CN116253732B - Beta-carboline derivative of N-N bridged isatin unit, and preparation method and application thereof - Google Patents
Beta-carboline derivative of N-N bridged isatin unit, and preparation method and application thereof Download PDFInfo
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- CN116253732B CN116253732B CN202310228794.6A CN202310228794A CN116253732B CN 116253732 B CN116253732 B CN 116253732B CN 202310228794 A CN202310228794 A CN 202310228794A CN 116253732 B CN116253732 B CN 116253732B
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- beta
- carbolin
- hydrazino
- indol
- methylene
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- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 title claims abstract description 50
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical group C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 7
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 7
- -1 3- (((E) - (beta-carbolin-3-yl) methylene) hydrazino) indol-2-one Chemical compound 0.000 claims description 99
- 239000007787 solid Substances 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- 238000000034 method Methods 0.000 claims description 34
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 239000012074 organic phase Substances 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 11
- 230000001105 regulatory effect Effects 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 8
- 238000000967 suction filtration Methods 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000011449 brick Substances 0.000 claims description 6
- 239000013067 intermediate product Substances 0.000 claims description 6
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 5
- 238000011010 flushing procedure Methods 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 claims description 4
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 238000001308 synthesis method Methods 0.000 claims description 4
- 229960004799 tryptophan Drugs 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 230000003009 desulfurizing effect Effects 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- QWLRZEUMTZEVAE-UHFFFAOYSA-N C(C)O.N1C(=O)C(=O)C2=CC=CC=C12 Chemical compound C(C)O.N1C(=O)C(=O)C2=CC=CC=C12 QWLRZEUMTZEVAE-UHFFFAOYSA-N 0.000 claims description 2
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 2
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 claims 1
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 claims 1
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 11
- 239000000047 product Substances 0.000 description 31
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 11
- 238000004809 thin layer chromatography Methods 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 8
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000005918 in vitro anti-tumor Effects 0.000 description 3
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 3
- 238000005057 refrigeration Methods 0.000 description 3
- 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 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 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 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 235000005811 Viola adunca Nutrition 0.000 description 1
- 240000009038 Viola odorata Species 0.000 description 1
- 235000013487 Viola odorata Nutrition 0.000 description 1
- 235000002254 Viola papilionacea Nutrition 0.000 description 1
- 238000002835 absorbance 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
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000005625 indol-2-ones Chemical class 0.000 description 1
- 229930005303 indole alkaloid Natural products 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 210000003470 mitochondria Anatomy 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
- 239000002547 new drug Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- IFGCUJZIWBUILZ-UHFFFAOYSA-N sodium 2-[[2-[[hydroxy-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyphosphoryl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid Chemical compound [Na+].C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O IFGCUJZIWBUILZ-UHFFFAOYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a beta-carboline derivative of an N-N bridged isatin unit, and a preparation method and application thereof. The invention discloses a novel compound, namely a beta-carboline derivative of an N-N bridged isatin unit, a preparation method of the beta-carboline derivative of the N-N bridged isatin unit and application of the beta-carboline derivative in preparation of antitumor drugs. The beta-carboline derivative of the N-N bridged isatin unit is a novel compound, is obtained by connecting beta-carboline and isatin derivative, has better anti-tumor activity, and can be applied to anti-tumor drugs.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a beta-carboline derivative of an N-N bridged isatin unit, and a preparation method and application thereof.
Background
Beta-carboline derivatives are a large class of natural and synthetic indole alkaloids with a broad range of biochemical and pharmacological properties, such as anxiolytic, antidepressant, sedative, analgesic, antitumor, antimalarial etc. In recent years, the prior art has studied in vitro and in vivo preparation of β -carboline derivatives having different substituents at positions 1, 2, 3, 7 and 9 of β -carboline and their antitumor activity, and the structure-activity relationship indicates: (1) The antitumor activity of the beta-carboline moiety is very important in drug design; (2) The introduction of suitable substituents at the 1, 3 and 9 positions (as shown below) of the beta-carboline may further enhance their antitumor efficacy.
Heterocyclic compounds are a common and important class of organic compounds having excellent biological and pharmacological properties. Among many nitrogen-containing heterocyclic compounds, isatin is a special structure with wide biological activity, and isatin and its derivatives are widely applied to dye, pesticide, medicine and other fields, especially in bioactive molecules, and have biological activities such as anti-tumor, antibiotic, antidepressant and the like.
In view of the above, the invention provides a novel beta-carboline derivative of a beta-carboline derivative N-N bridged isatin unit, which has important significance for synthesizing and discovering anti-tumor drugs.
Disclosure of Invention
The invention aims to provide a beta-carboline derivative of an N-N bridged isatin unit, which is a beta-carboline derivative with a novel structure and has important significance for synthesizing and discovering anti-tumor drugs.
In order to achieve the above purpose, the technical scheme adopted is as follows:
a β -carboline derivative of an N-N bridged isatin unit, said β -carboline derivative having the chemical structural formula:
further, in the chemical structural general formula of the beta-carboline derivative, R 1 Is one of hydrogen, methyl, isopropyl, 2-chlorophenyl and 2-thienyl;
R 9 is one of hydrogen, methyl, ethyl, n-butyl, isobutyl, benzyl, 4-fluorobenzyl, 3-chlorobenzyl and 3-phenylpropyl.
Still further, the β -carboline derivative is any one of the following compounds:
3- (((E) - (beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-ethyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-butyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-isobutyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-benzyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9- (4-fluorobenzyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9- (3-chlorobenzyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9- (3-phenylpropyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (1, 9-dimethyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-ethyl-1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-butyl-1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-benzyl-1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9- (4-fluorobenzyl) -1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9- (3-chlorobenzyl) -1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (1-methyl-9- (3-phenylpropyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-butyl-1-isopropyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-benzyl-1-isopropyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (1- (2-chlorophenyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-benzyl-1- (2-chlorophenyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (1- (2-chlorophenyl) -9- (4-fluorobenzyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (1- (2-thienyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-benzyl-1- (2-thienyl) - β -carbolin-3-yl) methylene) hydrazino) indol-2-one.
The invention also aims to provide a preparation method of the beta-carboline derivative, which is characterized in that the beta-carboline is connected with the isatin derivative through nucleophilic addition-condensation reaction, so as to obtain a series of beta-carboline derivatives with novel structures. The preparation method has better yield.
In order to achieve the above purpose, the technical scheme adopted is as follows:
the chemical reaction formula of the preparation method of the beta-carboline derivative is as follows:
further, the method specifically comprises the following steps:
(1) Adding NH to isatin ethanol solution 2 NH 2 ·H 2 O and reacting, cooling to room temperature after the reaction is finished, and refrigerating and suction filtering to obtain an intermediate product Y1;
(2) Dissolving the intermediate product Y1 and the corresponding 1-substituted-9-substituted-3-formyl-beta-carboline in ethanol, heating and refluxing for 1h at 95 ℃, adding glacial acetic acid, continuously heating and refluxing until the reaction is complete, generating orange-yellow solid, cooling to room temperature, refrigerating and suction filtering to obtain the beta-carboline derivative.
Still further, in the step (1), isatin and NH 2 NH 2 ·H 2 The molar ratio of O is 1:1;
in the step (2), the molar ratio of the intermediate product Y1 to the corresponding 1-substituted-9-substituted-3-formyl-beta-carboline is 1:1.
Still further, in the step (2), the chemical reaction formula of the synthesis method of the 1-substituted-9-substituted-3-formyl-beta-carboline is as follows:
still further, in the step (2), the synthesis method of the 1-substituted-9-substituted-3-formyl-beta-carboline specifically comprises the following steps:
a: dissolving L-tryptophan and NaOH in water, adding 40% HCHO solution, stirring at room temperature for reaction for 3.5h, heating and refluxing at 120 ℃, cooling, regulating pH, refrigerating, filtering, washing with water and acetone to obtain an intermediate 1;
b: dissolving the intermediate 1 in absolute ethanol, adding SOCl 2 Heating and refluxing until the reaction is complete, cooling to room temperature, and concentrating under reduced pressure to obtain a brick red solid; dissolving the brick red solid in water, and using NaHCO 3 After adjusting the pH, extracting an organic phase with ethyl acetate, washing with saturated brine, and concentrating under reduced pressure to obtain an intermediate 2 of a white solid;
c: dissolving the intermediate 2 in dimethylbenzene, and slowly adding S 8 Heating and refluxing at 150 ℃ until the reaction is complete, cooling to room temperature, refrigerating, filtering, flushing with dimethylbenzene and petroleum ether, decoloring and desulfurizing to obtain an intermediate 3 of a white solid;
d: dissolving the intermediate 3 in DMF, slowly adding 60% NaH, stirring, and slowly dripping CH 3 I, after stirring and reacting to be complete, pouring the mixture into ice water to quench NaH, extracting an organic phase by using ethyl acetate, washing the organic phase by using saturated NaCl, and adding absolute ethyl alcohol with the volume of 1/2 of the organic phase; regulating pH 3 with HCl, concentrating under reduced pressure to obtain pale yellow solid, recrystallizing, dissolving in water, and adding NaHCO 3 Adjusting pH 9, extracting with ethyl acetate, and concentrating under reduced pressure to obtain intermediate 4 of pale yellow pure product;
e: dissolving the intermediate 4 in THF solvent, slowly adding LiBH 4 After the reaction is stirred to be complete, cooling, regulating the pH to 3 by using HCl, stirring for 4 hours at room temperature, regulating the pH to 9 by using NaOH, extracting by using ethyl acetate, concentrating under reduced pressure, recrystallizing by using acetone, and carrying out suction filtration to obtain an intermediate 5 of a white solid;
f: dissolving the intermediate 5 in acetonitrile, slowly adding MnO 2 Heating and refluxing at 90 ℃ until the reaction is complete, passing through a thin layer chromatography silica gel short column, flushing the column with ethyl acetate, concentrating under reduced pressure, recrystallizing with acetone, and filtering to obtain white solid 1-substituted-9-substituted-3-formyl-beta-carboline.
Still further, in the step a, the molar ratio of L-tryptophan, naOH and HCHO is 1:1:1;
in the step d, the molar ratio of the intermediate 3 to the NaH is 1:3;
in the step e, the intermediate 4 and LiBH 4 The molar ratio of (2) is 1:3;
in the step f, the intermediate 5, mnO 2 The molar ratio of (2) is 1:3.
The invention also aims to provide the application of the beta-carboline derivative in preparing antitumor drugs.
Compared with the prior art, the invention has the beneficial effects that:
the invention makes the 1, 9-position of the beta-carboline ring have substituent groups at the same time by modifying the structure and effect relationship by referring to the structural characteristics of the beta-carboline ring containing pyridine ring. Specifically, the beta-carboline is connected with the isatin derivative through nucleophilic addition-condensation reaction, so that a series of beta-carboline derivatives with novel structures are obtained, and the beta-carboline derivatives have better anti-tumor activity, can be applied to anti-tumor medicines, and have important significance for synthesis and discovery of the anti-tumor medicines.
Detailed Description
In order to further illustrate the beta-carboline derivative of the N-N bridged isatin unit, the preparation method and the application thereof, the expected purpose of the invention is achieved, and the following is a detailed description of the specific implementation, the structure, the characteristics and the efficacy of the beta-carboline derivative of the N-N bridged isatin unit, the preparation method and the application thereof according to the preferred embodiment. In the following description, different "an embodiment" or "an embodiment" do not necessarily refer to the same embodiment. Furthermore, the particular features, structures, or characteristics of one or more embodiments may be combined in any suitable manner.
The following will further describe in detail the preparation method and application of the β -carboline derivative of the N-N bridged isatin unit according to the present invention by combining specific examples:
example 1.
An intermediate: the synthesis of 1-substituted-9-substituted-3-formyl-beta-carboline adopts the following reaction:
synthesis of Compounds 1a-1 f: taking 1a as an example, L-tryptophan (51.05 g,250 mmol) and NaOH (10 g,250 mmol) were weighed into a 1000mL round bottom flask and solvent H was added 2 O (500 mL), stirring thoroughly and dissolving uniformly to obtain orange red solution, then adding 40% HCHO solution (19 mL,250 mmol) into the orange red solution, stirring at room temperature for 3.5h, gradually deepening the color of the solution, and refluxing at 120 ℃ for 2.5h; TLC monitoring reaction progress; after the reaction was completed, the reaction solution was cooled to room temperature and poured into ice water (400 mL), pH 6 was adjusted with HCl, light yellow solid appeared, cold storage was performed overnight, more solid was precipitated, suction filtration was performed, filter cake was washed with water and acetone, and yellow solid was product 2a, yield: 97.11%.
Synthesis of Compounds 2a-2 f: taking 2a as an example, compound 1a (43.25 g,200 mmol) and absolute ethyl alcohol (600 mL) were weighed into a 1000mL three-necked flask, and stirred sufficiently to dissolve uniformly to obtain a yellow solution, followed by slowly dropping SOCl into the reaction solution 2 (40 mL) the solution gradually changed to brick red, and the solution was heated and refluxed for 5h; TLC monitoring reaction progress; after the reaction is completed, the reaction solution is cooled to room temperature, and is decompressed and concentrated to obtain a brick red solid which is dissolved in water and then is treated by NaHCO 3 Adjusting pH 9, extracting with ethyl acetate, washing the organic phase with saturated NaCl, and concentrating the organic phase under reduced pressure to obtain white solid, namely the product 2a, yield: 94.09%.
Synthesis of Compounds 3a-3 f: taking 3a as an example, compound 2a (24.4 g,100 mol) was weighed into a 500mL round bottom flask and dissolved by the addition of the solvent xylene followed by slow addition of S 8 (16 g,500 mmol) was refluxed at 150℃for 7h. (this reaction has H 2 S gas generation, requiring an exhaust treatment device); TLC monitoring reaction progress; after the reaction is completed, cooling the reaction liquid to room temperature, putting the reaction liquid into a refrigerator for refrigeration overnight, carrying out suction filtration on the reaction liquid the next day, flushing a filter cake with a small amount of dimethylbenzene, and washing the filter cake with petroleum ether to obtain a light red crude product; decolorizing and desulfurizing the crude product to obtain white solidProduct 3a, yield: 96%.
Synthesis of Compounds 4a '-3 t': taking 4b' as an example, weighing compound 3a (2.4 g,10 mmol) and putting into a 250mL eggplant-shaped bottle, adding solvent DMF to dissolve completely, then slowly adding 60% NaH (1.2 g,30 mmol), stirring for 5min, and slowly dripping CH 3 I (1.28 mL), thoroughly stirred; TLC monitoring reaction progress; after the reaction is completed, the reaction solution is poured into ice water to quench NaH, then extracted by ethyl acetate, then the organic phase is washed by saturated NaCl, the organic phase is combined, absolute ethanol with the volume of 1/2 of the organic phase is added, the pH 3 is regulated by HCl, the mixture is concentrated under reduced pressure to obtain pale yellow solid, acetone is used for recrystallization, a filter cake is obtained by suction filtration, the filter cake is dissolved by water, and NaHCO is used for preparing the mixture 3 Adjusting pH 9, extracting with ethyl acetate, and concentrating under reduced pressure to obtain pale yellow pure product 4b', yield: 92.5%.
Synthesis of compounds 5a '-5 t': taking 5b 'as an example, compound 4b' (3.48 g,10 mmol) was weighed into a 250mL eggplant-shaped bottle, added with solvent THF to dissolve completely, and then LiBH was slowly added 4 (0.65 g,30 mmol), stirred at room temperature for 10h; TLC monitoring reaction progress; after the reaction is completed, pouring the reaction solution into ice water, regulating the pH value to 3 by using HCl, stirring for 4 hours at room temperature, then regulating the pH value to 9 by using NaOH, extracting by using ethyl acetate, concentrating under reduced pressure, recrystallizing by using acetone, and carrying out suction filtration to obtain a white solid, namely a pure product 5b', wherein the yield is: 91.2%.
Synthesis of compounds 6a '-6 t': taking 6b 'as an example, compound 5b' (1.53 g,5 mmol) was weighed into a 250mL eggplant-shaped bottle, added with solvent acetonitrile to dissolve completely, and then added with MnO slowly 2 (1.31 g,15 mmol), heated at 90℃under reflux for 2h; TLC monitoring reaction progress; after the reaction is completed, passing through a thin layer chromatography silica gel short column while the reaction is hot, flushing the column with ethyl acetate, concentrating under reduced pressure, recrystallizing with acetone, and filtering to obtain white solid, namely pure product 6b', yield: 92.5%.
Example 2.
The synthesis of the beta-carboline derivatives of the N-N bridged isatin units employs the following reaction scheme:
(1) Synthesis of Compound Y1: weighing isatin (1.47 g,10 mmol) and putting into a 100mL eggplant-shaped bottle, adding ethanol solvent to dissolve completely, and adding NH 2 NH 2 ·H 2 O (4 mL,10 mmol), the reaction turned from orange to bright yellow with little solid formation; TLC monitoring reaction progress; after the reaction is completed, cooling the reaction liquid to room temperature, putting the reaction liquid into a refrigerator for refrigeration, and carrying out suction filtration on the next day to obtain a yellow solid which is the product Y1, wherein the next step can be carried out without further treatment, and the yield is: 93.1%.
(2) Synthesis of the target compound Y7 a': weighing compound Y1 (161.11 mg,1 mmol) and compound Y6a' (corresponding 1-substituted-9-substituted-3-formyl-beta-carboline, prepared by the method of example 1, 196.21mg,1 mmol), putting into a 100mL eggplant-shaped bottle, adding solvent ethanol to dissolve completely, heating and refluxing at 95 ℃ for 1h, adding 3 drops of glacial acetic acid, and continuously heating and refluxing for 4h, wherein the reaction solution is orange yellow; TLC monitoring reaction progress; after the reaction is completed, orange solid is generated, the orange solid is cooled to room temperature, the orange solid is put into a refrigerator for refrigeration, and the yellow solid is obtained after suction filtration in the next day, and the product Y7a' is obtained, and the yield is: 69.77%.
3- (((E) - (beta-carbolin-3-yl) methylene) hydrazino) indol-2-one (Y7 a'): orange yellow solid, 76.5% yield. m.p.320.4-321.2 deg.c. 1 H NMR(400MHz,DMSO-d 6 )δ12.06(s,1H),10.88(s,1H),9.05(s,1H),9.02(s,1H),8.66(s,1H),8.49(d,J＝8.0Hz,1H),8.13(d,J＝7.6Hz,1H),7.68(d,J＝7.6Hz,1H),7.62(t,J＝7.6Hz,1H),7.41(dt,J＝7.6,1.2Hz,1H),7.34(t,J＝8.0Hz,1H),7.08(dt,J＝7.6,0.8Hz,1H),6.92(d,J＝7.6Hz,1H). 13 C NMR(100MHz,DMSO-d 6 )δ165.09,161.66,150.72,145.43,141.62,141.55,137.60,134.93,134.12,129.65,129.32,128.58,123.04,122.97,121.34,120.62,116.97,115.37,112.90,111.25.
Example 3.
The procedure of example 3 is the same as in example 2, wherein R 9 Is methyl, R 1 Is hydrogen, the resulting product is 3- (((E) - (9-methyl-beta-carbolin-3-yl) methylene) hydrazino)) Indol-2-ones.
3- (((E) - (9-methyl- β -carbolin-3-yl) methylene hydrazino) indol-2-one (Y7 b'): yellow solid, 91.6% yield. m.p.267.2-267.8 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.89(s,1H),9.21(d,J＝0.8Hz,1H),9.03(d,J＝0.8Hz,1H),8.69(s,1H),8.52(d,J＝8.0Hz,1H),8.14(dd,J＝7.6,1.2Hz,1H),7.79(d,J＝8.4Hz,1H),7.73–7.68(m,1H),7.45–7.37(m,2H),7.09(td,J＝7.6,0.8Hz,1H),6.93(d,J＝8.0Hz,1H),4.07(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ165.07,161.64,150.72,145.42,142.45,141.79,138.05,134.09,133.61,129.63,129.39,128.11,123.05,122.94,121.02,120.78,116.96,115.01,111.23,111.00,30.08.
Example 4.
The procedure of example 4 is the same as in example 2, wherein R 9 Is ethyl, R 1 Is hydrogen, and the resulting product is 3- (((E) - (9-ethyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (9-ethyl- β -carbolin-3-yl) methylene hydrazino) indol-2-one (Y7 c'): orange yellow solid, yield 77.6%. m.p.280.1-280.5 deg.c. 1 H NMR(400MHz,DMSO-d 6 )δ10.89(s,1H),9.24(s,1H),9.04(s,1H),8.68(s,1H),8.53(d,J＝7.6Hz,1H),8.13(d,J＝7.6Hz,1H),7.82(d,J＝8.4Hz,1H),7.70(t,J＝7.2Hz,1H),7.46–7.34(m,2H),7.08(t,J＝8.0Hz,1H),6.92(d,J＝7.6Hz,1H),4.64(q,J＝7.2Hz,2H),1.41(t,J＝7.2Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ165.07,161.46,150.67,145.44,141.84,141.40,137.09,134.12,133.56,129.64,129.45,128.36,123.26,122.97,121.23,120.81,116.96,115.17,111.25,111.02,38.19,14.53.
Example 5.
The procedure of example 5 is the same as in example 2, wherein R 9 Is butyl, R 1 Is hydrogen, and the resulting product is 3- (((E) - (9-butyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (9-butyl- β -carbolin-3-yl) methylene hydrazino) indol-2-one (Y7 d'): orange yellow solid, 92.1% yield. m.p.260.3-260.9 deg.c. 1 H NMR(400MHz,DMSO-d 6 )δ10.90(s,1H),9.24(d,J＝1.2Hz,1H),9.04(d,J＝0.8Hz,1H),8.69(s,1H),8.53(d,J＝7.6Hz,1H),8.14(dd,J＝7.6,1.2Hz,1H),7.81(d,J＝8.4Hz,1H),7.72–7.67(m,1H),7.43(td,J＝7.6,1.2Hz,1H),7.38(td,J＝7.6,0.8Hz,1H),7.09(td,J＝7.6,1.2Hz,1H),6.93(d,J＝7.6Hz,1H),4.60(t,J＝7.2Hz,2H),1.88–1.81(m,2H),1.38–1.28(m,2H),0.90(t,J＝7.2Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ165.06,161.48,150.69,145.42,141.83,141.78,137.59,134.10,133.70,129.64,129.41,128.21,123.17,122.95,121.11,120.77,116.96,115.15,111.24,111.20,43.13,31.38,20.21,14.16.
Example 6.
The procedure of example 6 is the same as in example 2, wherein R 9 Is isobutyl, R 1 Is hydrogen, and the resulting product is 3- (((E) - (9-isobutyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (9-isobutyl- β -carbolin-3-yl) methylene) hydrazino) indol-2-one (Y7E'): yellow solid, 75.6% yield. m.p.263.5-263.9 deg.c. 1 H NMR(400MHz,DMSO-d 6 )δ10.88(s,1H),9.25(s,1H),9.03(s,1H),8.67(s,1H),8.52(d,J＝8.0Hz,1H),8.13(d,J＝7.6Hz,1H),7.82(d,J＝8.4Hz,1H),7.68(t,J＝7.6Hz,1H),7.44–7.35(m,2H),7.08(t,J＝7.6Hz,1H),6.92(d,J＝7.6Hz,1H),4.40(d,J＝7.2Hz,2H),2.37–2.29(m,1H),0.93(d,J＝6.8Hz,6H). 13 C NMR(100MHz,DMSO-d 6 )δ165.08,161.48,150.72,145.43,142.18,141.74,138.00,134.12,134.02,129.67,129.37,128.12,123.12,122.97,121.05,120.79,116.97,115.14,111.56,111.25,50.40,29.08,20.43.
Example 7.
The procedure of example 7 is the same as in example 2, wherein R 1 Is hydrogen, R 9 Is benzyl, the resulting product is 3- (((E) - (9-benzyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (9-benzyl- β -carbolin-3-yl) methylene) hydrazino) indol-2-one (Y7 f'): yellow solid, 86.6% yield. m.p.298.0-298.4 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.90(s,1H),9.28(d,J＝0.8Hz,1H),9.07(d,J＝1.2Hz,1H),8.67(s,1H),8.56(d,J＝8.0Hz,1H),8.12(dd,J＝7.6,1.2Hz,1H),7.84(d,J＝8.4Hz,1H),7.70–7.66(m,1H),7.45–7.38(m,2H),7.32–7.25(m,5H),7.08(td,J＝7.6,0.8Hz,1H),6.93(d,J＝8.0Hz,1H),5.88(s,2H). 13 C NMR(100MHz,DMSO-d 6 )δ165.03,161.10,150.62,145.44,142.21,141.95,137.70,137.54,134.13,133.87,129.63,129.60,129.22,128.58,128.09,127.40,123.27,122.97,121.32,121.09,116.93,115.17,111.46,111.25,46.64.
Example 8.
The procedure of example 8 is the same as in example 2, wherein R 1 Is hydrogen, R 9 Is 4-fluorobenzyl, and the resulting product is 3- (((E) - (9- (4-fluorobenzyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (9- (4-fluorobenzyl) - β -carbolin-3-yl) methylene hydrazino) indol-2-one (Y7 g'): yellow solid, yield 84.3%. m.p.287.1-287.4 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.89(s,1H),9.29(s,1H),9.06(s,1H),8.66(s,1H),8.55(d,J＝8.0Hz,1H),8.11(d,J＝7.6Hz,1H),7.84(d,J＝8.0Hz,1H),7.71–7.66(m,1H),7.45–7.38(m,2H),7.36–7.32(m,2H),7.17–7.12(m,2H),7.08(td,J＝7.6,1.0Hz,1H),6.92(d,J＝7.6Hz,1H),5.87(s,2H). 13 C NMR(100MHz,DMSO-d 6 )δ165.02,161.03,160.79(d,J＝242.1Hz),150.61,145.44,142.27,141.83,137.59,134.15,133.84,133.74(d,J＝3.2Hz),129.64,129.52(d,J＝8.3Hz),128.64,123.30,122.97,121.36,121.15,116.92,115.94(d,J＝21.3Hz),115.18,111.43,111.26,45.91.
Example 9.
The procedure of example 9 is the same as in example 2, wherein R 1 Is hydrogen, R 9 Is 3-chlorobenzyl, and the resulting product is 3- (((E) - (9- (3-chlorobenzyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (9- (3-chlorobenzyl) - β -carbolin-3-yl) methylene hydrazino) indol-2-one (Y7 h'): yellow solid, yield 80.5%. m.p.276.6-277.0 deg.c. 1 H NMR(400MHz,DMSO-d 6 )δ10.90(s,1H),9.30(d,J＝1.2Hz,1H),9.07(d,J＝0.8Hz,1H),8.66(s,1H),8.57(d,J＝8.0Hz,1H),8.12(dd,J＝7.6,1.2Hz,1H),7.85(d,J＝8.4Hz,1H),7.72–7.67(m,1H),7.45–7.38(m,3H),7.35–7.33(m,2H),7.17–7.14(m,1H),7.08(td,J＝7.6,1.2Hz,1H),6.93(d,J＝7.6Hz,1H),5.90(s,2H). 13 CNMR(100MHz,DMSO-d 6 )δ165.02,160.97,150.60,145.45,142.41,141.83,140.09,137.63,134.15,133.79,131.21,129.73,129.64,128.68,128.12,127.31,125.97,123.35,122.97,121.37,121.25,116.91,115.19,111.37,111.25,46.02.
Example 10.
The procedure of example 10 is the same as in example 2, wherein R 1 Is hydrogen, R 9 Is 3-phenylpropyl, and the obtained product is 3- (((E) - (9- (3-phenylpropyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (9- (3-phenylpropyl) - β -carbolin-3-yl) methylene) hydrazino) indol-2-one (Y7 i'): orange yellow solid, yield 90.1%. m.p.231.3-231.9 deg.c. 1 H NMR(400MHz,DMSO-d 6 )δ10.89(s,1H),9.19(s,1H),9.03(s,1H),8.68(s,1H),8.53(d,J＝8.0Hz,1H),8.13(d,J＝7.6Hz,1H),7.77(d,J＝8.4Hz,1H),7.71–7.66(m,1H),7.45–7.36(m,2H),7.29–7.24(m,2H),7.21–7.16(m,3H),7.08(t,J＝7.6Hz,1H),6.93(d,J＝7.6Hz,1H),4.63(t,J＝7.2Hz,2H),2.70(t,J＝7.6Hz,2H),2.22–2.14(m,2H). 13 C NMR(100MHz,DMSO-d 6 )δ165.05,161.37,150.66,145.43,141.86,141.79,141.53,137.54,134.11,133.61,129.63,129.44,128.81,128.61,128.31,126.38,123.21,122.95,121.18,120.83,116.95,115.15,111.24,111.11,43.09,32.86,30.83.
Example 11.
The procedure of example 11 is the same as in example 2, wherein R 1 Is methyl, R 9 Is hydrogen, and the resulting product is 3- (((E) - (1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (1-methyl- β -carbolin-3-yl) methylene hydrazino) indol-2-one (Y7 j'): orange-red solid, yield 61.1%. m.p.214.2-214.5 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ12.02(s,1H),10.88(s,1H),8.88(s,1H),8.62(s,1H),8.45(d,J＝8.0Hz,1H),8.14(d,J＝7.6Hz,1H),7.67(d,J＝8.4Hz,1H),7.61(t,J＝7.6Hz,1H),7.42(t,J＝7.6Hz,1H),7.32(t,J＝7.6Hz,1H),7.09(t,J＝7.6Hz,1H),6.92(d,J＝8.0Hz,1H),2.86(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ164.68,161.51,150.23,144.91,142.91,140.93,140.65,135.87,133.59,129.17,128.54,127.44,122.51,122.47,121.34,120.09,116.55,113.10,112.37,110.76,20.44.
Example 12.
The procedure of example 12 is the same as in example 2, wherein R 1 Is methyl, R 9 Is methyl, the resulting product is 3- (((E) - (1, 9-dimethyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (1, 9-dimethyl- β -carbolin-3-yl) methylene) hydrazino) indol-2-one (Y7 k'): orange yellow solid, yield 70.4%. m.p.255.6-260.0 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.87(s,1H),8.84(s,1H),8.58(s,1H),8.44(d,J＝7.6Hz,1H),8.12(d,J＝7.6Hz,1H),7.76(d,J＝8.4Hz,1H),7.65(t,J＝7.6Hz,1H),7.40(t,J＝7.2Hz,2H),7.34(t,J＝7.6Hz,2H),7.07(t,J＝7.6Hz,1H),6.91(d,J＝7.6Hz,1H),4.20(s,3H),3.10(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ164.64,161.02,150.20,144.90,142.66,142.17,140.38,136.37,133.56,129.15,128.64,128.13,122.46,122.06,120.54,120.20,116.51,112.96,110.73,110.61,32.18,23.40.
Example 13.
The procedure of example 13 is the same as in example 2, wherein R 1 Is methyl, R 9 For ethyl, the resulting product is 3- (((E) - (9-ethyl-1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (9-ethyl-1-methyl- β -carbolin-3-yl) methylene) hydrazino) indol-2-one (Y7 l'): yellow solid, yield 87.6%. m.p.234.1-234.5 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.88(s,1H),8.90(s,1H),8.59(s,1H),8.50(d,J＝8.0Hz,1H),8.12(d,J＝7.6Hz,1H),7.81(d,J＝8.4Hz,1H),7.68(t,J＝7.6Hz,1H),7.41(t,J＝7.6Hz,1H),7.37(t,J＝7.6Hz,1H),7.08(t,J＝7.6Hz,1H),6.92(d,J＝7.6Hz,1H),4.73(q,J＝7.2Hz,2H),3.08(s,3H),1.41(t,J＝7.2Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ164.61,160.67,150.11,144.92,141.97,141.25,140.48,135.42,133.61,129.15,128.83,128.66,122.50,122.28,120.91,120.41,116.49,113.04,110.76,110.65,42.02,23.21,15.66.
Example 14.
The procedure of example 14 is the same as in example 2, wherein R 1 Is methyl, R 9 The product obtained is 3- (((E) - (9-butyl-1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one for butyl.
3- (((E) - (9-butyl-1-methyl- β -carbolin-3-yl) methylene) hydrazino) indol-2-one (Y7 m'): orange yellow solid, yield 79.4%. m.p.165.2-165.7 deg.c. 1 H NMR(400MHz,DMSO-d 6 )δ10.89(s,1H),8.90(s,1H),8.60(s,1H),8.49(d,J＝7.6Hz,1H),8.12(d,J＝7.6Hz,1H),7.80(d,J＝8.4Hz,1H),7.69–7.65(m,1H),7.45–7.39(m,1H),7.36(t,J＝7.6Hz,1H),7.08(t,J＝7.6Hz,1H),6.93(d,J＝8.0Hz,1H),4.66(t,J＝7.6Hz,2H),3.07(s,3H),1.83–1.75(m,2H),1.47–1.36(m,2H),0.94(t,J＝7.2Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ165.06,161.10,150.58,145.39,142.44,142.18,140.95,136.08,134.08,129.62,129.25,129.13,122.97,122.69,121.24,120.85,116.96,113.48,111.36,111.23,44.66,33.12,23.78,20.02,14.18.
Example 15.
The procedure of example 15 is the same as in example 2, wherein R 1 Is methyl, R 9 Is benzyl, the resulting product is 3- (((E) - (9-benzyl-1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (9-benzyl-1-methyl- β -carbolin-3-yl) methylene) hydrazino) indol-2-one (Y7 n'): orange yellow solid, yield 95.4%. m.p.243.6-243.9 deg.c. 1 H NMR(400MHz,DMSO-d 6 )δ10.89(s,1H),8.97(s,1H),8.58(s,1H),8.56(d,J＝8.0Hz,1H),8.12(d,J＝7.2Hz,1H),7.76(d,J＝8.4Hz,1H),7.67–7.62(m,1H),7.45–7.37(m,2H),7.33–7.24(m,3H),7.09(td,J＝7.6,1.2Hz,1H),7.01–6.97(m,2H),6.93(d,J＝8.0Hz,1H),6.01(s,2H),2.89(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ165.04,160.80,150.54,145.41,142.64,142.62,141.45,139.02,136.50,134.11,129.63,129.52,129.40,129.36,127.77,125.77,122.98,122.83,121.33,121.21,116.94,113.56,111.36,111.24,47.96,23.37.
Example 16.
The procedure of example 16 is the same as in example 2, wherein R 1 Is methyl, R 9 Is 4-fluorobenzyl, and the resulting product is 3- (((E) - (9- (4-fluorobenzyl) -1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (9- (4-fluorobenzyl) -1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one (Y7 o')asa yellow solid in 76.3% yield. m.p.173.2-173.5 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.89(s,1H),8.96(s,1H),8.58(s,1H),8.56(d,J＝8.0Hz,1H),8.11(d,J＝7.6Hz,1H),7.75(d,J＝8.4Hz,1H),7.67–7.62(m,1H),7.44–7.37(m,2H),7.17–7.00(m,5H),6.92(d,J＝7.6Hz,1H),5.99(s,2H),2.88(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ165.05,160.75,160.60(d,J＝241.6Hz),150.55,145.43,142.58,142.53,141.52,136.40,135.12(d,J＝2.8Hz),134.13,129.64,129.58,129.45,127.81(d,J＝8.2Hz),122.98,122.86,121.38,121.28,116.94,116.13(d,J＝21.4Hz),113.57,111.34,111.26,47.33,23.37.
Example 17.
The procedure of example 17 is the same as in example 2, wherein R 1 Is methyl, R 9 Is 3-chlorobenzyl, and the product obtained is 3- (((E) - (9- (3-chlorobenzyl) -1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (9- (3-chlorobenzyl) -1-methyl- β -carbolin-3-yl) methylene) hydrazino) indol-2-one (Y7 p'): orange yellow solid, 65.4% yield. m.p.254.3-254.9 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.89(s,1H),8.96(s,1H),8.58–8.54(m,2H),8.11(d,J＝7.2Hz,1H),7.75(d,J＝8.4Hz,1H),7.64(t,J＝8.0Hz,1H),7.44–7.27(m,4H),7.13(s,1H),7.08(t,J＝7.6Hz,1H),6.92(d,J＝7.6Hz,1H),6.83(d,J＝6.4Hz,1H),6.02(s,2H),2.87(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ165.04,160.69,150.54,145.42,142.53,142.49,141.64,141.61,136.37,134.11,134.02,131.39,129.63,129.46,127.83,125.82,124.38,122.97,122.89,121.35,116.92,113.57,111.25,47.43,23.35.
Example 18.
The procedure of example 18 is the same as in example 2, wherein R 1 Is methyl, R 9 Is 3-phenylpropyl, and the obtained product is 3- (((E) - (1-methyl-9- (3-phenylpropyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (1-methyl-9- (3-phenylpropyl) - β -carbolin-3-yl) methylene) hydrazino) indol-2-one (Y7 q'): orange yellow solid, yield 66.8%. m.p.190.1-190.5 deg.c. 1 H NMR(400MHz,DMSO-d 6 )δ10.88(s,1H),8.89(s,1H),8.58(s,1H),8.49(d,J＝7.6Hz,1H),8.09(d,J＝7.6Hz,1H),7.72(d,J＝8.0Hz,1H),7.66(t,J＝8.0Hz,1H),7.44–7.21(m,7H),7.07(t,J＝7.6Hz,1H),6.92(d,J＝8.0Hz,1H),4.68(t,J＝8.0Hz,2H),2.93(s,3H),2.77(t,J＝8.0Hz,2H),2.17–2.06(m,2H). 13 C NMR(100MHz,DMSO-d 6 )δ165.07,161.07,150.57,145.40,142.44,142.09,141.47,141.02,136.08,134.09,129.63,129.27,129.15,128.87,128.84,126.50,122.97,122.74,121.34,120.91,116.96,113.50,111.24,44.43,32.66,32.44,23.59.
Example 19.
The procedure of example 19 is the same as in example 2, wherein R 1 Is isopropyl, R 9 The product obtained is 3- (((E) - (9-butyl-1-isopropyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one, which is butyl.
3- (((E) - (9-butyl-1-isopropyl- β -carbolin-3-yl) methylene) hydrazino) indol-2-one (Y7 r'): orange yellow solid, yield 80.8%. m.p.217.4-217.9 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.88(s,1H),8.86(s,1H),8.62(s,1H),8.47(d,J＝7.6Hz,1H),8.20(d,J＝7.6Hz,1H),7.82(d,J＝8.4Hz,1H),7.67(t,J＝7.6Hz,1H),7.39(dt,J＝21.2,7.6Hz,2H),7.06t,J＝7.6Hz,1H),6.92(d,J＝7.6Hz,1H),4.63(t,J＝6.8Hz,2H),3.83(p,J＝6.4Hz,1H),1.79(p,J＝7.6Hz,2H),1.47(d,J＝6.4Hz,6H),1.40(q,J＝7.6Hz,2H),0.93(t,J＝7.6Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ164.60,160.49,150.52,150.34,144.91,141.99,140.46,133.78,133.59,129.49,129.32,128.80,122.39,121.96,120.88,120.40,118.99,116.60,113.29,110.92,110.74,44.64,32.10,30.98,22.51,19.50,13.66.
Example 20.
The procedure of example 20 is the same as in example 2, wherein R 1 Is isopropyl, R 9 Is benzyl, the resulting product is 3- (((E) - (9-benzyl-1-isopropyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (9-benzyl-1-isopropyl- β -carbolin-3-yl) methylene) hydrazino) indol-2-one (Y7 s'): orange yellow solid, 76.6% yield. m.p.255.1-255.4 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.88(s,1H),8.91(s,1H),8.61(s,1H),8.54(d,J＝7.6Hz,1H),8.19(d,J＝7.6Hz,1H),7.76(d,J＝8.0Hz,1H),7.64(t,J＝7.6Hz,1H),7.44–7.37(m,2H),7.32–7.22(m,3H),7.06(t,J＝7.6Hz,1H),6.97(d,J＝7.2Hz,2H),6.92(d,J＝8.0Hz,1H),5.97(s,2H),3.74–3.64(m,1H),1.25(d,J＝6.0Hz,6H). 13 C NMR(100MHz,DMSO-d 6 )δ164.58,160.26,150.83,150.32,144.94,142.44,140.96,137.90,134.27,133.62,129.74,129.33,129.08,128.86,127.32,125.39,122.40,122.10,120.95,120.76,116.58,113.26,110.88,110.75,48.12,30.76,22.48.
Example 21.
The procedure of example 21 is the same as in example 2, wherein R 1 Is 2-chlorophenyl, R 9 Is hydrogen, and the product obtained is 3- (((E) - (1- (2-chlorophenyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (1- (2-chlorophenyl) - β -carbolin-3-yl) methylene hydrazino) indol-2-one (Y7 t'): orange yellow solid, 65.3% yield. m.p.218.3-218.9 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ11.77(s,1H),10.89(s,1H),9.09(s,1H),8.65(s,1H),8.53(d,J＝8.0Hz,1H),8.14(d,J＝7.6Hz,1H),7.74–7.68(m,2H),7.65–7.56(m,4H),7.43(t,J＝7.6Hz,1H),7.38–7.33(m,1H),7.09(t,J＝7.6Hz,1H),6.92(d,J＝7.6Hz,1H). 13 C NMR(100MHz,DMSO-d 6 )δ164.57,160.39,150.10,144.96,141.73,141.53,140.93,136.36,135.15,133.67,132.51,131.93,130.66,129.81,129.23,128.98,128.95,127.52,122.55,122.51,121.01,120.26,116.47,114.32,112.53,110.78.
Example 22.
Procedure and implementation of example 22Example 2 is the same, wherein R 1 Is 2-chlorophenyl, R 9 The product obtained is 3- (((E) - (9-benzyl-1- (2-chlorophenyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one for benzyl.
3- (((E) - (9-benzyl-1- (2-chlorophenyl) - β -carbolin-3-yl) methylene) hydrazino) indol-2-one (Y7 u'): orange yellow solid, 65.3% yield. m.p.166.3-166.5 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.90(s,1H),9.18(s,1H),8.65(d,J＝8.0Hz,1H),8.59(s,1H),8.10(d,J＝7.6Hz,1H),7.68–7.63(m,2H),7.58(d,J＝8.0Hz,1H),7.54-7.50(m,1H),7.43(t,J＝8.0Hz,2H),7.37(d,J＝7.6Hz,1H),7.30(t,J＝7.2Hz,1H),7.15-7.06(m,4H),6.93(d,J＝8.0Hz,1H),6.53(d,J＝8.0Hz,2H),5.49(d,J＝17.2Hz,1H),5.13(d,J＝17.2Hz,1H). 13 C NMR(100MHz,DMSO-d 6 )δ164.49,159.21,149.91,145.00,142.37,141.30,141.15,137.00,136.79,134.88,133.73,133.05,131.66,130.70,130.33,129.49,129.22,129.09,128.34,127.60,127.15,126.95,125.31,122.64,122.52,121.06,120.88,116.38,114.06,111.20,110.80,54.90,46.78.
Example 23.
The procedure of example 23 is the same as in example 2, wherein R 1 Is 2-chlorophenyl, R 9 Is 3- (((E) - (1- (2-chlorophenyl) -9- (4-fluorobenzyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (1- (2-chlorophenyl) -9- (4-fluorobenzyl) - β -carbolin-3-yl) methylene hydrazino) indol-2-one (Y7 v'): orange-red solid, yield 77.9%. m.p.268.2-268.6 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.90(s,1H),9.18(s,1H),8.66(d,J＝8.0Hz,1H),8.59(s,1H),8.09(d,J＝7.6Hz,1H),7.70–7.62(m,2H),7.61–7.48(m,2H),7.47–7.37(m,3H),7.37–7.29(m,1H),7.08(t,J＝7.6Hz,1H),6.98–6.89(m,3H),6.54(dd,J＝8.4,5.4Hz,2H),5.46(d,J＝17.2Hz,1H),5.13(d,J＝17.2Hz,1H). 13 C NMR(100MHz,DMSO-d 6 )δ164.49,160.02(d,J＝241.4Hz),159.14,149.90,145.01,142.29,141.38,141.14,136.96,134.74,133.73,133.06,132.96(d,J＝3.0Hz),131.68,130.75,130.41,129.57,129.21,129.13,127.29(d,J＝8.4Hz),126.95,122.67,122.51,121.13,120.89,116.38,115.27(d,J＝21.4Hz),114.07,111.08,110.81,46.18.
Example 24.
The procedure of example 24 is the same as in example 2, wherein R 1 Is 2-thienyl, R 9 Is hydrogen, and the resulting product is 3- (((E) - (1- (2-thienyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one.
3- (((E) - (1- (2-thienyl) - β -carbolin-3-yl) methylene) hydrazino) indol-2-one (Y7 w'): orange-red solid, yield 78.6%. m.p.196.2-196.7 deg.c. 1 H NMR(400MHz,DMSO-d 6 )δ11.90(s,1H),10.89(s,1H),8.92(s,1H),8.66(s,1H),8.48(d,J＝7.6Hz,1H),8.24(d,J＝7.6Hz,1H),8.20(d,J＝3.6Hz,1H),7.85–7.76(m,2H),7.66(t,J＝7.6Hz,1H),7.42–7.36(m,3H),7.09(t,J＝7.6Hz,1H),6.93(d,J＝7.6Hz,1H). 13 C NMR(100MHz,DMSO-d 6 )δ165.06,160.38,150.93,145.45,142.98,142.15,141.24,137.45,134.14,132.50,130.78,129.93,129.49,129.43,129.03,127.15,122.96,122.70,121.52,121.17,117.06,115.01,113.46,111.24.
Example 25.
The procedure of example 25 is the same as in example 2, wherein R 1 Is 2-thienyl, R 9 The product obtained was 3- (((E) - (9-benzyl-1- (2-thienyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one for benzyl.
3- (((E) - (9-benzyl-1- (2-thienyl) - β -carbolin-3-yl) methylene) hydrazino) indol-2-one (Y7 x'): orange-red solid, yield 85.6%. m.p.302.2-302.5 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.90(s,1H),9.10(s,1H),8.63–8.60(m,2H),8.12(d,J＝7.6Hz,1H),7.77–7.71(m,2H),7.66(t,J＝7.2Hz,1H),7.43(t,J＝7.6Hz,2H),7.35(d,J＝3.6Hz,1H),7.17–7.12(m,4H),7.08(t,J＝7.6Hz,1H),6.92(d,J＝7.6Hz,1H),6.65(dd,J＝6.4,2.8Hz,2H),5.58(s,2H). 13 C NMR(100MHz,DMSO-d 6 )δ164.49,159.20,154.45,150.06,145.01,142.81,141.40,139.83,137.37,137.02,135.22,133.73,131.25,129.50,129.29,129.05,128.48,128.40,127.14,126.90,125.70,122.58,122.51,121.18,121.04,117.04,116.41,114.00,111.66,110.79,47.27.
The chemical structural formulas of the products prepared in examples 2 to 25 are shown in Table 1.
TABLE 1 summary of chemical structures of target compounds
Example 26: in vitro anti-tumor Activity Studies
The 24 target compounds synthesized in examples 2-25 were tested for in vitro antitumor activity using the MTT method which is currently widely used in new drug screening and cytotoxicity.
Principle of MTT method: MTT is a tetrazolium salt, and is commercially available as thiazole blue, and the compound can enter cells and can be reduced by amber dehydrogenase in mitochondria of living cells as exogenous MTT, so that Formazan crystals which are indissolvable in water are generated, the Formazan crystals are blue-purple in color and are precipitated in the cells, but dead cells do not have the phenomenon. Dimethyl sulfoxide (DMSO) can dissolve Formazan crystals to produce a blue-violet solution, and the absorbance (OD value) is measured at a wavelength of 490nm using an enzyme-labeled instrument to obtain the number of cells.
The test method comprises the following steps: single cell suspensions were prepared from neonatal bovine serum and five tumor cells were concentrated at 1X 10 4 Each ml was inoculated into a 96-well plate at 37℃with 5% CO 2 After incubation for 4h, the incubation was stopped, the in-well culture solution was aspirated, DMSO was added thereto, shaking was performed for 10min to completely dissolve the precipitate, then the OD value was measured, and the results were recorded, as shown in table 2.
TABLE 2 in vitro anti-tumor Activity of Compounds Y7a '-Y7w' (IC 50 ,μmol·L -1 )Table 2In vitro anti-tumor activity ofcompounds Y7a’-Y7w’(IC 50 ,μmol·L -1 )
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Semi-inhibitory concentration of each cell line was IC 50 Is a concentration of a compound that reduces the optical density of cells by 50% compared to untreated cells. The data represent experimental data from three independent experiments performed in parallel using the MTT method, the data being expressed as mean ± SD (standard deviation).
The table shows that the synthesized beta-carboline derivative containing the isatin structure has better anti-tumor activity and can be applied to anti-tumor drugs.
The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the embodiment of the present invention in any way, but any simple modification, equivalent variation and modification of the above embodiment according to the technical substance of the embodiment of the present invention still fall within the scope of the technical solution of the embodiment of the present invention.
Claims (9)
1. The beta-carboline derivative of the N-N bridged isatin unit is characterized by having a chemical structural general formula:
in the chemical structural general formula of the beta-carboline derivative, R 1 Is one of hydrogen, methyl, isopropyl, 2-chlorophenyl and 2-thienyl;
R 9 is one of hydrogen, methyl, ethyl, n-butyl, isobutyl, benzyl, 4-fluorobenzyl, 3-chlorobenzyl and 3-phenylpropyl.
2. The β -carboline derivative according to claim 1,
the beta-carboline derivative is any one of the following compounds:
3- (((E) - (beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-ethyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-butyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-isobutyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-benzyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9- (4-fluorobenzyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9- (3-chlorobenzyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9- (3-phenylpropyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (1, 9-dimethyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-ethyl-1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-butyl-1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-benzyl-1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9- (4-fluorobenzyl) -1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9- (3-chlorobenzyl) -1-methyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (1-methyl-9- (3-phenylpropyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-butyl-1-isopropyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-benzyl-1-isopropyl-beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (1- (2-chlorophenyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-benzyl-1- (2-chlorophenyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (1- (2-chlorophenyl) -9- (4-fluorobenzyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (1- (2-thienyl) -beta-carbolin-3-yl) methylene) hydrazino) indol-2-one,
3- (((E) - (9-benzyl-1- (2-thienyl) - β -carbolin-3-yl) methylene) hydrazino) indol-2-one.
3. The method for preparing a beta-carboline derivative according to claim 1, wherein the chemical reaction formula of the preparation method is:
wherein R is as follows 1 、R 9 Having the definition of formula (I) as defined in claim 1.
4. A method of preparation according to claim 3, comprising the specific steps of:
(1) Adding NH to isatin ethanol solution 2 NH 2 ·H 2 O and reacting, cooling to room temperature after the reaction is finished, and refrigerating and suction filtering to obtain an intermediate product Y1;
(2) Dissolving the intermediate product Y1 and the corresponding 1-substituted-9-substituted-3-formyl-beta-carboline in ethanol, heating and refluxing for 1h at 95 ℃, adding glacial acetic acid, continuously heating and refluxing until the reaction is complete, generating orange-yellow solid, cooling to room temperature, refrigerating and suction filtering to obtain the beta-carboline derivative.
5. The method according to claim 4, wherein,
in the step (1), isatin and NH 2 NH 2 ·H 2 The molar ratio of O is 1:1;
in the step (2), the molar ratio of the intermediate product Y1 to the corresponding 1-substituted-9-substituted-3-formyl-beta-carboline is 1:1.
6. The method according to claim 4, wherein,
in the step (2), the chemical reaction formula of the synthesis method of the 1-substituted-9-substituted-3-formyl-beta-carboline is as follows:
wherein R is as follows 1 、R 9 Having the definition of formula (I) as defined in claim 1.
7. The method according to claim 6, wherein,
in the step (2), the synthesis method of the 1-substituted-9-substituted-3-formyl-beta-carboline specifically comprises the following steps:
a: dissolving L-tryptophan and NaOH in water, adding 40% HCHO solution, stirring at room temperature for reaction for 3.5h, heating and refluxing at 120 ℃, cooling, regulating pH, refrigerating, filtering, washing with water and acetone to obtain compounds 1a-1f, namely an intermediate 1;
b: dissolving the intermediate 1 in absolute ethanol, adding SOCl 2 Heating and refluxing until the reaction is complete, cooling to room temperature, and concentrating under reduced pressure to obtain a brick red solid; dissolving the brick red solid in water, and using NaHCO 3 After adjusting the pH, extracting an organic phase with ethyl acetate, washing with saturated brine, and concentrating under reduced pressure to obtain white solid compounds 2a-2f, namely an intermediate 2;
c: dissolving the intermediate 2 in dimethylbenzene, and slowly adding S 8 Heating and refluxing at 150 ℃ until the reaction is complete, cooling to room temperature, refrigerating, suction filtering, washing by dimethylbenzene and petroleum ether, and decolorizing and desulfurizing to obtain white solid compounds 3a-3f, namely an intermediate 3;
d: dissolving the intermediate 3 in DMF, slowly adding 60% NaH, stirring, and slowly dripping CH 3 I, after stirring and reacting to be complete, pouring the mixture into ice water to quench NaH, extracting an organic phase by using ethyl acetate, washing the organic phase by using saturated NaCl, and adding absolute ethyl alcohol with the volume of 1/2 of the organic phase; regulating pH 3 with HCl, concentrating under reduced pressure to obtain pale yellow solid, recrystallizing, dissolving in water, and adding NaHCO 3 Adjusting pH 9, extracting with ethyl acetate, concentrating under reduced pressure to obtain compound 4a '-4 t' as intermediate 4;
e: dissolving the intermediate 4 in THF solvent, slowly adding LiBH 4 After the reaction is stirred until the reaction is completed, cooling, stirring for 4 hours at room temperature, regulating the pH value to 3 by using HCl, regulating the pH value to 9 by using NaOH, extracting by using ethyl acetate, concentrating under reduced pressure, recrystallizing by using acetone, and carrying out suction filtration to obtain a white solid compound 5a '-5t', namely an intermediate 5;
f: dissolving the intermediate 5 in acetonitrile, slowly adding MnO 2 Heating and refluxing at 90 ℃ until the reaction is complete, passing through a thin-layer chromatographic silica gel short column, flushing the column with ethyl acetate, concentrating under reduced pressure, recrystallizing with acetone, and filtering to obtain a white solid compound 6a '-6t', namely 1-substituted-9-substituted-3-formyl-beta-carboline.
8. The method according to claim 7, wherein,
in the step a, the molar ratio of the L-tryptophan to the NaOH to the HCHO is 1:1:1;
in the step d, the molar ratio of the intermediate 3 to the NaH is 1:3;
in the step e, the intermediate 4 and LiBH 4 The molar ratio of (2) is 1:3;
in the step f, the intermediate 5, mnO 2 The molar ratio of (2) is 1:3.
9. The use of a β -carboline derivative according to claim 1 for the preparation of an antitumor drug.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63162689A (en) * | 1986-12-25 | 1988-07-06 | Kawaken Fine Chem Co Ltd | 7-bromo-beta-carboline derivative and production thereof |
| EP2003129A1 (en) * | 2007-06-11 | 2008-12-17 | Nerviano Medical Sciences S.r.l. | 1H-Pyrido[3,4-B]indol-1-one and 2,3,4,9-Tetrahydro-1H-Beta-Carbolin-1-one Derivatives |
| CN101397295A (en) * | 2008-11-12 | 2009-04-01 | 深圳微芯生物科技有限责任公司 | 2-dihydroindolemanone derivates as histone deacetylase inhibitor, preparation method and use thereof |
| WO2010138820A2 (en) * | 2009-05-28 | 2010-12-02 | President And Fellows Of Harvard College | N,n-diarylurea compounds and n,n'-diarylthiourea compounds as inhibitors of translation initiation |
| CN105732476A (en) * | 2016-02-04 | 2016-07-06 | 吉首大学 | Carbazole-isatin type compound and preparation method and application thereof |
| CN115477648A (en) * | 2021-06-16 | 2022-12-16 | 首都医科大学 | Carboline derivative, preparation method thereof and application thereof in preparing antitumor drugs |
| CN116354959A (en) * | 2023-03-10 | 2023-06-30 | 石河子大学 | Beta-carboline derivative of N-N bridged thiazole unit, and preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7863315B2 (en) * | 2008-01-15 | 2011-01-04 | Shenzhen Chipscreen Biosciences, Ltd. | 2-indolinone derivatives as selective histone deacetylase inhibitors |
-
2023
- 2023-03-10 CN CN202310228794.6A patent/CN116253732B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63162689A (en) * | 1986-12-25 | 1988-07-06 | Kawaken Fine Chem Co Ltd | 7-bromo-beta-carboline derivative and production thereof |
| EP2003129A1 (en) * | 2007-06-11 | 2008-12-17 | Nerviano Medical Sciences S.r.l. | 1H-Pyrido[3,4-B]indol-1-one and 2,3,4,9-Tetrahydro-1H-Beta-Carbolin-1-one Derivatives |
| CN101397295A (en) * | 2008-11-12 | 2009-04-01 | 深圳微芯生物科技有限责任公司 | 2-dihydroindolemanone derivates as histone deacetylase inhibitor, preparation method and use thereof |
| WO2010138820A2 (en) * | 2009-05-28 | 2010-12-02 | President And Fellows Of Harvard College | N,n-diarylurea compounds and n,n'-diarylthiourea compounds as inhibitors of translation initiation |
| CN105732476A (en) * | 2016-02-04 | 2016-07-06 | 吉首大学 | Carbazole-isatin type compound and preparation method and application thereof |
| CN115477648A (en) * | 2021-06-16 | 2022-12-16 | 首都医科大学 | Carboline derivative, preparation method thereof and application thereof in preparing antitumor drugs |
| CN116354959A (en) * | 2023-03-10 | 2023-06-30 | 石河子大学 | Beta-carboline derivative of N-N bridged thiazole unit, and preparation method and application thereof |
Non-Patent Citations (9)
| Title |
|---|
| 1-芳基四氢-β-咔啉-3-羧酸甲酯的合成;吴昊;马养民;李延超;;化学世界;20130125(第01期);32-36 * |
| C-3位五元螺环吲哚酮衍生物合成方法研究进展;刘奕彤;有机化学;20211031;第41卷(第10期);3965-3982 * |
| Design, synthesis, anticancer screening, docking studies and in silico ADME prediction of some β-carboline derivatives;Mohamed A Abdelsalam，等;Future Med Chem .;20180501;第10卷(第10期);1159-1175 * |
| Molecular hybrid design, synthesis, in vitro and in vivo anticancer evaluation, and mechanism of action of N-acylhydrazone linked, heterobivalent β-carbolines;Liang Guo，等;Bioorg Chem .;20200331;epub * |
| N-N桥连的β-咔啉衍生物的合成与抗肿瘤活性研究;马玲;石河子大学硕士学位论文;20230630;1-152 * |
| Synthesis and evaluation of novel hybrids β-carboline-4-thiazolidinones as potential antitumor and antiviral agents;Valéria Aquilino Barbosa，等;Eur J Med Chem .;20161129;第124卷;1093-1104 * |
| 咔啉类衍生物的合成及抗肿瘤活性研究;陈静;陶雪芬;;中国现代应用药学;20130328(第03期);6-11 * |
| 有机小分子不对称催化构建氧化吲哚C(3)位螺环化合物的研究进展;龙先文;黄伟杰;朱文润;庄冲;蒋才武;林宁;;化学试剂;20170215(第02期);46-54+72 * |
| 苯并咪唑桥连的双-β-咔啉衍生物的合成与生物活性;孙跃;霍新玉;王兆旭;韩小强;张洁;;精细化工;20200831(第08期);166-171 * |
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