無置換のアルキル基、又は、置換又は無置換のアリール基である)、請求項1〜7のいずれか1項に記載の化合物又はその塩。
- R3の一価の置換基が、アルキル基(例えば、メチル基)又はアルコキシカルボニル基(例えば、メトキシカルボニル基)である、請求項8に記載の化合物又はその塩。
- 請求項1〜9のいずれか1項に記載の化合物又はその医薬的に許容可能な塩を含む、プロドラッグ型抗がん剤。
- 請求項1〜9のいずれか1項に記載の化合物又はその医薬的に許容可能な塩を含む、がん細胞特異的な酵素活性により細胞選択的に作用するプロドラッグ型抗がん剤。
- 前記酵素が、ペプチダーゼ又はグリコシダーゼである、請求項11に記載のプロドラッグ型抗がん剤。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862638075P | 2018-03-03 | 2018-03-03 | |
US62/638,075 | 2018-03-03 | ||
PCT/JP2019/008483 WO2019172210A1 (ja) | 2018-03-03 | 2019-03-04 | がん特異的酵素活性を利用したプロドラッグ型抗がん剤 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPWO2019172210A1 true JPWO2019172210A1 (ja) | 2021-02-25 |
JP7442192B2 JP7442192B2 (ja) | 2024-03-04 |
Family
ID=67847066
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020505030A Active JP7442192B2 (ja) | 2018-03-03 | 2019-03-04 | がん特異的酵素活性を利用したプロドラッグ型抗がん剤 |
Country Status (7)
Country | Link |
---|---|
US (1) | US11655269B2 (ja) |
EP (1) | EP3763699A4 (ja) |
JP (1) | JP7442192B2 (ja) |
CN (1) | CN111801315A (ja) |
AU (1) | AU2019231422B9 (ja) |
CA (1) | CA3093110A1 (ja) |
WO (1) | WO2019172210A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2022177002A1 (ja) * | 2021-02-19 | 2022-08-25 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060142202A1 (en) * | 2000-12-08 | 2006-06-29 | 3M Innovative Properties Company | Compositions and methods for targeted delivery of immune response modifiers |
WO2008079924A1 (en) * | 2006-12-22 | 2008-07-03 | 3M Innovative Properties Company | Immune response modifier compositions and methods |
CN102603695A (zh) * | 2012-02-10 | 2012-07-25 | 山东大学 | 一种氨基酸-荧光团类化合物及其应用 |
WO2015178265A1 (ja) * | 2014-05-23 | 2015-11-26 | 日本化薬株式会社 | 新規なグルタミン酸誘導体およびその用途 |
JP2017502068A (ja) * | 2014-01-10 | 2017-01-19 | シャンハイ バーディー バイオテック インコーポレイテッド | Her2陽性腫瘍を処置するための化合物及び組成物 |
CN106831904A (zh) * | 2017-01-24 | 2017-06-13 | 昆药集团股份有限公司 | 一种化合物及其制备方法、制剂与应用 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200831105A (en) * | 2006-12-14 | 2008-08-01 | Astrazeneca Ab | Novel compounds |
US20200190101A1 (en) | 2015-11-18 | 2020-06-18 | Nippon Kayaku Kabushiki Kaisha | Composition Containing Novel Glutamic Acid Derivative And Block Copolymer, And Use Thereof |
US9881208B2 (en) * | 2016-06-20 | 2018-01-30 | Machine Learning Works, LLC | Neural network based recognition of mathematical expressions |
-
2019
- 2019-03-04 CA CA3093110A patent/CA3093110A1/en active Pending
- 2019-03-04 EP EP19764794.4A patent/EP3763699A4/en active Pending
- 2019-03-04 CN CN201980016801.8A patent/CN111801315A/zh active Pending
- 2019-03-04 AU AU2019231422A patent/AU2019231422B9/en active Active
- 2019-03-04 US US16/977,607 patent/US11655269B2/en active Active
- 2019-03-04 JP JP2020505030A patent/JP7442192B2/ja active Active
- 2019-03-04 WO PCT/JP2019/008483 patent/WO2019172210A1/ja unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060142202A1 (en) * | 2000-12-08 | 2006-06-29 | 3M Innovative Properties Company | Compositions and methods for targeted delivery of immune response modifiers |
WO2008079924A1 (en) * | 2006-12-22 | 2008-07-03 | 3M Innovative Properties Company | Immune response modifier compositions and methods |
CN102603695A (zh) * | 2012-02-10 | 2012-07-25 | 山东大学 | 一种氨基酸-荧光团类化合物及其应用 |
JP2017502068A (ja) * | 2014-01-10 | 2017-01-19 | シャンハイ バーディー バイオテック インコーポレイテッド | Her2陽性腫瘍を処置するための化合物及び組成物 |
WO2015178265A1 (ja) * | 2014-05-23 | 2015-11-26 | 日本化薬株式会社 | 新規なグルタミン酸誘導体およびその用途 |
