CN106432288B - The copper-nitrate complex of 1 (2 pyridine) 9 (2 Benzyloxyethyl) β carbolines and synthetic method and application - Google Patents
The copper-nitrate complex of 1 (2 pyridine) 9 (2 Benzyloxyethyl) β carbolines and synthetic method and application Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 21
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 title claims abstract description 18
- -1 Benzyloxyethyl Chemical group 0.000 title abstract description 3
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 title abstract description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 53
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 43
- 239000002798 polar solvent Substances 0.000 claims abstract description 28
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 230000000118 anti-neoplastic effect Effects 0.000 claims abstract description 7
- 238000010668 complexation reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 41
- 239000010949 copper Substances 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
- 239000013078 crystal Substances 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 14
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 12
- 229940125782 compound 2 Drugs 0.000 claims description 12
- 239000007800 oxidant agent Substances 0.000 claims description 11
- 230000001590 oxidative effect Effects 0.000 claims description 11
- 229940125904 compound 1 Drugs 0.000 claims description 10
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 claims description 5
- AQZMINLSVARCSL-UHFFFAOYSA-N 4-chloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile Chemical compound ClC1=CC(=O)C(C#N)=C(C#N)C1=O AQZMINLSVARCSL-UHFFFAOYSA-N 0.000 claims description 5
- MSBWDNNCBOLXGS-UHFFFAOYSA-L manganese(2+);diacetate;hydrate Chemical compound O.[Mn+2].CC([O-])=O.CC([O-])=O MSBWDNNCBOLXGS-UHFFFAOYSA-L 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 3
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 2
- 150000007529 inorganic bases Chemical group 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 238000007789 sealing Methods 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims 1
- JEHCHYAKAXDFKV-UHFFFAOYSA-J lead tetraacetate Chemical compound CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O JEHCHYAKAXDFKV-UHFFFAOYSA-J 0.000 claims 1
- 229910017604 nitric acid Inorganic materials 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 5
- 229910052697 platinum Inorganic materials 0.000 abstract description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 229940034982 antineoplastic agent Drugs 0.000 abstract description 2
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 abstract 1
- 239000000047 product Substances 0.000 description 23
- 229910002651 NO3 Inorganic materials 0.000 description 19
- 235000019441 ethanol Nutrition 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 238000001819 mass spectrum Methods 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 239000011259 mixed solution Substances 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- 239000000463 material Substances 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
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- 235000015097 nutrients Nutrition 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 4
- 239000011572 manganese Substances 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 4
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- 210000004881 tumor cell Anatomy 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- FWOHDAGPWDEWIB-UHFFFAOYSA-N 2-bromoethoxymethylbenzene Chemical class BrCCOCC1=CC=CC=C1 FWOHDAGPWDEWIB-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
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- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229940005561 1,4-benzoquinone Drugs 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DNXUGBMARDFRGG-UHFFFAOYSA-N 3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile Chemical compound O=C1C=CC(=O)C(C#N)=C1C#N DNXUGBMARDFRGG-UHFFFAOYSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 101000905241 Mus musculus Heart- and neural crest derivatives-expressed protein 1 Proteins 0.000 description 1
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000049 anti-anxiety effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
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- 206010017758 gastric cancer Diseases 0.000 description 1
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- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 229930002341 quinoline alkaloid Natural products 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
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- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a kind of copper-nitrate complex of 1 (2 pyridine) 9 (2 Benzyloxyethyl) β carbolines and synthetic method and application.Shown in the structural formula of the complex such as following formula (I), its synthetic method is：Compound and copper nitrate as shown in following formula (II) are taken, is dissolved in polar solvent, complexation reaction is carried out, produces；Wherein, described polar solvent is selected from one or both of methanol and ethanol and the combination more than one or both of water, acetone, chloroform, dichloromethane and N, N dimethylformamide.Complex of the present invention shows the antitumor activity more stronger than part and cis-platinum, has preferable potential medical value, is expected to be used for the preparation of various antineoplastics.Structure shown in formula (I) and formula (II) is as follows：。
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of 1- (2- pyridines) -9- (2- Benzyloxyethyls)-B-carboline
Copper-nitrate complex and synthetic method and application.
Background technology
B-carboline is a kind of alkaloid for being distributed widely in nature, and they are primarily present in a variety of terrestrial plants and ocean
In biology.Chemically classify in structure, beta-carboline alkaloid belongs to indoles alkaloid, and it is three be made up of trypoline
Member ring systems, its skeleton are a planar molecules, wherein two nitrogen-atoms of 2 and 9 exist with different hybridization states,
9 nitrogen-atoms are sp3Hydridization, is rich pi-electron system, and 2 nitrogen-atoms are sp2Hydridization, to lack pi-electron system.Two nitrogen-atoms with
The chemical property and bioactivity of such compound are closely related.There is such compound extensive biology and pharmacology to live
Property, including：Sedative, antianxiety, hypnosis, anti-spasm, antitumor, antiviral, desinsection and antibacterial activity etc..Therefore β-click
Quinoline alkaloid is increasingly paid attention to by researcher.
On the other hand, the Pharmaceutical Inorganic Chemistry based on medical active part is studied in recent years with bioinorganic chemistry
Flourish and turn into hot research field, the first, second and third generation platinum class especially with cis-platinum, carboplatin, oxaliplatin etc. for representative
Successful application of the cancer therapy drug as front-line chemotherapeutic agents, really indicate Metal Drugs research and the arrival of application New Times.
But have not yet to see using 1- (2- pyridines) -9- (2- Benzyloxyethyls)-B-carbolines as copper nitrate (II) complex of part and
Its synthetic method and the relevant report of application.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of structure novelty with 1- (2- pyridines) -9- (2- benzyloxy second
Base)-B-carboline be part copper nitrate (II) complex, and its synthetic method and application.
The present invention relates to compound shown in lower formula (I) or its pharmaceutically acceptable salt：
The synthetic method of compound is shown in above-mentioned formula (I)：Take compound and copper nitrate (Cu as shown in following formula (II)
(NO3)2·3H2O), it is dissolved in polar solvent, carries out complexation reaction, that is, obtain target product；Wherein, described polar solvent is
Selected from one or both of methanol and ethanol with water, acetone, chloroform, dichloromethane and DMF
One or more kinds of combinations；
Compound shown in the raw material formula (II) being related in above-mentioned synthetic method participates in reacting as part, and its chemical name is
1- (2- pyridines) -9- (2- Benzyloxyethyls)-B-carboline, in this application also referred to as L.Compound shown in the formula (II) can be certainly
Prepared by row design synthetic route, preferably prepared as follows：
Using tryptamines and pyridine-2-formaldehyde as raw material, reacted in the first organic solvent, compound is obtained by dehydrating condensation
1；Then compound 1 is placed in the second organic solvent, add oxidant cyclization and dehydrogenation obtain compound 2 (1- (2- pyridines)-
B-carboline)；Compound 2 is placed in the aprotic polar solvent of alkaline matter again, 2- benzyloxy bromoethanes is added and is substituted
Reaction, is produced；Wherein：
The first described organic solvent is one kind or two in toluene, methanol, ethanol, dichloromethane and chloroform
The combination of the kind above；
The second described organic solvent is one kind or two in benzene, toluene, paraxylene, glacial acetic acid and dichloromethane
The combination of the kind above；
Described oxidant is palladium carbon, manganese acetate hydrate (Mn (Ac)3·nH2O), lead tetraacetate (Pb (Ac)4) or 2,3-
Two chloro- 5,6- dicyan 1,4-benzoquinone (DDQ)；
Described alkaline matter is inorganic base；
Described aprotic polar solvent in N,N-dimethylformamide, dimethyl sulfoxide (DMSO) and acetone one kind or
Two or more combinations.
The synthetic route of compound method is as follows shown in above-mentioned preparation formula (II)：
Reagent：(a) the first organic solvent；(b) oxidant, the second organic solvent；(c) alkaline matter, aprotonic polar are molten
Agent.
The more specifically preparation method of compound shown in above-mentioned formula (II), comprises the following steps：
1. using tryptamines and pyridine-2-formaldehyde as raw material, reacted in the first organic solvent, discharge reaction life in course of reaction
Into water, question response terminates rear solvent evaporated, obtains compound 1；
2. compound 1 is placed in the second organic solvent, oxidant is added, is reacted under heating condition, question response terminates, mistake
Filter, filtrate is collected, is evaporated, obtains compound 2；
3. taking alkaline matter to be dissolved in aprotic polar solvent, then add compound 2 and 2- benzyloxies bromoethane is carried out
Reaction, question response terminate, and reactant is put into frozen water, gained mixture of ice and water is extracted, and collect organic phase, are evaporated molten
Agent, that is, obtain compound (i.e. compound 3) shown in formula (II).
Shown in above-mentioned formula (II) the step of compound synthesis method 1. in, the amount of the material of tryptamines and pyridine-2-formaldehyde it
Than being usually 0.8~1.2：1, reaction can be carried out under conditions of being heated or not heated, and water knockout drum can be used in course of reaction
Whether the water of discharge reaction generation, reaction can use thin-layer chromatography (TLC) tracing detection completely；Preferably, reaction uses
Heating reflux reaction, the time control now reacted are appropriate in 2~6h.In the step, what is obtained is the thick production of compound 1
Thing, in order to reduce the impurity in subsequent reactions, improve the yield of postorder reaction, preferably to residue obtained progress purification process after
Postorder reaction is carried out again.Specific purification process can be recrystallized to residue obtained with small polar solvent, gained recrystallization production
Thing is used further to postorder reaction.It is described be used for recrystallize small polar solvent it is same as the prior art, can be specifically petroleum ether and/
Or n-hexane etc..
Shown in above-mentioned formula (II) the step of compound synthesis method 2. in, reaction preferably use heating reflux reaction, reaction
Whether thin-layer chromatography tracing detection be able to can be used completely.In the step, what is obtained is the crude product of compound 2, in order to reduce
Impurity in subsequent reactions, the yield of postorder reaction is improved, preferably to carrying out postorder again after residue obtained progress purification process
Reaction.Specific purification process can be to it is residue obtained with selected from one or both of methanol, ethanol and dichloromethane with
On combination solvent recrystallized, or residue obtained upper silica gel column chromatography is purified, it is used in upper silica gel column chromatography
Eluant, eluent press 6 for petroleum ether and dichloromethane：1~1：The mixed solvent of 1 volume ratio composition.
Shown in above-mentioned formula (II) the step of compound synthesis method 2. in, according to the difference of oxidant, from different
Two organic solvents, it is specific as follows：
(1) when the selection of oxidant is palladium carbon, the second organic solvent is preferably one kind in benzene, toluene and paraxylene
Or two or more combinations, when two organic solvents selection for more than above two combination when, proportioning between them can be with
For any proportioning.Described palladium carbon can be 5%Pd/C or 10%Pd/C, and the addition of the palladium carbon generally presses 10mmol chemical combination
Thing 1 adds 2~4g palladium carbons and calculated.
(2) when the selection of oxidant is manganese acetate hydrate or lead tetraacetate, the second organic solvent is preferably glacial acetic acid；
The addition of the manganese acetate hydrate or lead tetraacetate is usually 2~8 times of the amount of the material of compound 1.When the choosing of oxidant
When being selected as manganese acetate hydrate or lead tetraacetate, preferably reaction uses pH >=7 of alkali lye regulation system after terminating, then it is extracted
Take, collect organic phase, the upper silica gel column chromatography purifying again of the residue obtained by solvent evaporated；Wherein, described alkali lye can be ammoniacal liquor,
The aqueous solution of the alkaline matters such as sodium acetate, sodium carbonate, sodium phosphate, sodium acid carbonate or potassium carbonate, the concentration of the alkali lye is preferably 5
~30w/w%；Solvent for system after extraction tune pH value can be specifically ethyl acetate, dichloromethane, chloroform or ether etc..
(3) when the selection of oxidant 5,6- dicyan 1,4-benzoquinone chloro- for 2,3- bis-, the second organic solvent is preferably benzene, first
One or more kinds of combinations of benzene and dichloromethane, when the selection of two organic solvents is the combination of more than above two,
Proportioning between them can be any proportioning.The addition of the chloro- 5,6- dicyan 1,4-benzoquinone of 2,3- bis- is usually compound 1
1~4 times of the amount of material.
Shown in above-mentioned formula (II) the step of compound synthesis method 3. in, the alkaline matter, compound 2 and 2- benzyloxies
The ratio between amount of material of bromoethane is usually 1~4：1：1~3, alkaline matter therein can be further sodium hydride, hydrogenation
Combination more than one or both of calcium, calcium hydroxide, sodium hydroxide, potassium hydroxide, cesium carbonate and potassium carbonate, works as basic species
When the selection of matter is combination more than above two, the proportioning between them can be any proportioning.In the step, reaction can be with
Carried out under the conditions of 0~80 DEG C, whether reaction can use thin-layer chromatography (TLC) tracing detection completely；Preferably, react
20~50 DEG C, the time control now reacted is appropriate in 1~6h.The solvent extracted to mixture of ice and water can be specifically
The conventional extraction solvent such as ethyl acetate, dichloromethane, chloroform, petroleum ether or ether.
(such as the first organic solvent, second have involved various solvents in compound synthesis method shown in above-mentioned formula (II)
Solvent and aprotic polar solvent etc.) dosage, with can dissolve participated in each step reaction raw material be advisable.
What the above method was prepared is the crude product of compound shown in formula (II), in order to further improve shown in formula (II)
The purity of compound, the progress of subsequent reactions is more beneficial for, is used again after preferably carrying out purification process to above-mentioned gained crude product
In the synthetic method of target product of the present invention.Described purification process is same as the prior art, can be specifically by crude product
Upper silica gel column chromatography purifying, to obtain pure compounds shown in formula (II)；In upper silica gel column chromatography, eluant, eluent used is two
Chloromethanes and methanol press 1000：1~50：The mixed solvent of 1 volume ratio composition.
In the synthetic method of compound shown in formula (I) of the present invention, in the composition of polar solvent, methanol or ethanol or
Person is that the combination of methanol and ethanol ratio shared in polar solvent is preferably 50~98v/v%；When containing in polar solvent
During two or more selections in water, acetone, chloroform, dichloromethane and DMF, do not surpass in their total amount
Go out under 50% precondition, their proportioning can be any proportioning.The dosage of the polar solvent can determine as needed,
Under normal circumstances, compound shown in 1mmol copper nitrate and 1mmol formulas (II) is dissolved with 5~80mL polar solvent.Having
In the dissolving step of body, additive polarity solvent again after typically compound shown in copper nitrate and formula (II) is mixed；Also can be by copper nitrate
Dissolved respectively with polar solvent with compound shown in formula (II), remix and react together.
In the synthetic method of compound shown in formula (I) of the present invention, compound shown in the copper nitrate and formula (II)
The ratio between amount of material can be 1~6：1.
Compound shown in formula (I) of the present invention specifically in synthesis, can use normal pressure solwution method or high pressure solvent heat
Method is synthesized.
When using normal pressure solwution method, its synthetic method includes：Compound shown in formula (II) and copper nitrate are taken, is dissolved in polarity
In solvent, gained mixed liquor reacts under the conditions of being heated or not heated, and reactant removes partial solvent, stands, and separates out, isolates
Crystal, produce target product.
In above-mentioned normal pressure solwution method, reaction can be carried out in 20 DEG C to polar solvent of reflow temperature range, preferably be adopted
With back flow reaction, further preferably reaction is carried out in 50 DEG C to polar solvent of reflow temperature range, more preferably 60
Reacted under the conditions of DEG C.Whether reaction can use thin-layer chromatography tracing detection completely.In this method, product is typically in the form of crystal
A large amount of generations, if the addition of polar solvent is larger in previous step (such as the upper limit close to proportioning) or solvent is to the molten of product
Solution property is preferable, then solution may be in clear state after reacting, because the product formed precipitates dissolves institute by polar solvent
Cause, gained reaction solution can now be concentrated or is evaporated under reduced pressure to remove partial solvent, typically concentration removes polar solvent and added
The 50~90% of amount.Isolated solid can be washed further with ether, acetone, ethanol, methanol or dichloromethane, it
It is dried again afterwards.
When the hot method of high pressure solvent, its synthetic method includes：Compound shown in formula (II) and copper nitrate are taken, it is molten to be dissolved in polarity
In agent, gained mixed liquor is placed in container, and vacuum is evacuated to after liquid nitrogen frozen, sealing, then anti-under the conditions of 30~140 DEG C
Should, obtain target product.
In the above-mentioned hot method of high pressure solvent, described container is usually heavy wall borosilicate glass tube, is reacted generally at 30~140 DEG C
Under the conditions of carry out, under this temperature conditions, the time of reaction is preferably controlled in 2~24h, can also be extended to according to actual conditions
More than 24h.Further preferred mixed solution is reacted under the conditions of 50~140 DEG C, more preferably mixed solution be 80~
Reacted under the conditions of 100 DEG C.When being carried out under normal temperature or heating condition of the reaction below 80 DEG C, when reaction needs longer
Between can just obtain higher yield.
Present invention additionally comprises compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I) in antineoplastic is prepared
Application.
Present invention additionally comprises what is prepared using compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I) as active component
Antineoplastic.
Compared with prior art, the invention provides a kind of new with 1- (2- pyridines) -9- (2- Benzyloxyethyls)-β-click
Quinoline is copper nitrate (II) complex of part, and its synthetic method and application.Applicant is by investigating it to kinds of tumors
The inhibitory action of cell line, the results showed that the complex has stronger anti tumor activity in vitro, and apparently higher than cis-platinum, has
Preferable potential medical value, is expected to be used for the preparation of various antineoplastics.
Brief description of the drawings
Fig. 1 is the x-ray crystal structure figure of final product made from the embodiment of the present invention 5.
Embodiment
With reference to specific embodiment, the present invention is described in further detail, to more fully understand present disclosure, but
The present invention is not limited to following examples.
Embodiment 1：Compound shown in formula (II) is the synthesis of 1- (2- pyridines) -9- (2- Benzyloxyethyls)-B-carbolines (L)
1) 1.6g (10mmol) tryptamines, 1.1g (10mmol) pyridine-2-formaldehydes and 50ml toluene are added into 150ml round bottoms to burn
Bottle, plus water knockout drum, condenser pipe group composition water reflux, is heated to reflux 4 hours, question response terminates rear solvent evaporated, residue
Compound 1 (2.3g, yield 92%) is recrystallized to give with 100ml n-hexanes；
2) 2.5g (10mmol) compound 1,2.5g palladium carbons (10%Pd/C) and 100ml paraxylene are added into 250ml circles
Bottom flask, it is heated to flowing back, and is terminated with thin-layer chromatography tracing detection to reaction, stands and filter and be evaporated filtrate, gained is residual
Silica gel column chromatography purifies (V on slagPetroleum ether：VDichloromethane=1:1) compound 2 (2.1g, yield 86%), is obtained；
3) 0.24g (10mmol) sodium hydrides and 15ml DMFs are added to 50ml round-bottomed flasks, room temperature
Stirring 10 minutes, adds 2.5g (10mmol) compound 2 and 10mmol 2- benzyloxy bromoethanes, and tracked with thin-layer chromatography
Detection to reaction terminates, and then puts into reaction solution in 500ml frozen water, with the extraction of 100ml ethyl acetate three times, merges organic
Phase, solvent evaporated, residue obtained upper silica gel column chromatography purifying (VDichloromethane：VMethanol=100:1) compound 3 (2.7g, yield, are obtained
71%).
Products therefrom is characterized：
(1) proton nmr spectra and carbon spectrum, their spectral data are as follows：
1H NMR(500MHz,CDCl3) δ 8.68 (d, J=4.7Hz, 1H), 8.55 (d, J=5.1Hz, 1H), 8.18 (d, J
=7.8Hz, 1H), 8.07 (d, J=5.1Hz, 1H), 7.86 (q, J=7.7Hz, 2H), 7.64-7.54 (m, 2H), 7.38 (t, J
=5.9Hz, 1H), 7.32 (t, J=7.2Hz, 1H), 7.24-7.16 (m, 3H), 6.96-6.88 (m, 2H), 4.48 (t, J=
6.1Hz, 2H), 4.16 (s, 2H), 3.47 (t, J=6.1Hz, 2H)
13C NMR(126MHz,CDCl3)δ148.21,142.93,142.16,137.70,136.99,134.45,
133.02,131.67,129.47,128.71,128.20,127.57,127.39,125.34,123.19,121.37,121.22,
120.11,114.61,110.77,72.97,68.07,45.04.
(2) high resolution mass spectrum, ESI-MS m/z:380[M+H]+.
Accordingly, it can be determined that above-mentioned product is 1- (2- pyridines) -9- (2- Benzyloxyethyls)-B-carboline, its chemical constitution
Shown in formula such as following formula (II)：
Embodiment 2：The synthesis of ligand L
Embodiment 1 is repeated, unlike：
In step 2), with Mn (Ac)3Instead of palladium carbon, paraxylene, control Mn (Ac) are replaced with glacial acetic acid3Addition be
2 times of the amount of the material of compound 1, react and are carried out under the conditions of 70 DEG C, and TLC tracing detections to reaction terminate, then will with ammoniacal liquor
The pH of system is adjusted to 7, then is extracted with ethyl acetate three times, merges organic phase, solvent evaporated, residue obtained upper silicagel column (chromatography
Purify (VPetroleum ether：VDichloromethane=1:1) compound 2, is obtained.
Proton nmr spectra, carbon-13 nmr spectra and high resolution mass spectrum analysis are carried out to the present embodiment products therefrom, it is determined that
For target product 1- (2- pyridines) -9- (2- Benzyloxyethyls)-B-carboline.
Embodiment 3：The synthesis of ligand L
Embodiment 2 is repeated, unlike：
In step 2), with Pb (Ac)4Instead of Mn (Ac)3, control Pb (Ac)4Addition for the material of compound 1 amount 5
Times, react and carried out under the conditions of 60 DEG C.
Proton nmr spectra, carbon-13 nmr spectra and high resolution mass spectrum analysis are carried out to the present embodiment products therefrom, it is determined that
For target product 1- (2- pyridines) -9- (2- Benzyloxyethyls)-B-carboline.
Embodiment 4：The synthesis of ligand L
Embodiment 1 is repeated, unlike：
In step 2), palladium carbon is replaced with chloro- 5, the 6- dicyan 1,4-benzoquinone of 2,3- bis-, paraxylene is replaced with dichloromethane, 2,
The addition of the chloro- 5,6- dicyan 1,4-benzoquinone of 3- bis- is equal with the amount of the material of compound 1.
Proton nmr spectra, carbon-13 nmr spectra and high resolution mass spectrum analysis are carried out to the present embodiment products therefrom, it is determined that
For target product 1- (2- pyridines) -9- (2- Benzyloxyethyls)-B-carboline.
Embodiment 5：Title complex [Cu (L) (NO3)2] synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.1mmol Cu (NO are directly added into3)2·3H2O and 0.1mmol match somebody with somebody
Body L, adding 0.6ml ethanol/methylenes mixed solution, (volume ratio of methanol and dichloromethane is 3:1), vacuumizing
Under the conditions of, openend is sealed, is then fully reacted 20 hours under the conditions of 50 DEG C, obtains green crystal type solid product.
Products therefrom is characterized：
(1) high resolution mass spectrum, ESI-MS m/z:504[Cu(L)(DMSO)(NO3)]+(DMSO makes when coming from mass spectrometric measurement
Solvent)
(2) X ray single crystal diffraction is analyzed, as shown in Figure 1.
Therefore can determine that above-mentioned product is the copper using 1- (2- pyridines) -9- (2- Benzyloxyethyls)-B-carbolines as part
(II) complex is title complex [Cu (L) (NO3)2], shown in its structural formula such as following formula (I)：
Embodiment 6：Title complex [Cu (L) (NO3)2] synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.2mmol Cu (NO are directly added into3)2·3H2O and 0.1mmol match somebody with somebody
Body L, adding 0.6ml ethanol/chloroform mixed solution, (volume ratio of ethanol and chloroform is 3:1), will, under conditions of vacuumizing
Openend seals, and is then fully reacted 12 hours under the conditions of 80 DEG C, obtains green crystal type solid product.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X ray single crystal diffraction, is defined as target cooperation
Thing [Cu (L) (NO3)2]。
Embodiment 7：Title complex [Cu (L) (NO3)2] synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.3mmol Cu (NO are directly added into3)2·3H2O and 0.1mmol match somebody with somebody
Body abbreviation L, add 0.6ml methanol/ethanols/N,N-dimethylformamide mixed solution (methanol, ethanol and N, N- dimethyl methyl
The volume ratio of acid amides is 5：1：1), under conditions of vacuumizing, openend is sealed, the then fully reaction 4 under the conditions of 100 DEG C
Hour, obtain green crystal type solid product.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X ray single crystal diffraction, is defined as target cooperation
Thing [Cu (L) (NO3)2]。
Embodiment 8：Title complex [Cu (L) (NO3)2] synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.4mmol Cu (NO are directly added into3)2·3H2O and 0.1mmol match somebody with somebody
Body L, adding 0.6ml ethanol/acetones mixed solution, (volume ratio of ethanol and acetone is 10:1), under conditions of vacuumizing,
Openend is sealed, is then fully reacted 4 hours under the conditions of 80 DEG C, obtains green crystal type solid product.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X ray single crystal diffraction, is defined as target cooperation
Thing [Cu (L) (NO3)2]。
Embodiment 9：Title complex [Cu (L) (NO3)2] synthesis
Take 6mmol Cu (NO3)2·3H2O and 1mmol ligand Ls are placed in round-bottomed flask, add 80ml ethanol/waters thereto
(volume ratio of second alcohol and water is 1 to mixed solution:1), after stirring and dissolving, 60 DEG C is heated to and is reacted 12 hours, reactant decompression is dense
Contracting removes partial solvent, stands, has green crystal precipitation, isolate solid, washed with ethanol, dries, obtains green crystal.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X ray single crystal diffraction, is defined as target cooperation
Thing [Cu (L) (NO3)2]。
Embodiment 10：Title complex [Cu (L) (NO3)2] synthesis
Take 2mmol Cu (NO3)2·3H2O and 1mmol ligand Ls are placed in round-bottomed flask, add 50ml methanol/the third thereto
(volume ratio of methanol, acetone and water is 30 to ketone/water mixed solution：1：10), after stirring and dissolving, it is small that 50 DEG C of reactions 12 are heated to
When, reactant, which is concentrated under reduced pressure, removes partial solvent, stands, has green crystal precipitation, isolate solid, washed with ethanol, dries,
Obtain green crystal.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X ray single crystal diffraction, is defined as target cooperation
Thing [Cu (L) (NO3)2]。
Embodiment 11：Title complex [Cu (L) (NO3)2] synthesis
Take 3mmol Cu (NO3)2·3H2O and 1mmol ligand Ls are placed in round-bottomed flask, add 30ml methanol/chlorine thereto
(volume ratio of methanol and chloroform is 1 to imitative mixed solution：1), after stirring and dissolving, reacted 18 hours in 20 DEG C, reactant decompression is dense
Contracting removes partial solvent, stands, has green crystal precipitation, isolate solid, washed with ethanol, dries, obtains green crystal.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X ray single crystal diffraction, is defined as target cooperation
Thing [Cu (L) (NO3)2]。
In order to absolutely prove purposes of the complex of the present invention in pharmacy, applicant has carried out extracorporeal anti-tumor to it
Activity experiment.
Experimental example 1：Copper nitrate (II) complex using 1- (2- pyridines) -9- (2- Benzyloxyethyls)-B-carbolines as part
(being made by the methods described of the embodiment of the present invention 5) and ligand L (being made by the methods described of the embodiment of the present invention 1) swell to a variety of mankind
Knurl strain carries out external inhibitory activity experiment
1st, cell line and cell culture
This experiment is non-from gastric carcinoma cells MGC-803, human hepatoma cell strain Hep G2, human bladder cancer cell T-24, people
Small cell lung cancer cell NCI-H460 and human normal cell line HL-7702 totally 5 kinds of cell lines.
All tumor cell lines are cultivated containing 10wt% small ox bloods, 100U/mL penicillin, 100U/mL streptomysins
In RPMI-1640 nutrient solutions, 37 DEG C of 5%CO containing volumetric concentration are put2Cultivated in incubator；Human normal cell line strain then cultivate containing
The small ox bloods of 10wt%, 100U/mL penicillin, 100U/mL streptomysins DMEM nutrient solutions in.
2nd, the preparation of testing compound
The DMSO liquid storages (concentration 0.002mol/L) of each testing compound are diluted successively by RMPI1640 culture mediums
Into five concentration gradients, respectively 20,10,5,2.5,1.25 μm of ol/L, wherein cosolvent DMSO final concentration≤1%.Survey first
20 μm of ol/L each testing compound is tried for the inhibiting rate of tumor cell proliferation, is considered as primary dcreening operation result；Test is different respectively again
Each testing compound is to the Proliferation Ability degree of various tumour cells under gradient concentration, to the Fitting Calculation half-inhibition concentration,
That is IC50Value.
3rd, cell growth inhibition test (mtt assay)
(1) take the logarithm the tumour cell in growth period, after Trypsin Induced, matched somebody with somebody with the nutrient solution containing 10% calf serum
The cell suspension that concentration is 5000/mL is made, is inoculated in every μ L of hole 190 in 96 well culture plates, makes cell density to be measured extremely
1000~10000/hole (edge hole is filled with sterile PBS)；
(2) 5%CO2, 37 DEG C of incubation 24h, bottom hole is paved with to cell monolayer, the medicine 10 of finite concentration gradient is added per hole
μ L, each concentration gradient set 4 multiple holes；
(3) 5%CO2, 37 DEG C are incubated 48 hours, are observed under inverted microscope；
(4) 10 μ L MTT solution (5mg/mL PBS, i.e. 0.5%MTT) is added per hole, continues to cultivate 4h；
(5) culture is terminated, carefully sucks nutrient solution in hole, 150 μ L DMSO are added per hole and fully dissolve first a ceremonial jade-ladle, used in libation precipitation, are shaken
Swing after device mixes, with wavelength be 570nm in ELIASA, reference wavelength is the OD value that 450nm determines each hole；
(6) while zeroing hole (culture medium, MTT, DMSO) is set, (the medicine dissolving of cell, same concentrations is situated between control wells
Matter, nutrient solution, MTT, DMSO).
(7) according to the OD value (OD values) measured, to judge living cells quantity, OD values are bigger, and cytoactive is stronger.
Calculate the inhibiting rate of compound on tumor cell growth.For cell of the inhibiting rate more than 50% under primary dcreening operation concentration
The inhibiting rate data of five concentration gradients are further fitted, obtain compound to different tumours by strain by SPSS softwares
Half-inhibition concentration (the IC of strain50Value, unit μm ol/L), IC of the compound for different cell lines50Value is as shown in table 1.
Table 1：IC of the compound of the present invention to 5 kinds of cell lines50It is worth (μm ol/L)
From the point of view of anti tumor activity in vitro test result, complex of the present invention has stronger antitumor activity, its
Activity is substantially better than cis-platinum, is expected to exploitation into antineoplastic.
Claims (10)
1. compound shown in lower formula (I)：
2. the synthetic method of compound described in claim 1, it is characterised in that：Take compound and nitric acid as shown in following formula (II)
Copper, it is dissolved in polar solvent, carries out complexation reaction, that is, obtain target product；Wherein, described polar solvent be selected from methanol and
One or both of ethanol with selected from one or both of water, acetone, chloroform, dichloromethane and DMF
Combination above；
3. synthetic method according to claim 2, it is characterised in that：Compound shown in formula (II) and copper nitrate are taken, is dissolved in
In polar solvent, gained mixed liquor reacts under the conditions of being heated or not heated, and reactant removes partial solvent, stands, and separates out, point
Crystal is separated out, produces target product.
4. synthetic method according to claim 3, it is characterised in that：React the reflux temperature model at 50 DEG C to polar solvent
Enclose interior progress.
5. synthetic method according to claim 2, it is characterised in that：Compound shown in formula (II) and copper nitrate are taken, is dissolved in
In polar solvent, gained mixed liquor is placed in container, and vacuum is evacuated to after liquid nitrogen frozen, sealing, then in 30~140 DEG C of conditions
Lower reaction, obtains target product.
6. synthetic method according to claim 5, it is characterised in that：Reaction is carried out under the conditions of 50~140 DEG C.
7. the synthetic method according to any one of claim 2~6, it is characterised in that：Compound shown in the formula (II)
Prepared as follows：
Using tryptamines and pyridine-2-formaldehyde as raw material, reacted in the first organic solvent, compound 1 is obtained by dehydrating condensation；So
Compound 1 is placed in the second organic solvent afterwards, oxidant cyclization is added and dehydrogenation obtains compound 2；Compound 2 is placed in again
In the aprotic polar solvent of alkaline matter, add 2- benzyloxies bromoethane and carry out substitution reaction, produce；Wherein：
The first described organic solvent be selected from one or both of toluene, methanol, ethanol, dichloromethane and chloroform with
On combination；
The second described organic solvent be selected from one or both of benzene, toluene, paraxylene, glacial acetic acid and dichloromethane with
On combination；
Described oxidant is palladium carbon, manganese acetate hydrate, lead tetraacetate or the chloro- 5,6- dicyan 1,4-benzoquinone of 2,3- bis-；
Described alkaline matter is inorganic base；
Described aprotic polar solvent is selected from one or both of N,N-dimethylformamide, dimethyl sulfoxide (DMSO) and acetone
Combination above；
The structure difference of the compound 1 and compound 2 is as follows：
8. synthetic method according to claim 7, it is characterised in that：Purifying behaviour is carried out to compound shown in gained formula (II)
Make.
9. application of the compound described in claim 1 in antineoplastic is prepared.
A kind of 10. antineoplastic pharmaceutical compositions, it is characterised in that：Contain compound described in the claim 1 as active component.
Priority Applications (1)
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2508570A2 (en) * | 2009-12-02 | 2012-10-10 | SFC Co., Ltd. | Organic metal dye, and photoelectric element and dye-sensitized solar cell using the organic metal dye |
| CN103254239A (en) * | 2013-03-20 | 2013-08-21 | 中山大学 | aryl ruthenium-beta-carboline complex and its preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN103254239A (en) * | 2013-03-20 | 2013-08-21 | 中山大学 | aryl ruthenium-beta-carboline complex and its preparation method and application |
Non-Patent Citations (4)
| Title |
|---|
| 3_甲基_咔啉衍生物的合成及其抑菌活性研究;张前亮;《西北农林科技大学硕士学位论文》;20131231;第1-2章 * |
| Copper(II/I) complexes of 5-pyridin-2-yl-[1,3]dioxolo[4,5-g] isoquinoline: Synthesis, crystal structure, antitumor activity and DNA interaction;Ke-Bin Huang et al;《European Journal of Medicinal Chemistry》;20131231;第70卷;第640-648页 * |
| Metal Cu(II) and Zn(II) bipyridyls as inhibitors of lactate dehydrogenas;Raj Kumar Koiri et al;《Biometals》;20081231;第21卷;第117-126页 * |
| Synthesis, characterization and in vitro biological activitystudies of Cu-M (M=Cu2+, Co2+, Ni2+, Mn2+, Zn2+) bimetallic complexes;K.R. Rupesh et al;《European Journal of Medicinal Chemistry》;20061231;第41卷;第1494-1503页 * |
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