CN106632418B - Using 1- (2- pyridines) -9- octyls-B-carboline as the chlorination copper complex and its synthetic method of ligand and application - Google Patents
Using 1- (2- pyridines) -9- octyls-B-carboline as the chlorination copper complex and its synthetic method of ligand and application Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 21
- 238000005660 chlorination reaction Methods 0.000 title claims abstract description 5
- 239000003446 ligand Substances 0.000 title abstract description 23
- 150000004699 copper complex Chemical class 0.000 title abstract description 4
- 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 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 42
- 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 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical class CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 22
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims abstract description 22
- 235000019441 ethanol Nutrition 0.000 claims abstract description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 8
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 238000010668 complexation reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 44
- 239000002904 solvent Substances 0.000 claims description 25
- 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
- 239000010949 copper Substances 0.000 claims description 16
- 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 229940125904 compound 1 Drugs 0.000 claims description 8
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 6
- VMKOFRJSULQZRM-UHFFFAOYSA-N 1-bromooctane Chemical class CCCCCCCCBr VMKOFRJSULQZRM-UHFFFAOYSA-N 0.000 claims description 5
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-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
- 239000000376 reactant 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
- 229960000583 acetic acid Drugs 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 3
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 239000000470 constituent Substances 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
- 238000006467 substitution reaction Methods 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- 230000000118 anti-neoplastic effect Effects 0.000 claims 1
- 229910052802 copper Inorganic materials 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
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- 229910052697 platinum Inorganic materials 0.000 abstract description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract description 4
- -1 octyl β carbolines Chemical class 0.000 abstract description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract 1
- 239000000047 product Substances 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 238000000034 method Methods 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 238000001819 mass spectrum Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 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
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 8
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 8
- 239000011259 mixed solution Substances 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
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- 238000004458 analytical method Methods 0.000 description 6
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- 230000002401 inhibitory effect Effects 0.000 description 5
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- 238000001308 synthesis method Methods 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 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
- 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
- 239000007787 solid Substances 0.000 description 4
- 239000012265 solid product Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method 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
- 238000012360 testing method Methods 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000000908 ammonium hydroxide Substances 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
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- 238000000338 in vitro Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000002156 mixing Methods 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
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- 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 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
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 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
- 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
- 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
- 150000001412 amines Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 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
- 230000033228 biological regulation Effects 0.000 description 1
- 239000006227 byproduct Substances 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
- 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
- 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
- 230000029087 digestion Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 208000010749 gastric carcinoma Diseases 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
- 230000000147 hypnotic effect Effects 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 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
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 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
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 229930002341 quinoline alkaloid Natural products 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
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000002893 slag Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 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
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- 238000003860 storage Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
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- 239000003643 water by type Substances 0.000 description 1
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 description 1
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)
Abstract
The invention discloses one kind using 1 (2 pyridine) 9 octyl β carbolines as the chlorination copper complex and its synthetic method of ligand and application.Shown in the structural formula of the complex such as following formula (I), synthetic method is：Take compound and copper chloride as shown in following formula (II), be dissolved in polar solvent, carry out complexation reaction to get；Wherein, the polar solvent be selected from one or both of methanol and ethyl alcohol with selected from water, acetone, chloroform, dichloromethane and N, the combination of one or more of N dimethylformamides.Complex of the present invention shows antitumor activity more stronger than ligand and cis-platinum, has preferable potential medical value, is expected to be used for the preparation of various antitumor drugs.Structure is as follows shown in formula (I) and formula (II)：
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to one kind is using 1- (2- pyridines) -9- octyls-B-carboline as ligand
Chlorination copper complex and its synthetic method and application.
Background technology
B-carboline is a kind of alkaloid for being distributed widely in nature, 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, it is three be made of trypoline
Member ring systems, its skeleton are a planar molecules, wherein 2 and 9 two nitrogen-atoms exist with different hybridization states,
9 nitrogen-atoms are sp3Hydridization, for rich pi-electron system, 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 ligand is studied in recent years with bioinorganic chemistry
It flourishes and becomes hot research field, be especially the first, second and third generation platinum class of representative with cis-platinum, carboplatin, oxaliplatin etc.
Successful application of the anticancer drug as front-line chemotherapeutic agents really indicates the arrival of Metal Drugs research and application new era.
But it has not yet to see using 1- (2- pyridines) -9- octyls-B-carboline as copper chloride (II) complex and its synthetic method of ligand
With the relevant report of application.
Invention content
The technical problem to be solved in the present invention is to provide a kind of structure novels with 1- (2- pyridines) -9- octyls-B-carboline
For copper chloride (II) complex of ligand and its synthetic method and application.
The present invention relates to compound shown in lower formula (I) or its pharmaceutically acceptable salts：
The synthetic method of compound shown in above-mentioned formula (I) is：Take compound and copper chloride as shown in following formula (II)
(CuCl2·2H2O), it is dissolved in polar solvent, carries out complexation reaction to get to target product；Wherein, the polar solvent is
Selected from one or both of methanol and ethyl alcohol in water, acetone, chloroform, dichloromethane and n,N-Dimethylformamide
A combination of one or more；
Compound shown in raw material formula (II) involved in above-mentioned synthetic method participates in reacting as ligand, its chemical name is
1- (2- pyridines) -9- octyls-B-carboline, in this application also referred to as L.Compound shown in the formula (II) can designed, designed synthesis
Prepared by route, preferably prepared as follows：
It using tryptamines and pyridine-2-formaldehyde as raw material, is reacted in the first organic solvent, compound is obtained by dehydrating condensation
1；Then compound 1 is placed in the second organic solvent, oxidant cyclization is added and dehydrogenation obtains the (1- (2- pyridines)-of compound 2
B-carboline)；Compound 2 is placed in the aprotic polar solvent of alkaline matter again, 1- bromooctanes are added and carry out substitution reaction, i.e.,
；Wherein：
First organic solvent is one kind or two in toluene, methanol, ethyl alcohol, dichloromethane and chloroform
Kind or more combination；
Second organic solvent is one kind or two in benzene, toluene, paraxylene, glacial acetic acid and dichloromethane
Kind or more combination；
The 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)；
The alkaline matter is inorganic base；
The aprotic polar solvent be one kind in N,N-dimethylformamide, dimethyl sulfoxide (DMSO) and acetone or
Two or more combinations.
The synthetic route of compound method shown in above-mentioned preparation formula (II) is as follows：
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), includes the following steps：
1. using tryptamines and pyridine-2-formaldehyde as raw material, reacted in the first organic solvent, discharge reaction life in reaction process
At water, wait for solvent evaporated after reaction, obtain compound 1；
2. compound 1 is placed in the second organic solvent, oxidant is added, is reacted under heating condition, to the end of reaction, mistake
Filter collects filtrate, is evaporated, obtains compound 2；
3. alkaline matter is taken to be dissolved in aprotic polar solvent, compound 2 then is added and 1- bromooctanes are reacted, waits for
Reaction terminates, by reactant put into ice water in, gained mixture of ice and water is extracted, collect organic phase, solvent evaporated to get
To 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 substance of tryptamines and pyridine-2-formaldehyde it
Than being usually 0.8~1.2：1, reaction can carry out under conditions of being heated or not heated, and water knockout drum can be used in reaction process
Whether the water that discharge reaction generates, reaction can be used thin-layer chromatography (TLC) tracing detection completely；Preferably, reaction uses
Heating reflux reaction, the time control reacted at this time are appropriate in 2~6h.In the step, what is obtained is the thick production of compound 1
Object improves the yield of postorder reaction to reduce the impurity in subsequent reactions, preferably to residue obtained progress purification process after
Postorder reaction is carried out again.Specific purification process can be recrystallized with small polar solvent to residue obtained, gained recrystallization production
Object is used further to postorder reaction.It is described for recrystallization 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 can be 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 improves the yield of postorder reaction, 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, ethyl alcohol 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 be that petroleum ether and dichloromethane press 6：1~1：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, select different
Two organic solvents, it is specific as follows：
(1) when oxidant is when being selected as palladium carbon, the second organic solvent is preferably one kind in benzene, toluene and paraxylene
Or two or more combinations, when the combination for being selected as above two or more of two organic solvents, proportioning between them can be with
Arbitrarily to match.The palladium carbon can be 5%Pd/C or 10%Pd/C, and the addition of the palladium carbon usually presses 10mmol chemical combination
Object 1 is added 2~4g palladium carbons and calculates.
(2) when oxidant is when being selected as 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 1 substance of compound.When the choosing of oxidant
When being selected as manganese acetate hydrate or lead tetraacetate, pH >=7 of lye regulation system are preferably used after reaction, then it is extracted
It takes, collects organic phase, the upper silica gel column chromatography purifying again of the residue obtained by solvent evaporated；Wherein, the lye can be ammonium hydroxide,
The concentration of the aqueous solution of the alkaline matters such as sodium acetate, sodium carbonate, sodium phosphate, sodium bicarbonate or potassium carbonate, the lye is preferably 5
~30/w/w%；For extract adjust pH value after the solvent of system can be specifically ethyl acetate, dichloromethane, chloroform or ether
Deng.
(3) when oxidant is when being selected as 2,3-, bis- chloro- 5,6- dicyan 1,4-benzoquinone, the second organic solvent is preferably benzene, first
The a combination of one or more of benzene and dichloromethane, when the combination for being selected as above two or more of two organic solvents,
Proportioning between them can be arbitrary proportioning.The addition of bis- chloro- 5,6- dicyan 1,4-benzoquinone of the 2,3- is usually compound 1
1~4 times of the amount of substance.
Shown in above-mentioned formula (II) the step of compound synthesis method 3. in, the alkaline matter, compound 2 and 1- bromooctanes
The ratio between the amount of substance be usually 1~4：1：1~3, alkaline matter therein may further be sodium hydride, calcium hydride, hydrogen-oxygen
The combination for changing one or more of calcium, sodium hydroxide, potassium hydroxide, cesium carbonate and potassium carbonate, when the choosing of alkaline matter
When being selected as the combination of above two or more, the proportioning between them can be arbitrary proportioning.In the step, reaction can 0~
It is carried out under the conditions of 80 DEG C, whether reaction can be used thin-layer chromatography (TLC) tracing detection completely；Preferably, reaction 20~
50 DEG C, the time control reacted at this time is appropriate in 1~6h.The solvent extracted to mixture of ice and water can be specifically acetic acid
The conventional extractions solvent such as ethyl ester, 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 increase shown in formula (II)
The purity of compound is more advantageous to the progress of subsequent reactions, 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.The 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 ethyl alcohol or
Person is that the combination of methanol and ethyl alcohol ratio shared in polar solvent is preferably 50~98v/v%；When containing in polar solvent
When two or more selections in water, acetone, chloroform, dichloromethane and n,N-Dimethylformamide, do not surpass in their total amount
Go out under 50% precondition, their proportioning can be arbitrary proportioning.The dosage of the polar solvent can determine as needed,
Under normal conditions, compound shown in the copper chloride of 1mmol and 1mmol formulas (II) is dissolved with the polar solvent of 5~80mL.Having
In the dissolving step of body, additive polarity solvent again after generally mixing compound shown in copper chloride and formula (II)；It also can be by copper chloride
It is dissolved respectively with polar solvent with compound shown in formula (II), remixes and react together.
In the synthetic method of compound shown in formula (I) of the present invention, compound shown in the copper chloride and formula (II)
The ratio between amount of substance can be 1~6：1.
Specifically in synthesis, normal pressure solwution method or high pressure solvent heat can be used in compound shown in formula (I) of the present invention
Method is synthesized.
When using normal pressure solwution method, synthetic method includes：Compound and copper chloride shown in formula (II) are taken, polarity is dissolved in
In solvent, gained mixed liquor reacts under the conditions of being heated or not heated, and reactant removes partial solvent, stands, and is precipitated, isolates
Crystal is to get target product.
In above-mentioned normal pressure solwution method, reaction can carry out in 20 DEG C to polar solvent of reflow temperature range, preferably adopt
With back flow reaction, further preferably reaction is carried out in 50 DEG C to polar solvent of reflow temperature range, more preferably 60
It is reacted under the conditions of DEG C.Whether reaction can be used thin-layer chromatography tracing detection completely.In this method, product is generally in the form of crystal
It is a large amount of to generate, 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, this is because be formed by product precipitation dissolves institute by polar solvent
It causes, gained reaction solution can be concentrated or is evaporated under reduced pressure to remove partial solvent at this time, typically concentration removes polar solvent and is added
The 50~90% of amount.Isolated solid can be washed further with ether, acetone, ethyl alcohol, methanol or dichloromethane, it
It is dried again afterwards.
When the hot method of high pressure solvent, synthetic method includes：Compound and copper chloride shown in formula (II) 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
It answers, obtains target product.
In the above-mentioned hot method of high pressure solvent, the container is usually heavy wall borosilicate glass tube, is reacted usually at 30~140 DEG C
Under the conditions of carry out, under this temperature condition, time of reaction is preferably controlled in 2~for 24 hours, can also be extended to according to actual conditions
More than for 24 hours.Further preferred mixed solution is reacted under the conditions of 50~140 DEG C, more preferable mixed solution be 80~
It is reacted under the conditions of 100 DEG C.When reaction carries out under 80 DEG C of room temperature or heating condition below, when reaction needs longer
Between just can get higher yield.
The invention also includes compound or its pharmaceutically acceptable salts shown in above-mentioned formula (I) in the preparation of antitumor drugs
Application.
The invention also includes what is prepared as active constituent using compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I)
Antitumor drug.
Compared with prior art, the present invention provides a kind of new using 1- (2- pyridines) -9- octyls-B-carboline as ligand
Copper chloride (II) complex and its synthetic method and application.Applicant is by investigating its suppression to various tumor cell strains
It makes and uses, the results showed that the complex has stronger anti tumor activity in vitro, and is apparently higher than cis-platinum, has preferable potential
Medical value is expected to be used for the preparation of various antitumor drugs.
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.
Specific implementation mode
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 embodiments.
Embodiment 1：The synthesis of the octyls of compound, that is, 1- (2- pyridines) -9- shown in formula (II)-B-carboline (L)
1) 150ml round bottoms are added in 1.6g (10mmol) tryptamines, 1.1g (10mmol) pyridine-2-formaldehydes and 50ml toluene to burn
Bottle, in addition water knockout drum, condenser pipe group ingredient water reflux, are heated to reflux 4 hours, wait for solvent evaporated after reaction, residue
It is recrystallized to give compound 1 (2.3g, yield 92%) with 100ml n-hexanes；
2) 250ml circles are added in 2.5g (10mmol) compound 1,2.5g palladium carbons (10%Pd/C) and 100ml paraxylene
Bottom flask is heated to flowing back, and thin-layer chromatography tracing detection to reaction is used in combination to terminate, and stands and filters 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 n,N-Dimethylformamide are added to 50ml round-bottomed flasks, room temperature
Stirring 10 minutes, adds 2.5g (10mmol) compound 2 and 10mmol 1- bromooctanes, thin-layer chromatography tracing detection is used in combination extremely
Reaction terminates, and then puts into reaction solution in 500ml ice water, three times with the extraction of 100ml ethyl acetate, merges organic phase, is evaporated
Solvent, residue obtained upper silica gel column chromatography purify (VDichloromethane：VMethanol=100:1) compound 3 (2.8g, yield 78%), is obtained.
Products therefrom is characterized：
(1) nuclear magnetic resonance spectroscopy and carbon spectrum, their spectral data are as follows：
1H NMR(500MHz,CDCl3) δ 8.77 (d, J=4.7Hz, 1H), 8.57 (d, J=4.1Hz, 1H), 8.20 (d, J
=7.7Hz, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.96 (t, J=6.9Hz, 1H), 7.63 (t, J=6.7Hz, 1H),
7.48 (d, J=8.4Hz, 1H), 7.47-7.42 (m, 1H), 7.33 (t, J=7.5Hz, 1H), 4.19 (t, J=7.9Hz, 2H),
1.39 (dt, J=15.6,7.8Hz, 2H), 1.25-1.19 (m, 2H), 1.16-1.04 (m, 4H), 1.00 (dt, J=14.1,
7.0Hz,2H),0.91–0.80(m,5H).
13C NMR(126MHz,CDCl3)δ156.62,148.68,143.03,141.12,137.20,136.16,
133.96,132.42,129.40,125.68,123.74,121.91,121.03,120.38,114.97,110.46,45.45,
31.73,29.12,29.11,28.97,26.75,22.63,14.13.
(2) high resolution mass spectrum, ESI-MS m/z:358.2[M+H]+.
Accordingly, it can be determined that above-mentioned product is 1- (2- pyridines) -9- octyls-B-carboline, chemical structural formula such as following formula
(II) shown in：
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 1 substance of compound, reaction carry out under the conditions of 70 DEG C, and TLC tracing detections to reaction terminate, then will with ammonium hydroxide
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.
Nuclear magnetic resonance spectroscopy, carbon-13 nmr spectra and high resolution mass spectrum analysis are carried out to the present embodiment products therefrom, determined
For target product 1- (2- pyridines) -9- octyls-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 be 1 substance of compound amount 5
Times, reaction carries out under the conditions of 60 DEG C.
Nuclear magnetic resonance spectroscopy, carbon-13 nmr spectra and high resolution mass spectrum analysis are carried out to the present embodiment products therefrom, determined
For target product 1- (2- pyridines) -9- octyls-B-carboline.
Embodiment 4：The synthesis of ligand L
Embodiment 1 is repeated, unlike：
In step 2), palladium carbon is replaced with 2,3-, bis- chloro- 5,6- dicyan 1,4-benzoquinone, paraxylene is replaced with dichloromethane, 2,
The addition of bis- chloro- 5,6- dicyan 1,4-benzoquinone of 3- is equal with the amount of the substance of compound 1.
Nuclear magnetic resonance spectroscopy, carbon-13 nmr spectra and high resolution mass spectrum analysis are carried out to the present embodiment products therefrom, determined
For target product 1- (2- pyridines) -9- octyls-B-carboline.
Embodiment 5：Title complex [Cu (L) Cl2] synthesis
In the heavy wall borosilicate glass tube being open at one end, it is directly added into 0.1mmol CuCl2·2H2O and 0.1mmol ligands
L, adding 0.6ml ethanol/methylenes mixed solution, (volume ratio of methanol and dichloromethane is 3:1), in the item vacuumized
Under part, open end is sealed, is then fully reacted under the conditions of 50 DEG C 20 hours, green crystal type solid product is obtained.
Products therefrom is characterized：
(1) high resolution mass spectrum, ESI-MS m/z:533[Cu(L)(DMSO)Cl]+(DMSO is used when coming from mass spectrometric measurement
Solvent)
(2) X-ray single crystal diffraction is analyzed, as shown in Figure 1.
Therefore it can determine that above-mentioned product is using 1- (2- pyridines) -9- octyls-B-carboline as copper (II) complex of ligand
That is title complex [Cu (L) Cl2], shown in structural formula such as following formula (I)：
Embodiment 6：Title complex [Cu (L) Cl2] synthesis
In the heavy wall borosilicate glass tube being open at one end, it is directly added into 0.2mmol CuCl2·2H2O and 0.1mmol ligands
L, adding 0.6ml ethyl alcohol/chloroform mixed solution, (volume ratio of ethyl alcohol and chloroform is 3:1) it, under conditions of vacuumizing, will open
Mouth end sealing, then fully reacts 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 determined as target cooperation
Object [Cu (L) Cl2]。
Embodiment 7：Title complex [Cu (L) Cl2] synthesis
In the heavy wall borosilicate glass tube being open at one end, it is directly added into 0.3mmol CuCl2·2H2O and 0.1mmol ligands
Abbreviation L adds 0.6ml methanol/ethanols/N,N-dimethylformamide mixed solution (methanol, ethyl alcohol and N, N- dimethyl formyls
The volume ratio of amine is 5：1：1), under conditions of vacuumizing, open end is sealed, it is small then fully to react 4 under the conditions of 100 DEG C
When, 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 determined as target cooperation
Object [Cu (L) Cl2]。
Embodiment 8：Title complex [Cu (L) Cl2] synthesis
In the heavy wall borosilicate glass tube being open at one end, it is directly added into 0.4mmol CuCl2·2H2O and 0.1mmol ligands
L, adding 0.6ml ethanol/acetones mixed solution, (volume ratio of ethyl alcohol and acetone is 10:It 1), will, under conditions of vacuumizing
Open end seals, and is then fully reacted under the conditions of 80 DEG C 4 hours, 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 determined as target cooperation
Object [Cu (L) Cl2]。
Embodiment 9：Title complex [Cu (L) Cl2] synthesis
Take 6mmol CuCl2·2H2O and 1mmol ligand Ls are placed in round-bottomed flask, and it is mixed that 80ml ethanol/waters are added thereto
Closing solution, (volume ratio of second alcohol and water is 1:1), after stirring and dissolving, 60 DEG C is heated to and is reacted 12 hours, reactant is concentrated under reduced pressure
Partial solvent is removed, is stood, is had green crystal precipitation, isolate solid, washed with ethyl alcohol, it is dry, obtain green crystal.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X-ray single crystal diffraction, is determined as target cooperation
Object [Cu (L) Cl2]。
Embodiment 10：Title complex [Cu (L) Cl2] synthesis
Take 2mmol CuCl2·2H2O and 1mmol ligand Ls are placed in round-bottomed flask, be added thereto 50ml methanol/acetones/
(volume ratio of methanol, acetone and water is 30 to water mixed solution：1：10), after stirring and dissolving, be heated to 50 DEG C react 12 hours, instead
It answers object to be concentrated under reduced pressure and removes partial solvent, stand, have green crystal precipitation, isolate solid, washed with ethyl alcohol, it is dry, it obtains
Green crystal.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X-ray single crystal diffraction, is determined as target cooperation
Object [Cu (L) Cl2]。
Embodiment 11：Title complex [Cu (L) Cl2] synthesis
Take 3mmol CuCl2·2H2O and 1mmol ligand Ls are placed in round-bottomed flask, and 30ml methanol/chloroform is added thereto
(volume ratio of methanol and chloroform is 1 to mixed solution：1) it, after stirring and dissolving, is reacted 18 hours in 20 DEG C, reactant is concentrated under reduced pressure
Partial solvent is removed, is stood, is had green crystal precipitation, isolate solid, washed with ethyl alcohol, it is dry, obtain green crystal.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X-ray single crystal diffraction, is determined as target cooperation
Object [Cu (L) Cl2]。
In order to absolutely prove that purposes of the complex of the present invention in pharmacy, applicant have carried out extracorporeal anti-tumor to it
Activity experiment.
Experimental example 1：It is (real by the present invention as copper chloride (II) complex of ligand using 1- (2- pyridines) -9- octyls-B-carboline
Apply 5 the method for example be made) and ligand L (by 1 the method for the embodiment of the present invention be made) to a variety of human tumor strains progress body
Outer inhibitory activity experiment
1, cell strain and cell culture
This experiment selects gastric carcinoma cells MGC-803, human hepatoma cell strain Hep G2, human bladder cancer cell T-24, people non-
Small cell lung cancer cell NCI-H460 and human normal cell line HL-7702 totally 5 kinds of cell strains.
All tumor cell lines are cultivated containing 10wt% small ox bloods, 100U/mL penicillin, 100U/mL streptomysins
In RPMI-1640 culture solutions, 37 DEG C of 5%CO containing volumetric concentration are set2It is cultivated in incubator；Human normal cell line strain then cultivate containing
The small ox bloods of 10wt%, 100U/mL penicillin, 100U/mL streptomysins DMEM culture solutions in.
2, the preparation of untested compound
The DMSO liquid storages (a concentration of 0.002mol/L) of each untested compound are diluted successively by RMPI1640 culture mediums
At five concentration gradients, respectively 20,10,5,2.5,1.25 μm of ol/L, wherein cosolvent DMSO final concentration≤1%.It surveys first
Each untested compound of 20 μm of ol/L is tried for the inhibiting rate of tumor cell proliferation, is considered as primary dcreening operation result；Test is different respectively again
Each untested compound is to the Proliferation Ability degree of various tumour cells under gradient concentration, to the Fitting Calculation half-inhibition concentration,
That is IC50Value.
3, cell growth inhibition test (mtt assay)
(1) tumour cell of logarithmic growth phase is matched after trypsin digestion with the culture solution containing 10% calf serum
The cell suspension of a concentration of 5000/mL is made, is inoculated in 96 well culture plates with 190 μ L of every hole, makes cell density to be measured extremely
1000~10000/hole (edge hole is filled with sterile PBS)；
(2) 5%CO2, 37 DEG C are incubated for 24 hours, until cell monolayer is paved with bottom hole, the drug 10 of a certain 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) the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L is added per hole, continues to cultivate 4h；
(5) culture is terminated, culture solution in hole is carefully sucked, 150 μ L DMSO are added per hole and fully dissolve first a ceremonial jade-ladle, used in libation precipitation, shake
With wavelength it is 570nm in microplate reader, reference wavelength is the OD value that 450nm measures each hole after swinging device mixing；
(6) while zeroing hole (culture medium, MTT, DMSO) is set, (the drug dissolving of cell, same concentrations is situated between control wells
Matter, culture solution, MTT, DMSO).
(7) according to the OD value (OD values) measured, to judge living cells quantity, OD values are bigger, and cell activity is stronger.
Calculate the inhibiting rate of compound on tumor cell growth.For under primary dcreening operation concentration inhibiting rate be more than 50% cell
Strain, is further fitted by the inhibiting rate data of five concentration gradients of SPSS softwares pair, finds out compound to different tumours
Half-inhibition concentration (the IC of strain50Value, unit μm ol/L), IC of the compound for different cell strains50Value is as shown in table 1.
Table 1：The IC of 5 kinds of cell strains of compound pair of the present invention50It 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,
Activity is substantially better than cis-platinum, is expected to exploitation into antitumor drug.
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 chlorination as shown in following formula (II)
Copper is dissolved in polar solvent, carries out complexation reaction to get to target product；Wherein, the polar solvent be selected from methanol and
One or both of ethyl alcohol with selected from one or both of water, acetone, chloroform, dichloromethane and n,N-Dimethylformamide
Above combination；
3. synthetic method according to claim 2, it is characterised in that：Compound and copper chloride shown in formula (II) 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 is precipitated, point
Crystal is separated out to get 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 and copper chloride shown in formula (II) 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 carries 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)
It is prepared as follows：
It using tryptamines and pyridine-2-formaldehyde as raw material, is 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, be added 1- bromooctanes carry out substitution reaction to get；Wherein：
First organic solvent be selected from one or both of toluene, methanol, ethyl alcohol, dichloromethane and chloroform with
On combination；
Second organic solvent be selected from one or both of benzene, toluene, paraxylene, glacial acetic acid and dichloromethane with
On combination；
The oxidant is palladium carbon, bis- chloro- 5,6- dicyan 1,4-benzoquinone of manganese acetate hydrate, lead tetraacetate or 2,3-；
The alkaline matter is inorganic base；
The aprotic polar solvent is selected from one or both of N,N-dimethylformamide, dimethyl sulfoxide (DMSO) and acetone
Above combination；
The structure of the compound 1 and compound 2 difference 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. compound application in preparation of anti-tumor drugs described in claim 1.
10. a kind of antineoplastic pharmaceutical compositions, it is characterised in that：Contain compound described in the claim 1 as active constituent.
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| CN201610852923.9A CN106632418B (en) | 2016-09-26 | 2016-09-26 | Using 1- (2- pyridines) -9- octyls-B-carboline as the chlorination copper complex and its synthetic method of ligand and application |
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| CN201610852923.9A CN106632418B (en) | 2016-09-26 | 2016-09-26 | Using 1- (2- pyridines) -9- octyls-B-carboline as the chlorination copper complex and its synthetic method of ligand and application |
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| 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 |
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| CN1500789A (en) * | 2002-11-19 | 2004-06-02 | 北京大学 | Complex ML(DCA) of copper(II), gallium(III) and rare earth ion(Ln**) containing non-methyl canthridic acid radical |
| 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 |
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