CN106831904A (zh) * | 2017-01-24 | 2017-06-13 | 昆药集团股份有限公司 | 一种化合物及其制备方法、制剂与应用 |
Non-Patent Citations (7)
Title |
---|
BIOCONJUGATE CHEMISTRY, vol. 27(3), JPN6023005309, 2016, pages 660 - 666, ISSN: 0004988751 * |
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 11(13), JPN6023005310, 2001, pages 1769 - 1773, ISSN: 0004988752 * |
BIOORGANIC CHEMISTRY, vol. 18(3), JPN6023005308, 1990, pages 330 - 344, ISSN: 0004988750 * |
CELL PROLIFERATION, vol. 47(3), JPN6023005304, 2014, pages 219 - 230, ISSN: 0004988747 * |
JOURNAL OF MEDICINAL CHEMISTRY, vol. 24(5), JPN6023005311, 1981, pages 479 - 480, ISSN: 0004988753 * |
JOURNAL OF ORGANIC CHEMISTRY, vol. 80(16), JPN6023005306, 2015, pages 8458 - 8463, ISSN: 0004988748 * |
JOURNAL OF THE CHINESE CHEMICAL SOCIETY (TAIPEI, TAIWAN), vol. 53(2), JPN6023005307, 2006, pages 479 - 488, ISSN: 0004988749 * |
Also Published As
Publication number | Publication date |
---|---|
AU2019231422B2 (en) | 2024-03-07 |
CA3093110A1 (en) | 2019-09-12 |
EP3763699A4 (en) | 2021-12-08 |
CN111801315A (zh) | 2020-10-20 |
JP7442192B2 (ja) | 2024-03-04 |
US20200399305A1 (en) | 2020-12-24 |
AU2019231422B9 (en) | 2024-03-21 |
AU2019231422A1 (en) | 2020-10-15 |
WO2019172210A1 (ja) | 2019-09-12 |
EP3763699A1 (en) | 2021-01-13 |
US11655269B2 (en) | 2023-05-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10905665B2 (en) | Chemical modulators of signaling pathways and therapeutic use | |
KR102159442B1 (ko) | 체크포인트 키나아제 1(chk1) 억제제로서 유용한 3,5-이치환된 피라졸, 및 이의 제조 및 적용 | |
JP6976618B2 (ja) | 活性酸素種スカベンジャーの調製および使用 | |
TW202309042A (zh) | 依沙替康(exatecan)衍生物及其抗體藥物結合物 | |
TW201735926A (zh) | 作為蛋白質去乙醯酶抑制劑之反式醯胺化合物及其使用方法 | |
CN105263924B (zh) | Cxcr7受体调节剂 | |
US20190070154A1 (en) | New methods of use for an anti-diarrhea agent | |
CN112409376A (zh) | 一种基于dcaf15的蛋白降解靶向嵌合体及其制备方法和应用 | |
KR20050089157A (ko) | 티오펜 히드록삼산 유도체들의 거울상 이성질체 및hdac 저해제로서의 이들의 용도 | |
WO2019056120A1 (en) | PENTAFLUOROPHENYL SULFONAMIDE COMPOUNDS, COMPOSITIONS AND USES THEREOF | |
US20150306070A1 (en) | Use of maleimide derivatives for preventing and treating leukemia | |
JP7442192B2 (ja) | がん特異的酵素活性を利用したプロドラッグ型抗がん剤 | |
JP5330377B2 (ja) | 3,4−ジヒドロキナゾリン誘導体 | |
JP7370032B2 (ja) | Parr阻害剤としてのキナゾリン―2.4―ジオン誘導体 | |
JP2018537526A (ja) | ボルテゾミブ複合体及びその使用方法 | |
JP2002517494A (ja) | シンナモイルジスタマイシン類似誘導体、その製造方法及びその抗腫瘍剤としての使用 | |
JP6790256B2 (ja) | フェノチアジン誘導体及びその使用方法 | |
CN112512999A (zh) | 新型联苯衍生物化合物及其用途 | |
CN101215276B (zh) | N,n’-取代苯丙氨基酸苯丙氨基醇酯类衍生物及其制备方法 | |
JP2007527411A5 (ja) | ||
GB2619249A (en) | Novel adamantyl derivative or pharmaceutically acceptable salt thereof, and use thereof | |
WO2021019071A1 (en) | Aminothiolester compounds and uses thereof | |
CN115385912A (zh) | 吡嗪并吡嗪并喹啉酮类衍生物、其制备方法和其医药上的用途 | |
KR20100047495A (ko) | 신규 갈바닉산 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 다약제내성 억제용 약학적 조성물 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20201027 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220215 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230214 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230417 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230801 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230928 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20231128 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20240116 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20240213 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7442192 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |