CN115054599B - 2-氨基吲哚类化合物在抗肿瘤药物中的应用 - Google Patents
2-氨基吲哚类化合物在抗肿瘤药物中的应用 Download PDFInfo
- Publication number
- CN115054599B CN115054599B CN202210164465.5A CN202210164465A CN115054599B CN 115054599 B CN115054599 B CN 115054599B CN 202210164465 A CN202210164465 A CN 202210164465A CN 115054599 B CN115054599 B CN 115054599B
- Authority
- CN
- China
- Prior art keywords
- human
- cancer
- compound
- cancer cells
- cdcl
- 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.)
- Active
Links
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 13
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 13
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical class C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 title claims description 22
- -1 2-aminoindole compound Chemical class 0.000 claims abstract description 21
- 206010008342 Cervix carcinoma Diseases 0.000 claims abstract description 14
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims abstract description 14
- 201000010881 cervical cancer Diseases 0.000 claims abstract description 14
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 10
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 10
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 9
- 201000007270 liver cancer Diseases 0.000 claims abstract description 9
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 9
- 201000005202 lung cancer Diseases 0.000 claims abstract description 9
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 9
- 206010005003 Bladder cancer Diseases 0.000 claims abstract description 8
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims abstract description 8
- 201000005112 urinary bladder cancer Diseases 0.000 claims abstract description 8
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 7
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 7
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 claims abstract description 7
- 208000005017 glioblastoma Diseases 0.000 claims abstract description 7
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 7
- 201000001441 melanoma Diseases 0.000 claims abstract description 7
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 7
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 abstract description 30
- 238000003786 synthesis reaction Methods 0.000 abstract description 25
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 13
- 239000001257 hydrogen Substances 0.000 abstract description 13
- 125000000217 alkyl group Chemical group 0.000 abstract description 9
- 150000002431 hydrogen Chemical group 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 8
- 229910052736 halogen Inorganic materials 0.000 abstract description 8
- 150000002367 halogens Chemical group 0.000 abstract description 8
- 125000003118 aryl group Chemical group 0.000 abstract description 7
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 abstract description 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract description 6
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical group O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 abstract description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 abstract description 5
- 238000011160 research Methods 0.000 abstract description 5
- 102220002645 rs104894309 Human genes 0.000 abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 4
- 125000002252 acyl group Chemical group 0.000 abstract description 4
- 150000002148 esters Chemical group 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 125000003342 alkenyl group Chemical group 0.000 abstract description 2
- 125000003545 alkoxy group Chemical group 0.000 abstract description 2
- 230000005764 inhibitory process Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 102
- 238000005481 NMR spectroscopy Methods 0.000 description 62
- 238000006243 chemical reaction Methods 0.000 description 62
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
- 210000004027 cell Anatomy 0.000 description 56
- 239000007787 solid Substances 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- SRMJRXAKBYSQQO-UHFFFAOYSA-N (2-aminobenzoyl) 2-aminobenzoate Chemical compound NC1=CC=CC=C1C(=O)OC(=O)C1=CC=CC=C1N SRMJRXAKBYSQQO-UHFFFAOYSA-N 0.000 description 28
- 239000003208 petroleum Substances 0.000 description 28
- 230000015572 biosynthetic process Effects 0.000 description 23
- 239000002904 solvent Substances 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 239000002994 raw material Substances 0.000 description 18
- 239000012043 crude product Substances 0.000 description 17
- 238000004809 thin layer chromatography Methods 0.000 description 17
- 238000010898 silica gel chromatography Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000004821 distillation Methods 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 238000012544 monitoring process Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 230000003013 cytotoxicity Effects 0.000 description 5
- 231100000135 cytotoxicity Toxicity 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 150000001728 carbonyl compounds Chemical class 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 3
- ZXMGHDIOOHOAAE-UHFFFAOYSA-N 1,1,1-trifluoro-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)NS(=O)(=O)C(F)(F)F ZXMGHDIOOHOAAE-UHFFFAOYSA-N 0.000 description 3
- 108010087230 Sincalide Proteins 0.000 description 3
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 3
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- BPVYMDMPLCOQPJ-UHFFFAOYSA-L bis(trifluoromethylsulfonyloxy)mercury Chemical compound [Hg+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F BPVYMDMPLCOQPJ-UHFFFAOYSA-L 0.000 description 3
- 238000010609 cell counting kit-8 assay Methods 0.000 description 3
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000012578 cell culture reagent Substances 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 210000001985 kidney epithelial cell Anatomy 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- NLRKCXQQSUWLCH-UHFFFAOYSA-N nitrosobenzene Chemical compound O=NC1=CC=CC=C1 NLRKCXQQSUWLCH-UHFFFAOYSA-N 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- HCJTYESURSHXNB-UHFFFAOYSA-N propynamide Chemical class NC(=O)C#C HCJTYESURSHXNB-UHFFFAOYSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- QMGHHBHPDDAGGO-IIWOMYBWSA-N (2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[5-bromo-4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]pyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide Chemical compound CN(CCCNC1=NC(NC2=CC=C(OCCCOCCCCOCCCOCC(=O)N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)NCC3=CC=C(C=C3)C3=C(C)N=CS3)C(C)(C)C)C=C2)=NC=C1Br)C(=O)C1CCC1 QMGHHBHPDDAGGO-IIWOMYBWSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- RTTUBUXMNUJHRR-DXRVJIQQSA-N (3s)-4-[[(e)-2-[1-(4-fluorophenyl)-3-propan-2-ylindol-2-yl]ethenyl]-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound C12=CC=CC=C2C(C(C)C)=C(\C=C\P(O)(=O)C[C@@H](O)CC(O)=O)N1C1=CC=C(F)C=C1 RTTUBUXMNUJHRR-DXRVJIQQSA-N 0.000 description 1
- WHQUHTXULUACFD-KRWDZBQOSA-N (3s)-4-[[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]methoxy-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1COP(O)(=O)C[C@@H](O)CC(O)=O WHQUHTXULUACFD-KRWDZBQOSA-N 0.000 description 1
- VPMIAOSOTOODMY-KJAPKAAFSA-N (4r)-6-[(e)-2-[6-tert-butyl-4-(4-fluorophenyl)-2-propan-2-ylpyridin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1/C=C/C=1C(C(C)C)=NC(C(C)(C)C)=CC=1C1=CC=C(F)C=C1 VPMIAOSOTOODMY-KJAPKAAFSA-N 0.000 description 1
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 1
- QRDAPCMJAOQZSU-KQQUZDAGSA-N (e)-3-[4-[(e)-3-(3-fluorophenyl)-3-oxoprop-1-enyl]-1-methylpyrrol-2-yl]-n-hydroxyprop-2-enamide Chemical compound C1=C(\C=C\C(=O)NO)N(C)C=C1\C=C\C(=O)C1=CC=CC(F)=C1 QRDAPCMJAOQZSU-KQQUZDAGSA-N 0.000 description 1
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 1
- BOOYHBPHFVNWNH-OAHLLOKOSA-N 1-tert-butyl-6-[[(1R)-1-(4-chlorophenyl)ethyl]amino]-5-[(4-fluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C[C@H](C1=CC=C(C=C1)Cl)NC2=NC3=C(C=NN3C(C)(C)C)C(=O)N2CC4=CC=C(C=C4)F BOOYHBPHFVNWNH-OAHLLOKOSA-N 0.000 description 1
- QLVGHFBUSGYCCG-UHFFFAOYSA-N 2-amino-n-(1-cyano-2-phenylethyl)acetamide Chemical compound NCC(=O)NC(C#N)CC1=CC=CC=C1 QLVGHFBUSGYCCG-UHFFFAOYSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- DGJMHKMYSDYOFP-MRXNPFEDSA-N C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O Chemical compound C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O DGJMHKMYSDYOFP-MRXNPFEDSA-N 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 1
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 1
- 229940126650 Compound 3f Drugs 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- KGPGFQWBCSZGEL-ZDUSSCGKSA-N GSK690693 Chemical compound C=12N(CC)C(C=3C(=NON=3)N)=NC2=C(C#CC(C)(C)O)N=CC=1OC[C@H]1CCCNC1 KGPGFQWBCSZGEL-ZDUSSCGKSA-N 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- XJTWGMHOQKGBDO-GOSISDBHSA-N N-[(3-Fluorophenyl)methyl]-1-[(1r)-1-Naphthalen-1-Ylethyl]piperidine-4-Carboxamide Chemical compound C1CN([C@H](C)C=2C3=CC=CC=C3C=CC=2)CCC1C(=O)NCC1=CC=CC(F)=C1 XJTWGMHOQKGBDO-GOSISDBHSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- BEXZJJQVPWJPOA-VOTSOKGWSA-N [(e)-hept-2-enyl] 6-methyl-4-(4-nitrophenyl)-2-oxo-3,4-dihydro-1h-pyrimidine-5-carboxylate Chemical compound CCCC\C=C\COC(=O)C1=C(C)NC(=O)NC1C1=CC=C([N+]([O-])=O)C=C1 BEXZJJQVPWJPOA-VOTSOKGWSA-N 0.000 description 1
- HGDWHTASNMRJMP-UHFFFAOYSA-N [1-(hydroxyamino)-1-oxo-5-(3-phenoxyphenyl)pentan-2-yl]phosphonic acid Chemical compound ONC(=O)C(P(O)(O)=O)CCCC1=CC=CC(OC=2C=CC=CC=2)=C1 HGDWHTASNMRJMP-UHFFFAOYSA-N 0.000 description 1
- 238000010958 [3+2] cycloaddition reaction Methods 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 150000008316 benzisoxazoles Chemical class 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125796 compound 3d Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000012531 culture fluid Substances 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- MUTCAPXLKRYEPR-ITWZMISCSA-N methyl (e,3r,5s)-7-[4-bromo-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\N1C(C(C)C)=C(Br)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 MUTCAPXLKRYEPR-ITWZMISCSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属有机化学合成领域，公开了一种2‑氨基吲哚类化合物及其制备方法和在抗肿瘤药物中的应用。其为通式（I）结构，其中，EWG选自恶唑烷酮，烷基取代的磺酰基或芳基取代的磺酰基；R1选自氢，烷氧基，卤素；R2选自烷基，酰基，烯基，芳基，烯丙基，酯基，氢；R3选自烷基，芳基，烯丙基，链状硅醚；R4选自烷基，链状硅醚，氢。该类化合物对人膀胱癌细胞5637、人胶质母细胞瘤细胞A172、人恶性黑色素瘤细胞A375、人子宫颈癌细胞C33A、人结肠癌细胞HCT 116和SW480、人宫颈癌细胞Hela、人胰腺癌细胞CFPAC‑1、人肝癌细胞Hep G2、人肺癌细胞A549和人乳腺癌细胞MCF‑7具有很强的抑制活性，将其应用在抗肿瘤药物的制备如膀胱癌、胶质母细胞瘤、恶性黑色素瘤、子宫颈癌、结肠癌、宫颈癌、胰腺癌、肝癌、肺癌和乳腺癌的药物研究中具有很好的应用前景。
Description
技术领域
本发明属有机化学合成领域，具体涉及一种2-氨基吲哚类化合物及其制备方法和在抗肿瘤药物中的应用。
背景技术
2-氨基吲哚类化合物是许多天然产物和药物中极为重要的活性成分，被用于预防或治疗过敏、炎症以及癌症和动脉粥样硬化等。因此，对2-氨基吲哚类化合物进行合成方法的研究具有重要的意义。早期文献报道构建2-氨基吲哚类化合物主要有苯胺法、Fischer法、硝基苯法等。这些方法均具有反应时间长、步骤多、反应条件苛刻等缺点。近些年来随着过渡金属催化的发展，越来越多的化学家们选择利用过渡金属催化法合成2-氨基吲哚类化合物。但是，这些方法通常需要在高温和昂贵的过渡金属催化剂Au、Pd或Rh条件下进行。经过文献调研，我们发现氨茴内酐由于其N-O键容易断裂,常被用来合成含氮杂环化合物。因此，我们设想能否通过炔酰胺与氨茴内酐的[3+2]环加成反应构建2-氨基吲哚类化合物。Hashmi课题组虽然也利用炔酰胺与氨茴内酐的[3+2]环加成反应合成了2-氨基吲哚类化合物(Angew.Chem.Int.Ed.,2016,55,794-797)，但是他们用价格昂贵的Au催化剂，并且只得到了3位为H或芳基的2-氨基吲哚类化合物，反应底物范围窄，不利于实际应用。因此，开发一种对环境友好、成本低、反应条件温和、底物普适性广的构建2-氨基吲哚类化合物的方法，并对其进行活性研究是目前的迫切需求。发明人前期对其进行了研究，发表了文章“Metal-Free[3+2]Annulation of Ynamides with Anthranils to Construct 2-Aminoindoles(Org.Lett.,2021,23,2029-2035.)”。该文中侧重对其抗病毒活性进行了初步研究。
发明内容
在前期工作基础上，对其进行了一步研究，发现该类化合物在抗肿瘤方面具有很好的活性，可以作为抗肿瘤药物。
为此，本发明目的在于提供2-氨基吲哚类化合物在抗肿瘤药物中的应用。
具体技术方案如下：
所述2-氨基吲哚类化合物结构通式为：
其中，EWG选自恶唑烷酮，烷基取代的磺酰基或芳基取代的磺酰基；R1选自氢，卤素,烷氧基；R2选自烷基，酰基，烯基，芳基，烯丙基，酯基，氢；R3选自烷基，芳基，烯丙基，链状硅醚；R4选自氢，烷基，链状硅醚。
优选：EWG选自C1-3烷基取代的磺酰基或苯基取代的磺酰基；R1选自氢，卤素或C1-3烷氧基；R2选自C1-6烷基，C2-7酰基，C2-4烯基或取代的C2-4烯基，C2-4酯基或苯基；R3选自C1-4烷基，苄基，苯基，烯丙基，C1-3烷氧硅醚基比如(CH2)nOTBS；R4选自氢，C1-6烷基，C1-3烷氧硅醚基比如(CH2)nOTBS。
更优选：EWG选自甲基磺酰基或被甲氧基、卤素、硝基、甲基取代的苯磺酰基；R1选自氢，卤素，C1-3烷氧基或环烷氧基；R2选自C1-3烷基，被卤素取代的C1-3烷基，C2-7酰基，C2-4烯基，被苯取代的C2-4烯基，C2-4酯基，苯基；R3选自C1-4烷基，苄基，C1-3烷氧硅醚基；R4选自氢，C1-6烷基。
最优选：EWG选自被甲氧基、硝基或甲基取代的苯磺酰基；R1选自氢或卤素；R2选自C1-3烷基，被卤素取代的C1-3烷基；R3选自苄基，C1-4烷基；R4选自氢，C1-3烷基。
上所述2-氨基吲哚类化合物合成路线如下：
具体合成步骤如下：
氮气保护下，向干燥的反应管中依次加入炔酰胺2或2'或2”、氨茴内酐1和二氯甲烷，对应的温度下加入三氟甲磺酸三甲基硅酯或双(三氟甲烷磺酰)亚胺，封闭反应管，对应温度下搅拌；薄层色谱法监测反应进程，待反应完成后，加Et3N淬灭，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到2-氨基吲哚化合物3。
所述步骤中当R4为氢时，所用催化剂为双(三氟甲烷磺酰)亚胺；当R4为烷基或链状硅醚时，所用催化剂为三氟甲磺酸三甲基硅酯；氨茴内酐1、炔酰胺2或2'或2”、三氟甲磺酸三甲基硅酯或双(三氟甲烷磺酰)亚胺的摩尔比为3:2:1。
进一步地，在上述技术方案中，所述原料氨茴内酐1的合成路线如下：
原料氨茴内酐1a-1i的合成路线如下：
具体合成步骤如下：
向反应瓶中加入相应的羰基化合物4、SnCl2·2H2O、甲醇和乙酸乙酯，室温搅拌过夜；薄层色谱法监测反应进程，待反应完成后，加饱和碳酸氢钠淬灭，过滤，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，抽滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到原料氨茴内酐1。
所述步骤中羰基化合物4和SnCl2·2H2O的摩尔比为1:3；甲醇和乙酸乙酯体积比1:1。
原料氨茴内酐1j的合成路线如下：
具体合成步骤如下：
室温条件下，向反应瓶中依次加入氢氧化钾、甲醇和氨基查耳酮5，再缓慢地加入二乙酸碘苯，室温搅拌过夜；薄层色谱法监测反应进程，待反应完成后，减压蒸馏除去溶剂，将残余物于水中搅拌，水相用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到原料氨茴内酐1j。
所述步骤中氨基查耳酮5、二乙酸碘苯和氢氧化钾的摩尔比为1:1.1:3。
原料氨茴内酐1k的合成路线如下：
具体合成步骤如下：
室温条件下，向反应瓶中依次加入硝基炔6、二氯乙烷和三氟甲磺酸汞，室温搅拌；薄层色谱法监测反应进程，待反应完成后，将反应混合物通过砂芯漏斗铺硅胶抽滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到原料氨茴内酐1k。
所述步骤中硝基炔6和三氟甲磺酸汞的摩尔比为1:0.05。
原料氨茴内酐1l的合成路线如下：
具体合成步骤如下：
室温条件下，向干燥的反应管中依次加入乙醛酸甲酯8、二氯甲烷、BF3·Et2O和溶于二氯甲烷的亚硝基苯7溶液，密封反应管，45℃下搅拌；薄层色谱法监测反应进程，待反应完成后，将反应液冷却至室温，砂芯漏斗铺硅胶抽滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到原料氨茴内酐1l。
所述步骤中乙醛酸甲酯8、BF3·Et2O和亚硝基苯7的摩尔比为1:0.1:2。
进一步地，在上述技术方案中，所述原料炔酰胺2、2'或2”的合成路线如下：
原料炔酰胺2和2'的合成路线如下：
具体合成步骤如下：
1)向反应瓶中加入TIPS取代的炔酰胺9，进行氮气保护，加入无水四氢呋喃进行溶解，在0℃下缓慢滴入四丁基氟化铵，0℃下搅拌，薄层色谱法监测反应进程，待反应完成后，加饱和氯化铵淬灭，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到炔酰胺2。
2)向反应瓶中加入炔酰胺2，进行氮气保护，加入无水四氢呋喃进行溶解，在–78℃下缓慢滴入双(三甲硅基)氨基锂，缓慢升至–60℃搅拌1.0h，在–60℃下缓慢滴入碘代烷化合物，升至室温搅拌；薄层色谱法监测反应进程，待反应完成后，加水淬灭，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，抽滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到原料炔酰胺2'。
所述步骤中TIPS取代的炔酰胺9和四丁基氟化铵的的摩尔比为1:1.5；炔酰胺2、双(三甲硅基)氨基锂和碘代烷化合物的摩尔比为1:1.5:2。
原料炔酰胺2”的合成路线如下：
氮气保护下，向反应瓶依次中加入恶唑烷酮11、炔基溴10、碳酸钾、五水硫酸铜、1,10-邻二氮杂菲和甲苯，加热搅拌；薄层色谱法监测反应进程，待反应完成后，将反应液冷却至室温，砂芯漏斗铺硅胶抽滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到原料炔酰胺2”。
所述步骤中恶唑烷酮11、炔基溴10、碳酸钾、五水硫酸铜和1,10-邻二氮杂菲的摩尔比为1:1.2:2.0:0.2:0.4。
进一步地，在上述技术方案中，所述2-氨基吲哚类化合物在抗肿瘤药物中的应用，经体外活性细胞实验验证，2-氨基吲哚类化合物显示出抑制5637、Hela、SW480、Hep G2、A549和MCF-7的活性，可将其应用于治疗膀胱癌、胶质母细胞瘤、恶性黑色素瘤、子宫颈癌、结肠癌、宫颈癌、胰腺癌、肝癌、肺癌和乳腺癌的研究。
与现有技术相比，本发明提供的2-氨基吲哚类化合物在抗肿瘤药物中的应用，具有如下优势：该类化合物具有抑制抑制人膀胱癌细胞5637、人胶质母细胞瘤细胞A172、人恶性黑色素瘤细胞A375、人子宫颈癌细胞C33A、人结肠癌细胞HCT 116和SW480、人宫颈癌细胞Hela、人胰腺癌细胞CFPAC-1、人肝癌细胞Hep G2、人肺癌细胞A549和人乳腺癌细胞MCF-7的活性，将其应用于抗肿瘤药物的研究，具有良好的应用前景。
具体实施方式
下面通过具体实施方式，对发明技术方案做进一步的详细描述，但本发明的保护范围并不局限于此。若未特别指明，以下实施例中所用的技术手段为本领域技术人员所熟知的常规手段。
主要仪器与化学试剂
核磁共振波谱仪：Bruker AscendTM 400；高分辨质谱仪：Bruker MicrOTOF-Q II质谱仪；红外光谱仪：知微Smart傅立叶变换红外光谱仪(天津港东科技股份有限公司)；三用紫外线分析仪：ZF-6型(上海高鹏科技有限公司)；测定用熔点仪：XT4A显微熔点测定仪(北京科仪电光仪器厂)。
本应用实施过程中所用的原料、溶剂均为商业途径购进。
实施例1：原料氨茴内酐1的合成
1.1原料氨茴内酐1a-1i的合成(Angew.Chem.Int.Ed.2016,55,794-797；Tetrahedron Lett.2012,53,4951-4954；Org.Lett.2019,21,6245-6248)
以氨茴内酐原料1a具体合成步骤为例，向圆底烧瓶中加入相应的羰基化合物4a(825.8mg,5.00mmol)，SnCl2·2H2O(3.4g,15.00mmol)和甲醇-乙酸乙酯(体积比1:1,15.0mL)，室温搅拌过夜；薄层色谱法监测反应进程，待反应完成后，加饱和碳酸氢钠淬灭(15.0mL)，过滤，乙酸乙酯萃取(5×10mL)，合并有机相，无水硫酸钠干燥，抽滤，减压蒸馏除去溶剂，所得粗产物以石油醚/二氯甲烷(40:1～35:1)为洗脱剂，经硅胶柱层析分离得到氨茴内酐1a(619.1mg,4.65mmol)，产率为93％。
将对应的羰基化合物4b-4i分别按本实施例中上述方法制备原料氨茴内酐1，对应得到氨茴内酐1b-1i。氨茴内酐1a-1i的合成分别采用以下参考文献，1a和1d(TetrahedronLett.2012,53,4951-4954)，1b、1e、1f、1h和1i(Angew.Chem.Int.Ed.2016,55,794-797)，1c和1g(Org.Lett.2019,21,6245-6248)。
化合物1a：白色固体，93％产率，1H NMR(400MHz,CDCl3)δ7.51(dq,J＝9.2,0.9Hz,1H),7.43(dq,J＝8.8,1.1Hz,1H),7.29-7.24(m,1H),6.92(dd,J＝8.5,6.6Hz,1H),2.79(s,3H).
化合物1b：无色油状物，90％产率，Rf＝0.62[石油醚/乙酸乙酯(10:1)]；1H NMR(400MHz,CDCl3)δ7.51(dt,1H,J＝9.1,1.0Hz),7.45(dt,1H,J＝8.8,1.0Hz),7.25(ddd,1H,J＝9.0,6.3,1.0Hz),6.90(ddd,1H,J＝8.8,6.4,0.8Hz),3.14(t,2H,J＝7.5Hz),1.88-1.80(m,2H),1.45-1.36(m,2H),0.95(t,3H,J＝7.4Hz)；13C NMR(100MHz,CDCl3)δ169.8,157.1,130.8,122.8,120.0,115.3,115.0,30.0,26.5,22.4,13.7；IR(neat)(cm-1)2954w,2871w,1642m,1519w,1461m,1431w；HRMS(ESI):m/z calcd for C11H14NO[M+H]+:176.1070；found176.1066.
化合物1c：白色固体，79％产率，1H NMR(400MHz,CDCl3)δ7.58(ddt,J＝18.9,8.8,1.0Hz,2H),7.33(ddd,J＝9.1,6.4,1.0Hz,1H),7.08(ddd,J＝8.8,6.4,0.7Hz,1H),4.90(s,2H).
化合物1d：白色固体，83％产率，1H NMR(400MHz,CDCl3)δ8.03(d,2H,J＝7.4Hz),7.84(d,1H,J＝8.9Hz),7.56(ddd,4H,J＝26.8,19.2,8.1Hz),7.33(dd,1H,J＝9.1,6.3Hz),7.07(dd,1H,J＝8.9,6.3Hz).
化合物1e：黄色油状物，68％产率，Rf＝0.50[石油醚/乙酸乙酯(10:1)]；1H NMR(400MHz,CDCl3)δ3.94(dt,2H,J＝6.5,1.5Hz),5.24-5.31(m,2H),6.00-6.10(m,1H),6.93(ddd,1H,J＝8.8,6.4,0.8Hz),7.25-7.29(m,1H),7.51(ddt,2H,J＝16.9,8.8,1.0Hz)；13CNMR(100MHz,CDCl3)δ31.5,115.2,115.6,119.0,120.1,123.2,131.0,131.3,157.4,166.6；IR(neat)(cm-1)1640w,1519w,1459w,1155w,1057w,924m；HRMS(ESI):m/z calcd forC10H10NO[M+H]+:160.0757；found 160.0754.
化合物1f：浅黄色固体，93％产率，Rf＝0.60[石油醚/乙酸乙酯(10:1)]；mp＝77–78℃；1H NMR(400MHz,CDCl3)δ7.45-7.39(m,2H),7.22-7.17(m,1H),6.87-6.84(m,1H),6.41-6.39(m,1H),2.22(s,3H),2.00(s,3H)；13C NMR(100MHz,CDCl3)δ164.7,156.8,146.1,130.9,123.0,120.2,115.9,114.8,110.3,27.9,21.6；IR(neat)(cm-1)2928w,1643m,1517m,1453m,1348w,1149w；HRMS(ESI):m/z calcd for C11H12NO[M+H]+:174.0913；found174.0909.
化合物1g：白色固体，88％产率，1H NMR(400MHz,CDCl3)δ7.64(dd,J＝1.7,0.9Hz,1H),7.42(dd,J＝9.4,0.9Hz,1H),7.29(dd,J＝9.4,1.7Hz,1H),2.76(s,3H).
化合物1h：白色固体，89％产率，Rf＝0.32[石油醚/乙酸乙酯(10:1)]；mp＝92–93℃；1H NMR(400MHz,CDCl3)δ7.74-7.73(m,1H),7.33(dd,1H,J＝9.1,0.8Hz),7.00(dd,1H,J＝9.1,1.5Hz),2.79(s,3H)；13C NMR(100MHz,CDCl3)δ166.9,157.7,127.2,126.0,121.4,117.2,114.4,12.2；IR(neat)(cm-1)2919w,1639s,1499w,1440s,1290m,1153w；HRMS(ESI):m/z calcd for C8H7BrNO[M+H]+:211.9706；found 211.9703.
化合物1i：白色固体，90％产率，Rf＝0.24[石油醚/乙酸乙酯(10:1)]；mp＝131–132℃；1H NMR(400MHz,CDCl3)δ6.70(s,1H),6.54(s,1H),5.97(s,2H),2.63(s,3H)；13C NMR(100MHz,CDCl3)δ162.9,156.5,153.0,146.6,112.4,101.8,92.6,89.7,11.7；IR(neat)(cm-1)3074w,2912w,1667w,1483s,1365s,1120m；HRMS(ESI):m/z calcd for C9H8NO3[M+H]+:178.0499；found 178.0498.
1.2原料氨茴内酐1j的合成(Tetrahedron Lett.1997,38,3147-3150)
室温条件下，向反应瓶中依次加入氢氧化钾(505.0mg,9.00mmol)、甲醇(15.0mL)和氨基查耳酮5(669.8mg,3.00mmol)，再缓慢地加入二乙酸碘苯(1.1g,3.30mmol)，室温搅拌过夜；薄层色谱法监测反应进程，待反应完成后，减压蒸馏除去溶剂，将残余物于水中搅拌，水相用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到原料氨茴内酐1j(460.0mg,2.07mmol)，产率为69％。
化合物1j：白色固体，69％产率，1H NMR(400MHz,CDCl3)δ7.58(ddd,5H,J＝18.6,12.4,8.8Hz,5H),7.41-7.25(m,5H),6.99(dd,1H,J＝8.7,6.4Hz).
1.3原料氨茴内酐1k的合成(Synthesis 2017,49,4173-4182)
室温条件下，向反应瓶中依次加入硝基炔6(693.9mg,3.00mmol)、二氯乙烷(30.0mL)和三氟甲磺酸汞(74.8mg,0.15mmol)，室温搅拌；薄层色谱法监测反应进程，待反应完成后，将反应混合物通过砂芯漏斗铺硅胶抽滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到原料氨茴内酐1k(589.8mg,2.55mmol)，产率为85％。
化合物1k：白色固体，85％产率，1H NMR(400MHz,CDCl3)δ8.05(dt,1H,J＝8.8,1.1Hz,1H),7.81-7.66(m,1H),7.40(ddd,1H,J＝9.0,6.4,1.0Hz),7.29-7.25(m,1H),3.17(t,2H,J＝7.4Hz),1.82(p,2H,J＝7.4Hz),1.48-1.30(m,6H),0.90(t,3H,J＝7.1Hz).
1.4原料氨茴内酐1l的合成(J.Org.Chem.2014,79,8296-8303)
室温条件下，向干燥的反应管中依次加入乙醛酸甲酯8(176.1mg,2.00mmol)、二氯甲烷(30.0mL)和BF3·Et2O(25.2μL,0.20mmol)，将亚硝基苯(428.4mg,4.00mmol)溶于二氯甲烷(10mL)，加入反应体系，密封反应管，45℃下搅拌；薄层色谱法监测反应进程，待反应完成后，将反应液冷却至室温，砂芯漏斗铺硅胶抽滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到原料氨茴内酐1l(248.0mg,1.40mmol)，产率为70％。
化合物1l：浅黄色固体，70％产率，Rf＝0.38[石油醚/乙酸乙酯(8:1)]；mp＝66–67℃；1H NMR(400MHz,CDCl3)δ7.92(d,1H,J＝8.8Hz),7.72(d,1H,J＝9.1Hz),7.40(ddd,1H,J＝9.1,6.4,0.9Hz),7.27-7.22(m,1H),4.09(s,3H).13C NMR(100MHz,CDCl3)δ157.71,157.68,153.6,131.4,128.2,120.6,120.5,116.3,53.0.IR(neat)(cm-1)1733s,1451m,1313s,1228s,1198s,1162m；HRMS(ESI):m/z calcd for C9H8NO3[M+H]+:178.0504；found178.0497.
实施例2：原料炔酰胺2、2'和2”的合成
2.1炔酰胺2a-2g和2'a的合成(Org.Lett.2016,18,5022-5025).
特别说明化合物结构中简写：Ts代表对甲基苯磺酰基，Mbs代表对甲氧基苯磺酰基。
具体合成步骤如下：
1)在氮气保护下，向100mL圆底烧瓶中加入9a(1.77g,4.0mmol)，加入无水四氢呋喃(20.0mL)进行溶解，在0℃下缓慢滴入四丁基氟化铵(6.0mL,1.0M四氢呋喃溶液)，0℃下搅拌0.5h，薄层色谱法监测反应进程，待反应完成后，加饱和氯化铵淬灭，乙酸乙酯萃取(3×10.0mL)，合并有机相，无水硫酸钠干燥，抽滤，减压蒸馏除去溶剂，所得粗产物以石油醚/乙酸乙酯/二氯甲烷(20:1:5)加3％Et3N为洗脱剂柱层析分离得到白色固体产物2a(1.10g,3.85mmol)，产率为96％。
将对应的TIPS取代的炔酰胺9b-9g按本实施例中上述方法步骤1制备炔酰胺2，对应得到炔酰胺2b-2g。
2)在氮气保护下，向50mL圆底烧瓶中加入炔酰胺2a(1.10g,3.85mmol)，加入无水四氢呋喃(30.0mL)进行溶解，在–78℃下缓慢滴入双(三甲硅基)氨基锂(5.77mL,1.0M四氢呋喃溶液)，搅拌并缓慢升至–60℃后，在–60℃下搅拌1.0h，然后缓慢滴入碘甲烷(0.49mL,7.69mmol)，升至室温搅拌12h；薄层色谱法监测反应进程，待反应完成后，加水淬灭，乙酸乙酯萃取(3×10.0mL)，合并有机相，无水硫酸钠干燥，抽滤，减压蒸馏除去溶剂，所得粗产物以石油醚/乙酸乙酯/二氯甲烷(100:3:5～100:5:5)加3％Et3N为洗脱剂，硅胶柱层析分离得到白色固体产物2'a(1.02g,3.41mmol)，产率为89％。
化合物2a：白色固体，96％产率，1H NMR(400MHz,CDCl3)δ7.77-7.74(m,2H),7.33-7.30(m,7H),4.50(s,2H),2.68(s,1H),2.45(s,3H).
化合物2b：黄色油状物，87％产率，1H NMR(400MHz,CDCl3)δ7.80(dt,J＝2.0,8.5Hz,2H),7.31(s,5H),.6.97(dt,J＝2.5,8.5Hz,2H),4.51(s,2H),2.89(s,3H),2.69(s,1H).
化合物2c：白色固体，96％产率，1H NMR(400MHz,CDCl3)δ7.73-7.77(m,2H),7.44-7.47(m,2H),7.27-7.31(m,5H),4.53(s,2H),2.71(s,1H).
化合物2d：白色固体，64％产率，1H NMR(400MHz,CDCl3)δ8.31-8.28(m,2H),7.96-7.93(m,2H),7.31-7.28(m,5H),4.61(s,2H),2.79(s,1H).
化合物2e：黄色油状物，95％产率，1H NMR(400MHz,CDCl3)δ7.39-7.46(m,5H),4.63(s,2H),2.89(s,3H),2.84(s,1H).
化合物2f：白色固体，56％产率，1H NMR(400MHz,CDCl3)δ7.81(d,J＝8.2Hz,2H),7.37(d,J＝8.2Hz,2H),3.07(s,3H),2.68(s,1H),2.46(s,3H).
化合物2g：白色固体，95％产率，1H NMR(400MHz,CDCl3)δ9.09(s,1H),7.71-7.77(m,2H),7.35-7.40(m,2H),3.38-3.45(m,2H),2.46(s,3H),1.45-1.57(m,2H),1.18-1.37(m,2H),0.86(t,J＝7.3Hz,3H).
化合物2'a：白色固体，89％产率，1H NMR(400MHz,CDCl3)δ7.76-7.73(m,2H),7.32-7.28(m,7H),4.44(s,2H),2.44(s,3H),1.81(s,3H).
2.2炔酰胺2”a的合成(J.Am.Chem.Soc.2017,139,9615-9620).
氮气保护下，向反应瓶依次中加入恶唑烷酮11(3.11g,35.7mmol)、炔基溴10(8.10g,42.8mmol)、碳酸钾(9.858g.71.4mmol)、五水硫酸铜(1.78g,7.1mmol)、1,10-邻二氮杂菲(2.83g,14.3mmol)和甲苯(60mL)，90℃下加热搅拌；薄层色谱法监测反应进程，待反应完成后，将反应液冷却至室温，砂芯漏斗铺硅胶抽滤，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析分离得到原料炔酰胺2”a(6.18g,31.6mmol)，产率为89％。
化合物2”a：黄色油状物，89％产率，1H NMR(400MHz,CDCl3)δ4.40(t,J＝8.2Hz,2H),3.87(t,J＝8.2Hz,2H),2.29(t,J＝7.0Hz,2H),1.52(qn,J＝7.0Hz,2H),1.40-1.20(m,6H),0.89(t,J＝7.0Hz,3H).
实施例3：2-氨基吲哚类化合物3的合成
3.1 2-氨基吲哚类化合物3a-3m的合成
特别说明，化合物结构中简写：Ts代表对甲基苯磺酰基，Mbs代表对甲氧基苯磺酰基。
以化合物3a具体合成步骤为例，氮气保护室温的条件下，向干燥的反应管中依次加入炔酰胺2b(60.3mg,0.2mmol)、氨茴内酐1a(39.9mg,0.30mmol)、二氯甲烷(2.0mL)和双(三氟甲烷磺酰)亚胺(28.1mg,0.10mmol)，封闭反应管，室温搅拌10.0min；薄层色谱法监测反应进程，待反应完成后，加Et3N(13.9μL,0.10mmol)淬灭，减压蒸馏除去溶剂，所得粗产物以石油醚/二氯甲烷/乙酸乙酯(30:10:1～20:10:1)为洗脱剂，经硅胶柱层析分离得到2-氨基吲哚化合物3a(82.6mg,0.19mmol)，产率为95％。
将实施例1中制备得到的氨茴内酐1a与实施例2中制备得到的炔酰胺2c、2d、2f和2g分别按本实施例中上述方法制备化合物3，对应得到2-氨基吲哚类化合物3b、3c、3d和3e；将氨茴内酐1b、1c、1e、1f、1j、1k和1l与炔酰胺2a分别按本实施例中上述方法制备化合物3，对应得到2-氨基吲哚类化合物3f、3g、3i、3j、3k、3l和3m；氨茴内酐1d与炔酰胺2e按本实施例中上述方法制备2-氨基吲哚类化合物3h。
化合物3a：白色固体，95％产率，Rf＝0.48[石油醚/乙酸乙酯(2:1)]；mp＝116–117℃；1H NMR(400MHz,CDCl3)δ10.66(s,1H),7.70(dd,1H,J＝7.6,1.0Hz),7.65-7.61(m,3H),7.33-7.30(m,2H),7.26-7.17(m,3H),7.08(t,1H,J＝7.7Hz),6.93-6.89(m,2H),5.92(d,1H,J＝2.4Hz),4.74(s,2H),3.84(s,3H),2.66(s,3H)；13C NMR(100MHz,CDCl3)δ199.9,163.5,135.9,135.6,132.5,129.9,129.0,128.7,128.5,128.1,128.0,126.5,124.9,120.0,119.2,114.4,95.0,55.8,54.2,26.6；IR(neat)(cm-1)3431w,1656w,1354m,1262s,1159s,1090w；HRMS(ESI):m/z calcd for C24H23N2O4S[M+H]+:435.1373；found 435.1372.
化合物3b：白色固体，93％产率，Rf＝0.41[石油醚/乙酸乙酯(4:1)]；mp＝152–153℃；1H NMR(400MHz,CDCl3)δ10.61(s,1H),7.72(dd,1H,J＝7.6,1.0Hz),7.65(d,1H,J＝7.8Hz),7.63-7.60(m,2H),7.44-7.41(m,2H),7.32-7.29(m,2H),7.27-7.20(m,3H),7.10(t,1H,J＝7.7Hz),5.95(d,1H,J＝2.4Hz),4.75(s,2H),2.66(s,3H)；13C NMR(100MHz,CDCl3)δ200.0,140.1,135.9,135.2,135.0,132.5,129.6,129.1,128.8,128.3,128.2,126.7,125.2,120.1,119.4,95.8,54.6,26.6,其中在128.2ppm处有一个碳信号重叠；IR(neat)(cm-1)3351w,1667w,1553w,1356s,1268m,1164s；HRMS(ESI):m/z calcd forC23H20ClN2O3S[M+H]+:439.0878；found 439.0876.
化合物3c：黄色固体，92％产率，Rf＝0.29[石油醚/乙酸乙酯(4:1)]；mp＝181–182℃；1H NMR(400MHz,CDCl3)δ10.58(s,1H),8.31-8.27(m,2H),7.86-7.83(m,2H),7.75(d,1H,J＝7.6Hz),7.67(d,1H,J＝7.8Hz),7.32-7.23(m,5H),7.14(t,1H,J＝7.7Hz),5.98(d,1H,J＝2.4Hz),4.80(s,2H),2.67(s,3H)；13C NMR(100MHz,CDCl3)δ200.1,150.5,143.2,134.8,134.2,132.6,129.0,128.9,128.4,128.3,128.1,126.9,125.6,124.4,120.2,119.7,96.6,55.2,26.6；IR(neat)(cm-1)3367w,1664w,1527s,1376m,1347s,1174s；HRMS(ESI):m/zcalcd for C23H20N3O5S[M+H]+:450.1118；found 450.1117.
化合物3d：白色固体，59％产率，Rf＝0.36[石油醚/乙酸乙酯(4:1)]；mp＝148–149℃；1H NMR(400MHz,CDCl3)δ10.98(s,1H),7.74(dd,1H,J＝7.7,1.0Hz),7.68(d,1H,J＝7.8Hz),7.52-7.48(m,2H),7.20(d,2H,J＝8.0Hz),7.14(t,1H,J＝7.7Hz),5.84(d,1H,J＝2.5Hz),3.21(s,3H),2.71(s,3H),2.37(s,3H)；13C NMR(100MHz,CDCl3)δ200.0,144.5,138.2,132.5,132.4,129.8,128.6,127.7,126.1,124.6,119.9,119.3,91.5,37.3,26.7,21.7；IR(neat)(cm-1)3326w,1655m,1547w,1355m,1343s,1277m；HRMS(ESI):m/z calcd forC18H19N2O3S[M+H]+:343.1111；found 343.1112.
化合物3e：黄色油状物，62％产率，Rf＝0.45[石油醚/乙酸乙酯(4:1)]；1H NMR(400MHz,CDCl3)δ10.66(s,1H),7.77(dd,1H,J＝7.6,1.0Hz),7.72(d,1H,J＝7.8Hz),7.54-7.51(m,2H),7.23(d,2H,J＝8.0Hz),7.15(t,1H,J＝7.7Hz),5.96(d,1H,J＝2.4Hz),3.54(t,2H,J＝7.2Hz),2.70(s,3H),2.40(s,3H),1.58-1.51(m,2H),1.41-1.32(m,2H),0.88(t,3H,J＝7.3Hz)；13C NMR(100MHz,CDCl3)δ200.0,144.1,135.8,134.4,132.5,129.7,128.5,127.7,126.5,125.0,120.1,119.3,95.1,50.6,30.2,26.7,21.7,19.9,13.7；IR(neat)(cm-1)3435w,2958w,1655m,1538s,1441w,1354s；HRMS(ESI):m/z calcd for C21H25N2O3S[M+H]+:385.1580；found 385.1581.
化合物3f：白色固体，93％产率，Rf＝0.47[石油醚/乙酸乙酯(4:1)]；mp＝90–91℃；1H NMR(400MHz,CDCl3)δ10.72(s,1H),7.73(d,1H,J＝7.4Hz),7.62-7.57(m,3H),7.33-7.31(m,2H),7.25-7.16(m,5H),7.07(t,1H,J＝7.7Hz),5.92(d,1H,J＝2.5Hz),4.73(s,2H),3.03(t,2H,J＝7.5Hz),2.40(s,3H),1.80-1.72(m,2H),1.48-1.39(m,2H),0.97(t,3H,J＝7.3Hz)；13C NMR(100MHz,CDCl3)δ202.3,144.4,135.6,134.5,132.7,129.9,128.7,128.5,128.1,128.0,127.7,126.3,124.1,119.7,119.2,95.1,54.3,38.1,26.9,22.7,21.8,14.2,其中在135.6ppm处有一个碳信号重叠；IR(neat)(cm-1)3438w,2957w,1658m,1540w,1353s,1161s；HRMS(ESI):m/z calcd for C27H29N2O3S[M+H]+:461.1893；found461.1886.
化合物3g：浅黄色固体，80％产率，Rf＝0.33[石油醚/乙酸乙酯(4:1)]；mp＝169–170℃；1H NMR(400MHz,CDCl3)δ10.59(s,1H),7.72(dd,J＝7.7,1.0Hz,1H),7.67(dt,J＝7.8,0.8Hz,1H),7.60-7.57(m,2H),7.33-7.30(m,2H),7.28-7.18(m,5H),7.10(t,J＝7.8Hz,1H),5.94(d,J＝2.4Hz,1H),4.74(s,2H),4.53(s,2H),2.42(s,3H)；13C NMR(100MHz,CDCl3)δ192.5,144.5,136.0,135.5,134.4,133.0,130.0,128.82,128.76,128.1,127.7,127.6,124.8,119.4,116.8,95.3,54.2,30.8,21.8,其中在128.1ppm处有一个碳信号重叠；IR(neat)(cm-1)3429w,1645w,1533m,1352s,1278s,1159s；HRMS(ESI):m/z calcd forC24H22BrN2O3S[M+H]+:497.0529,found 497.0520.
化合物3h：黄色固体，94％产率，Rf＝0.48[石油醚/乙酸乙酯(4:1)]；mp＝114–115℃；1H NMR(400MHz,CDCl3)δ10.59(s,1H),7.76-7.73(m,3H),7.60-7.55(m,2H),7.52-7.47(m,2H),7.42-7.39(m,2H),7.34-7.26(m,3H),7.12(t,1H,J＝7.7Hz),6.33(d,1H,J＝2.4Hz),4.95(s,2H),3.01(s,3H)；13C NMR(100MHz,CDCl3)δ197.6,138.9,135.7,135.5,133.7,131.7,129.6,128.9,128.6,128.4,128.34,128.32,128.2,126.5,119.4,119.3,95.4,54.5,38.2；IR(neat)(cm-1)3414w,1618w,1589w,1539s,1441w,1354s；HRMS(ESI):m/zcalcd for C23H21N2O3S[M+H]+:405.1267；found 405.1268.
化合物3i：白色固体，82％产率，Rf＝0.47[石油醚/乙酸乙酯(4:1)]；mp＝124–125℃；1H NMR(400MHz,CDCl3)δ10.68(s,1H),7.73(d,1H,J＝7.1Hz),7.63(d,1H,J＝7.8Hz),7.60-7.56(m,2H),7.33-7.29(m,2H),7.25-7.16(m,5H),7.08(t,1H,J＝7.7Hz),6.18-6.07(m,1H),5.92(d,1H,J＝2.4Hz),5.26-5.21(m,2H),4.73(s,2H),3.83(dt,2H,J＝6.8,1.5Hz),2.40(s,3H)；13C NMR(100MHz,CDCl3)δ199.6,144.4,135.7,135.6,134.4,132.7,131.4,129.9,128.7,128.6,128.05,127.97,127.7,126.6,124.3,119.23,119.19,118.9,95.1,54.2,43.3,21.8；IR(neat)(cm-1)3428w,1653w,1537w,1353m,1159m,1087w；HRMS(ESI):m/z calcd for C26H25N2O3S[M+H]+:445.1580；found 445.1570.
化合物3j：白色固体，80％产率，Rf＝0.45[石油醚/乙酸乙酯(4:1)]；mp＝110–111℃；1H NMR(400MHz,CDCl3)δ10.83(s,1H),7.73(d,1H,J＝7.6Hz),7.61-7.58(m,3H),7.34-7.32(m,2H),7.26-7.16(m,5H),7.07(t,1H,J＝7.7Hz),6.88(s,1H),5.93(d,1H,J＝2.5Hz),4.74(s,2H),2.41(s,3H),2.24(s,3H),2.03(s,3H)；13C NMR(100MHz,CDCl3)δ192.5,155.6,144.3,135.7,135.4,134.5,133.2,129.9,128.7,128.5,128.1,128.0,127.8,125.9,123.9,121.5,120.8,119.1,95.4,54.3,28.2,21.8,21.3；IR(neat)(cm-1)3433w,1536w,1353s,1264s,1159s,1086m；HRMS(ESI):m/z calcd for C27H27N2O3S[M+H]+:459.1737；found 459.1725.
化合物3k：黄色固体，73％产率，Rf＝0.36[石油醚/乙酸乙酯(4:1)]；mp＝157–158℃；1H NMR(400MHz,CDCl3)δ10.94(s,1H),7.92-7.87(m,2H),7.76(d,1H,J＝15.6Hz),7.70-7.65(m,3H),7.63-7.59(m,2H),7.46-7.39(m,3H),7.36-7.34(m,2H),7.27-7.17(m,5H),7.14(t,1H,J＝7.7Hz),5.95(d,1H,J＝2.5Hz),4.77(s,2H),2.41(s,3H)；13C NMR(100MHz,CDCl3)δ190.2,144.4,143.9,135.8,135.6,135.2,134.6,133.3,130.6,129.9,129.1,128.73,128.66,128.6,128.1,128.0,127.8,126.6,124.0,121.2,120.5,119.3,95.1,54.2,21.8；IR(neat)(cm-1)3424w,1644w,1589w,1529m,1357s,1294m；HRMS(ESI):m/zcalcd for C31H27N2O3S[M+H]+:507.1737；found 507.1741.
化合物3l：黄色固体，77％产率，Rf＝0.57[石油醚/乙酸乙酯(4:1)]；mp＝75–76℃；1H NMR(400MHz,CDCl3)δ10.62(s,1H),7.72-7.67(m,2H),7.59-7.56(m,2H),7.34-7.31(m,2H),7.26-7.17(m,5H),7.08(t,1H,J＝7.7Hz),5.94(d,1H,J＝2.4Hz),4.74(s,2H),2.90(t,2H,J＝7.4Hz),2.40(s,3H),1.75-1.67(m,2H),1.42-1.29(m,6H),0.89(t,3H,J＝6.9Hz)；13C NMR(100MHz,CDCl3)δ203.5,193.8,144.6,136.0,135.4,134.2,133.1,129.9,128.7,128.6,128.2,128.0,127.7,127.4,119.6,114.9,95.1,54.1,39.0,31.7,29.0,23.0,22.6,21.7,14.2,其中在128.0ppm处有一个碳信号重叠；IR(neat)(cm-1)3420w,1639m,1540s,1446w,1356s,1161s；HRMS(ESI):m/z calcd for C30H33N2O4S[M+H]+:517.2156；found 517.2158.
化合物3m：黄色固体，54％产率，Rf＝0.28[石油醚/乙酸乙酯(4:1)]；mp＝115–116℃；1H NMR(400MHz,CDCl3)δ10.52(s,1H),7.79(dd,1H,J＝7.7,1.0Hz),7.72(d,1H,J＝7.8Hz),7.61-7.57(m,2H),7.34-7.31(m,2H),7.28-7.19(m,5H),7.13(t,1H,J＝7.8Hz),5.96(d,1H,J＝2.4Hz),4.75(s,2H),4.00(s,3H),2.42(s,3H)；13C NMR(100MHz,CDCl3)δ186.7,163.9,144.6,136.1,135.4,134.3,133.0,130.0,128.8,128.7,128.6,128.13,128.08,127.7,127.4,119.7,115.6,95.5,54.2,53.0,21.8；IR(neat)(cm-1)3425w,1736m,1541m,1448w,1354s,1231s；HRMS(ESI):m/z calcd for C25H23N2O5S[M+H]+:463.1322；found 463.1310.
3.2 2-氨基吲哚类化合物3n-3q的合成
以化合物3n具体合成步骤为例，氮气保护下，向干燥的反应管中依次加入炔酰胺2”a(39.1mg,0.2mmol)、氨茴内酐1a(39.9mg,0.30mmol)和二氯甲烷(2.0mL)，然后把反应管放入0℃的低温反应冷阱中，滴入三氟甲磺酸三甲基硅酯(18.1μL,0.10mmol)，封闭反应管，0℃下搅拌4.0h；薄层色谱法监测反应进程，待反应完成后，加Et3N(13.9μL,0.10mmol)淬灭，减压蒸馏除去溶剂，所得粗产物以石油醚/乙酸乙酯(8:1～2:1)为洗脱剂，经硅胶柱层析分离得到2-氨基吲哚化合物3n(52.2mg,0.16mmol)，产率为79％。
将实施例1中制备得到的氨茴内酐1g、1h和1i与实施例2中制备得到的炔酰胺2'a分别按本实施例中上述方法在对应的反应温度下制备化合物3，对应得到2-氨基吲哚类化合物3o(–50℃)、3p(–20℃)和3q(–20℃)。
化合物3n：黄色固体，79％产率，Rf＝0.41[石油醚/乙酸乙酯(2:1)]；mp＝84–85℃；1H NMR(400MHz,CDCl3)δ10.60(s,1H),7.79-7.75(m,2H),7.16(t,1H,J＝7.7Hz),4.60-4.56(m,2H),4.15-4.11(m,2H),2.73(t,2H,J＝7.8Hz),2.68(s,3H),1.67-1.60(m,2H),1.43-1.25(m,6H),0.88(t,3H,J＝7.0Hz)；13C NMR(100MHz,CDCl3)δ200.2,156.5,132.3,129.2,129.0,125.3,120.0,118.9,108.4,62.8,47.3,31.9,31.1,29.6,26.7,23.9,22.8,14.3,其中在125.3ppm处有一个碳信号重叠；IR(neat)(cm-1)3388w,2926w,1736s,1655s,1467s,1240s；HRMS(ESI):m/z calcd for C19H25N2O3[M+H]+:329.1860；found 329.1859.
化合物3o：白色固体，82％产率，Rf＝0.40[石油醚/乙酸乙酯(4:1)]；mp＝151–152℃；1H NMR(400MHz,CDCl3)δ9.65(s,1H),7.70(dd,J＝21.9,1.8Hz,2H),7.59-7.56(m,2H),7.23(d,J＝7.9Hz,2H),7.15-7.09(m,5H),4.65(s,2H),2.54(s,3H),2.39(s,3H),1.58(s,3H)；13C NMR(100MHz,CDCl3)δ199.0,144.4,136.3,135.6,131.2,131.0,130.6,130.1,128.9,128.7,128.3,128.0,127.6,121.0,111.2,109.7,55.0,26.7,21.8,7.9,其中在128.3ppm处有一个碳信号重叠；IR(neat)(cm-1)3337w,2330w,1674m,1355s,1243m,1163s；HRMS(ESI):m/z calcd for C25H24BrN2O3S[M+H]+:511.0686,found 511.0687.
化合物3p：白色固体，60％产率，Rf＝0.35[石油醚/乙酸乙酯(4:1)]；mp＝197–198℃；1H NMR(400MHz,CDCl3)δ9.96(s,1H),7.69-7.66(m,2H),7.51(d,1H,J＝8.1Hz),7.32(d,2H,J＝8.0Hz),7.25-7.18(m,6H),4.72(s,2H),2.60(s,3H),2.47(s,3H),1.97(s,3H)；13CNMR(100MHz,CDCl3)δ199.5,144.4,136.5,135.6,133.7,131.2,130.1,128.9,128.7,128.3,127.7,126.9,126.4,123.4,122.6,118.9,111.8,55.2,26.7,21.8,10.4；IR(neat)(cm-1)3362m,2922w,1664s,1560m,1347s,1180s；HRMS(ESI):m/z calcd for C25H24BrN2O3S[M+H]+:511.0686；found 511.0673.
化合物3q：黄色固体，91％产率，Rf＝0.58[石油醚/乙酸乙酯(2:1)]；mp＝200–201℃；1H NMR(400MHz,CDCl3)δ9.90(s,1H),7.70-7.66(m,2H),7.32(d,2H,J＝8.0Hz),7.27(s,1H),7.22(s,5H),6.04(s,2H),4.70(s,2H),2.53(s,3H),2.46(s,3H),1.81(s,3H)；13C NMR(100MHz,CDCl3)δ197.5,145.2,144.3,139.8,136.4,135.7,133.0,130.4,130.1,128.9,128.7,128.2,127.7,113.2,112.4,108.0,107.4,102.0,54.9,26.5,21.8,9.2；IR(neat)(cm-1)3362w,1661w,1562w,1408m,1348s,1228s；HRMS(ESI):m/z calcd for C26H25N2O5S[M+H]+:477.1479；found 477.1478.
实施例4：本发明实施例3所合成的代表性化合物的抗肿瘤活性研究
化合物3a-3q抗肿瘤活性研究所用的细胞株、细胞培养试剂、实验仪器及来源见表1、表2和表3。
表1细胞株种类及来源
表2细胞培养试剂及生产厂家
表3实验仪器及生产厂家
化合物3a-3q的抗癌细胞活性及细胞毒性检测
取对数生长期的癌细胞计数，配制成浓度为5×104个/mL细胞悬液，震荡混匀后接种于96孔板，每孔加入细胞悬液100μL，37℃、体积百分比5％CO2培养条件下培养4-8h；用新鲜的培养基配置含不同浓度化合物的培养液培养48h；48h后，甩掉96孔板孔内培养液，每孔加入10％CCK8溶液100μL，继续培养1-4h，然后在450nm波长下检测吸光度。抑制率＝[(Ac-As)/(Ac-Ab)]×100％；As:实验孔吸光度(含细胞、培养基、CCK-8溶液，化合物培养液处理组)；Ac：对照孔吸光度(含细胞、培养基、CCK-8溶液，不含化合物培养液处理组)；Ab：空白孔吸光度(含培养基和CCK-8溶液，不含细胞和化合物)。使用GraphPad Prism 9.0计算化合物的IC50。
表4化合物3a-3q对Hep G2、A549及MCF-7的抑制活性
首先测试化合物3a-3q对3种癌细胞Hep G2、A549及MCF-7的抑制活性并计算出IC50(表4)。由表4知，化合物3c、3g和3o对癌细胞的抑制活性最强。在此初筛结果的基础上，扩大了细胞株的种类(含11种癌细胞和1种正常细胞)，以VCR(长春新碱)为阳性对照药，对化合物3c、3g和3o抑制人膀胱癌细胞5637、人胶质母细胞瘤细胞A172、人恶性黑色素瘤细胞A375、人子宫颈癌细胞C33A、人结肠癌细胞HCT 116和SW480、人宫颈癌细胞Hela、人胰腺癌细胞CFPAC-1、人肝癌细胞Hep G2、人肺癌细胞A549和人乳腺癌细胞MCF-7的活性，以及对正常细胞293T(肾上皮细胞)细胞毒性进行了检测，结果如下表5.1和表5.2。
表5.1化合物3c、3g和3o对5637、A172、A375、C33A、HCT 116及Hela的抑制活性
表5.2 3c、3g和3o对CFPAC-1、SW480、Hep G2、A549、MCF-7及293T的抑制活性
本试验采用本领域技术人员熟知的方法进行，利用12种细胞株(含11种癌细胞和1种正常细胞)评价本发明所合成的化合物3a-3q的抗肿瘤活性和安全性。实验结果表明：2-氨基吲哚类化合物3c对人肝癌细胞Hep G2、人肺癌细胞A549和人乳腺癌细胞MCF-7均具有很好的抑制活性，及对正常细胞293T(肾上皮细胞)低的细胞毒性；3g对所测的几乎所有的细胞株(人膀胱癌细胞5637、人胶质母细胞瘤细胞A172、人恶性黑色素瘤细胞A375、人子宫颈癌细胞C33A、人结肠癌细胞HCT 116和SW480、人宫颈癌细胞Hela、人胰腺癌细胞CFPAC-1、人肝癌细胞Hep G2、人肺癌细胞A549和人乳腺癌细胞MCF-7)均具有很好的抑制活性，但对正常细胞293T(肾上皮细胞)细胞毒性稍强；3o对人膀胱癌细胞5637和人乳腺癌细胞MCF-7具有很好的抑制活性，及对正常细胞293T(肾上皮细胞)低的细胞毒性。本发明在抗肿瘤药物的制备与研究中具有很好的应用前景。
Claims (3)
1.结构式如下的2-氨基吲哚类化合物在制备抗肿瘤药物中的应用：
2.如权利要求1所述2-氨基吲哚类化合物在制备抗肿瘤药物中的应用，其特征在于，所述肿瘤为膀胱癌、胶质母细胞瘤、恶性黑色素瘤、子宫颈癌、结肠癌、宫颈癌、胰腺癌、肝癌、肺癌或乳腺癌。
3.结构式如下的2-氨基吲哚类化合物在制备抗肝癌、肺癌或乳腺癌药物中的应用，
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210164465.5A CN115054599B (zh) | 2022-02-23 | 2022-02-23 | 2-氨基吲哚类化合物在抗肿瘤药物中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210164465.5A CN115054599B (zh) | 2022-02-23 | 2022-02-23 | 2-氨基吲哚类化合物在抗肿瘤药物中的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115054599A CN115054599A (zh) | 2022-09-16 |
| CN115054599B true CN115054599B (zh) | 2023-05-16 |
Family
ID=83196514
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210164465.5A Active CN115054599B (zh) | 2022-02-23 | 2022-02-23 | 2-氨基吲哚类化合物在抗肿瘤药物中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115054599B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117567349A (zh) * | 2023-12-07 | 2024-02-20 | 长春工业大学 | 新型含有吲哚结构药物小分子的设计合成及抗肿瘤活性研究 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000239252A (ja) * | 1999-02-16 | 2000-09-05 | Mitsubishi Chemicals Corp | インドール誘導体 |
| CN103554008A (zh) * | 2013-11-04 | 2014-02-05 | 天津科技大学 | 1,3-取代-5-乙酰氨基吲哚酮类化合物及其在抗肿瘤药物中的应用 |
| AU2015202828A1 (en) * | 2010-08-24 | 2015-06-11 | Oncternal Therapeutics, Inc. | Compounds for treatment of cancer |
| CN113845461A (zh) * | 2021-10-11 | 2021-12-28 | 浙江师范大学行知学院 | 一种4-(2-金刚烷-1h-吲哚-5-基)氨基脲衍生物及其制备方法和用途 |
-
2022
- 2022-02-23 CN CN202210164465.5A patent/CN115054599B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000239252A (ja) * | 1999-02-16 | 2000-09-05 | Mitsubishi Chemicals Corp | インドール誘導体 |
| AU2015202828A1 (en) * | 2010-08-24 | 2015-06-11 | Oncternal Therapeutics, Inc. | Compounds for treatment of cancer |
| CN103554008A (zh) * | 2013-11-04 | 2014-02-05 | 天津科技大学 | 1,3-取代-5-乙酰氨基吲哚酮类化合物及其在抗肿瘤药物中的应用 |
| CN113845461A (zh) * | 2021-10-11 | 2021-12-28 | 浙江师范大学行知学院 | 一种4-(2-金刚烷-1h-吲哚-5-基)氨基脲衍生物及其制备方法和用途 |
Non-Patent Citations (3)
| Title |
|---|
| Template-free, controllable and scalable synthesis of poly(5-aminoindole) nanoparticles for printable electrochemical immunosensor with ultra-high sensitivity;Taotao Yang et al.，;《J. Mater. Chem. B》;第10卷;第78-86页 * |
| 含吲哚环2,4-二氨基嘧啶类化合物的合成及抗肿瘤活性;黎秋;汪雨;胡孟金;陈鹏;游文玮;赵培亮;;有机化学(第04期);第967-974页 * |
| 新型 3，5-二取代 1H-吲哚衍生物的合成及抗肿瘤活性研究;刘斯宇等;《化学通报》;第81卷(第5期);第456-460页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115054599A (zh) | 2022-09-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109180653B (zh) | 一种铜催化制备苯并呋喃-吡咯类化合物的方法 | |
| CN112174989B (zh) | 一种克立硼罗的制备方法 | |
| CN111116676B (zh) | 一种具有蝶烯结构的n-杂环卡宾钯配合物及其应用 | |
| Kemp et al. | Peptide synthesis by prior thiol capture. 2. Design of templates for intramolecular O, N-acyl transfer. 4, 6-Disubstituted dibenzofurans as optimal spacing elements | |
| CN115054599B (zh) | 2-氨基吲哚类化合物在抗肿瘤药物中的应用 | |
| CN112239424B (zh) | 一种马兜铃生物碱及其中间体的制备方法 | |
| CN114591194B (zh) | 一种对位官能团化芳胺化合物及其合成方法 | |
| CN109438317B (zh) | 一种氮-烷基（氘代烷基）芳杂环和烷基（氘代烷基）芳基醚类化合物的制备方法 | |
| CN113416162B (zh) | 一种双手性联萘o-n-n三齿配体及其制备方法 | |
| CN114436918B (zh) | 环丁-1-烯胺类化合物及其制备方法和在药物中的应用 | |
| TWI642658B (zh) | 茚並異喹啉衍生物的製備方法 | |
| CN110305122A (zh) | 一种吡啶环C4位磺酰基、磷氧基官能团化的Pybox配体及其合成方法和应用 | |
| CN113912609B (zh) | 一种天然生物碱色胺酮及其衍生物的制备方法 | |
| CN113387886B (zh) | 一种2-胺基二苯并[c,e]吖庚因化合物及其合成方法 | |
| CN111978322B (zh) | 一种四氢异喹啉并环化合物和四氢-β-咔啉并环化合物的合成方法 | |
| CN110240572B (zh) | 一种反式-1,1-环丙烷二羧酸酯的合成方法 | |
| CN103694182A (zh) | 一种喹喔啉类化合物的制备方法 | |
| CN115057816B (zh) | 4-氨基喹啉类化合物及其制备方法和在抗肿瘤药物中的应用 | |
| CN110437227A (zh) | 一种具有多环桥环骨架的多取代四氢异喹啉及其制备方法 | |
| CN102010348A (zh) | 水杨酰胺酯类衍生物、制备方法及其应用 | |
| CN111808121A (zh) | 一类含杂原子的新型高b环小檗碱类似物及其c-h活化合成方法 | |
| CN104860881A (zh) | 8-(硝基甲基)喹啉类化合物和8-甲氨基四氢喹啉类化合物的合成方法 | |
| KR102451135B1 (ko) | 오르쏘-카보레인-융합 피라졸 화합물 및 이의 제조방법 | |
| CN118047710A (zh) | N-取代马来酰亚胺类化合物及其制备方法和在抗肿瘤药物中的应用 | |
| CN113200980B (zh) | 一种银催化合成中氮茚类化合物的方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |