CN106543208A - Copper chloride (II) chelate and its synthetic method and application with 1 pyridine β carbolines as part - Google Patents
Copper chloride (II) chelate and its synthetic method and application with 1 pyridine β carbolines as part Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 22
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 title claims description 12
- 239000013522 chelant Substances 0.000 title abstract description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title abstract description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title abstract description 3
- -1 pyridine β carbolines Chemical class 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 239000002798 polar solvent Substances 0.000 claims abstract description 23
- 239000012467 final product Substances 0.000 claims abstract description 11
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 7
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 7
- 238000010668 complexation reaction Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 229940125904 compound 1 Drugs 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000007800 oxidant agent Substances 0.000 claims description 11
- 230000001590 oxidative effect Effects 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 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 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 6
- 239000012362 glacial acetic acid Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 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 claims description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 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 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 2
- 238000007710 freezing Methods 0.000 claims description 2
- 230000008014 freezing Effects 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 230000036571 hydration Effects 0.000 claims 3
- 238000006703 hydration reaction Methods 0.000 claims 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 2
- 239000000460 chlorine Substances 0.000 claims 2
- 229910052801 chlorine Inorganic materials 0.000 claims 2
- 229910052802 copper Inorganic materials 0.000 claims 2
- 239000010949 copper Substances 0.000 claims 2
- MPTQRFCYZCXJFQ-UHFFFAOYSA-L copper(II) chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Cu+2] MPTQRFCYZCXJFQ-UHFFFAOYSA-L 0.000 abstract description 16
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 abstract description 5
- 229960004316 cisplatin Drugs 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 4
- 239000013078 crystal Substances 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 14
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 229910002476 CuII Inorganic materials 0.000 description 12
- 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
- 238000000746 purification Methods 0.000 description 11
- 206010028980 Neoplasm Diseases 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 description 9
- 239000012043 crude product Substances 0.000 description 8
- 230000004044 response Effects 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 7
- 239000012046 mixed solvent Substances 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 241000196324 Embryophyta Species 0.000 description 5
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- 238000005292 vacuum distillation Methods 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 239000012531 culture fluid Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
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- 206010059866 Drug resistance Diseases 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- BXNJHAXVSOCGBA-UHFFFAOYSA-N Harmine Chemical compound N1=CC=C2C3=CC=C(OC)C=C3NC2=C1C BXNJHAXVSOCGBA-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- 239000011572 manganese Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
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- 230000001629 suppression Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 208000035126 Facies Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000005388 borosilicate glass Substances 0.000 description 2
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- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 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
- 241000283690 Bos taurus Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- RERZNCLIYCABFS-UHFFFAOYSA-N Harmaline hydrochloride Natural products C1CN=C(C)C2=C1C1=CC=C(OC)C=C1N2 RERZNCLIYCABFS-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010023774 Large cell lung cancer Diseases 0.000 description 1
- 101000905241 Mus musculus Heart- and neural crest derivatives-expressed protein 1 Proteins 0.000 description 1
- 101001031591 Mus musculus Heart- and neural crest derivatives-expressed protein 2 Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 240000005523 Peganum harmala Species 0.000 description 1
- 235000005126 Peganum harmala Nutrition 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 241000159213 Zygophyllaceae Species 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
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
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- 229940079593 drug Drugs 0.000 description 1
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- 230000012010 growth Effects 0.000 description 1
- VJHLDRVYTQNASM-UHFFFAOYSA-N harmine Natural products CC1=CN=CC=2NC3=CC(=CC=C3C=21)OC VJHLDRVYTQNASM-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
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- 231100000053 low toxicity Toxicity 0.000 description 1
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- 208000013371 ovarian adenocarcinoma Diseases 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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- 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
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of copper chloride (II) chelate and its synthetic method and application with 1 pyridine β carbolines as part.Shown in the structural formula such as following formula (I) of the copper chloride (II) chelate, its preparation method is：Compound and Copper dichloride dihydrate as shown in following formula (II) is taken, is dissolved in polar solvent, carried out complexation reaction, obtain final product.Copper chloride (II) chelate of the present invention shows the anti-tumor activity more higher than part and cisplatin, with preferable potential medical value, is expected to be used for the preparation of various antitumor drug.Formula (I) and structure shown in formula (II) are as follows.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of copper chloride (II) with 1- pyridines-B-carboline as part
Chelate and its synthetic method and application.
Background technology
Cancer (also known as malignant tumor) be a kind of polygenes participate in, progressively develop general, systemic disease.There is money
Material statistics shows that cancer has become dead first inducement in considerable countries and regions, and variation is presented, persistently increases
Morbidity situation, it is contemplated that to the year two thousand twenty, global cancer patient will break through 20,000,000, and this situation is more tight in developing country
Weight.How to capture cancer becomes the objective of the struggle of medical circle, with medical science applied development people it is constantly deep to the understanding of tumor
Enter, each link of tumor development is likely to become the potential target spot for the treatment of.
In recent years, with the clinical practice of the medicines such as cisplatin, Metal Substrate chelate antitumor drug has been increasingly becoming research
Focus.The combination of the build-in attribute and biologically active ligand molecule of metal is some efficient, low toxicities, spectrum is wide and lives for targeting
Property new drug development provide wide space.
Beta-carboline alkaloid is the alkaloid of a big class natural origin, and distributed in nature is extensive.It is wherein many from zygophyllaceae
The most commonly seen beta-carboline alkaloid extracted in year raw herbaceous plant seed of peganum harmala, mainly including harmine
Alkali and banisterine.Correlational study finds that beta-carboline alkaloid shows the anti-tumor activity of wide spectrum, and the secondary work of poison both at home and abroad
With relatively small.The structural modification of beta-carboline alkaloid enjoys the concern of researcher always.It is generally believed that most of β-
The planar conjugate structure of carboline alkaloid and different substituents group are (such as benzyl (- C6H5), methoxyl group (- OCH3)) presence
There is significant relation with its anti-tumor activity.Research to beta-carboline alkaloid at present mainly includes the following aspects：One
It is to find in the plant for study based on natural product chemistry never equal category and carry out separating-purifying；Two is by organic synthesiss side
Method carries out complete synthesis or semi-synthetic to beta-carboline alkaloid, and its structure is modified.It is other then be to its pharmacologically active (such as
Anti-tumor activity) carry out molecular mechanism research.DNA is such as inserted, suppressed topoisomerase, suppressed CDK etc..But from current research
From the point of view of progress, content of the beta-carboline alkaloid in natural plants is general all than relatively low, and extracts relatively complicated, no
Beneficial to furtheing investigate to which, though and organic semisynthesis on yield with certain advantage, produced cost
Restriction, therefore the expansion research at present to beta-carboline alkaloid is still inadequate.
On the other hand, although cisplatin has successfully listed many decades successful treatment kinds cancer, but clinical effectiveness is aobvious
Show which yet suffers from some problems, such as Drug resistance and toxic and side effects, have that certain cancers are natural to show the drug resistance to cisplatin
Property, cancer also gradually also shows induction property Drug resistance after Primary treatment.Preclinical and clinical experiment shows：Non- platinum
Series antineoplastic medicament has vast potential for future development, but copper chloride (II) chelate with 1- pyridines-B-carboline as part at present
Research still belong to blank.
The content of the invention
The technical problem to be solved in the present invention be to provide a kind of structure it is novel with 1- pyridines-chlorination of the B-carboline as part
Copper (II) chelate, and its synthetic method and application.
The present invention relates to compound shown in lower formula (I) or its pharmaceutically acceptable salt：
Shown in above-mentioned formula (I), the synthetic method of compound is：Take compound and Copper dichloride dihydrate as shown in following formula (II)
(CuCl2·2H2O), it is dissolved in polar solvent, carries out complexation reaction, that is, obtains target product；
The synthetic route of above-mentioned synthetic method is as follows：
In above-mentioned synthetic method, involved raw material formula (II) participates in reacting as part, its chemical name be 1- pyridines-
B-carboline (1-Pyridine- β-Carboline), abbreviation KL.The compound can designed, designed synthetic route be prepared, preferably
Following methods are prepared：With tryptamines and pyridine-2-formaldehyde as raw material, react in the first organic solvent, through dehydrating condensation
Obtain compound 1；Then compound 1 is placed in the second organic solvent, adds oxidant cyclization dehydrogenation, obtain final product；Wherein：
The first described organic solvent is the one kind or two in toluene, methanol, ethanol, dichloromethane and chloroform
Plant the combination of the above；
The second described organic solvent is the one kind or two in benzene, toluene, xylol, glacial acetic acid and dichloromethane
Plant the combination of the 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.
Shown in above-mentioned preparation formula (II), the synthetic route of compound method is as follows：
Reagent：(a) first organic solvent；(b) oxidant, the second organic solvent.
The more specifically synthetic method of compound shown in above-mentioned formula (II), comprises the following steps：
1. with tryptamines and pyridine-2-formaldehyde as raw material, react in the first organic solvent, in course of reaction, discharge reaction life
Into water, question response terminates rear solvent evaporated, obtains compound 1；
2. compound 1 is placed in the second organic solvent, adds oxidant, reacted under heating condition, question response terminates, mistake
Filter, collects filtrate, is evaporated, obtains compound i.e. compound 2 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
The water that reaction is generated is discharged, whether react completely can be can adopt thin layer chromatography (TLC) tracing detection；Preferably, reaction is adopted
Heating reflux reaction, the time control now reacted are appropriate in 2～6h.In the step, what is obtained is the thick product of compound 1
Thing, in order to reduce the impurity in subsequent reactions, improves the yield of postorder reaction, preferably carries out after purification process to residue obtained
Postorder reaction is carried out again.Specific purification process can be with little polar solvent recrystallization, gained recrystallization product to residue obtained
Thing is used further to postorder reaction.The little polar solvent for recrystallization is same as the prior art, can be specifically petroleum ether and/
Or normal hexane etc..
Shown in above-mentioned formula (II) the step of compound synthesis method 2. in, reaction preferably adopt heating reflux reaction, reaction
Whether completely can be so that thin layer chromatography tracing detection can be adopted.In the step, according to the difference of oxidant, have from different second
Machine solvent, it is specific as follows：
(1) when the selection of oxidant is palladium carbon, the second organic solvent is preferably the one kind in benzene, toluene and xylol
Or two or more combinations, when two organic solvents selection for more than above two combination when, the proportioning between them can be with
For any proportioning.The addition of the palladium carbon generally presses the addition 2～3g palladium carbons of 10mmol compounds 1, and described palladium carbon can be
5%Pd/C or 10%Pd/C.
(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 1 material of compound.When the choosing of oxidant
When being selected as manganese acetate hydrate or lead tetraacetate, pH >=7 of alkali liquor regulation system are used in preferred reaction after terminating, then which is extracted
Take, collect organic faciess, the residue obtained by solvent evaporated goes up silica gel column chromatography purification again；Wherein, described alkali liquor can be ammonia,
The aqueous solution of the alkaline matters such as sodium acetate, sodium carbonate, sodium phosphate, sodium bicarbonate or potassium carbonate, the concentration of the alkali liquor are preferably 5
～30/w/w%；Can be specifically ethyl acetate, dichloromethane, chloroform or ether for extracting the solvent for adjusting system after pH value
Deng.
(3) when the selection of oxidant is 2,3-, bis- chloro- 5,6- dicyan 1,4-benzoquinone, the second organic solvent is preferably benzene, first
One or more combination 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 bis- chloro- 5,6- dicyan 1,4-benzoquinone of the 2,3- is usually compound 1
1～4 times of the amount of material.
What said method was prepared is the crude product of compound shown in formula (II), in order to further improve its purity, is had
Beneficial to the carrying out of subsequent reactions, the above-mentioned gained crude product of preferred pair carries out purification, is used further to target product of the present invention after purification
In synthetic method.Described purification process is same as the prior art, and specific purification process can use methanol to residue obtained
Recrystallization, or by residue obtained upper silica gel column chromatography purification, in upper silica gel column chromatography, eluant used is petroleum ether
6 are pressed with dichloromethane：1～1：The mixed solvent of 1 volume ratio composition.
In the synthetic method of compound shown in formula (I) of the present invention, described polar solvent be methanol with selected from water, third
One kind or arbitrarily two or more combinations in ketone, chloroform, dimethyl sulfoxide, DMF and acetonitrile.It is preferred that first
The shared ratio in polar solvent of alcohol is 70～85v/v%.When sub- containing water, acetone, chloroform, dimethyl in polar solvent
During any two or more selection in sulfone, DMF and acetonitrile, before their total amount is without departing from 30%
Under the conditions of carrying, their proportioning can be any proportioning.The consumption of the polar solvent can determine as needed, normal conditions
Under, shown in 1mmol formulas (II), compound and 1mmol Copper dichloride dihydrates are dissolved using the polar solvent of 35～40mL.In tool
In the dissolving step of body, typically polar solvent will be added after compound shown in formula (II) and Copper dichloride dihydrate mixing；Also may be used
Compound and Copper dichloride dihydrate shown in formula (II) are dissolved using polar solvent respectively, is remixed and is reacted.
In the synthetic method of compound shown in formula (I) of the present invention, the Copper dichloride dihydrate and formula (II) shownization
It is 1 that the mol ratio of compound is stoichiometric proportion:1.
Compound shown in formula (I) of the present invention specifically in synthesis, can adopt normal pressure solwution method or high pressure solvent heat
Method is synthesized.
When using normal pressure solwution method, its synthetic method includes：Take compound shown in formula (II) and Copper dichloride dihydrate is molten
In polar solvent, gained mixed liquor is reacted under heating condition, and reactant removes partial solvent, is stood, and is separated out, and is isolated solid
Body, obtains final product target product.
In above-mentioned normal pressure solwution method, reaction preferably adopts back flow reaction, and reaction is preferably returned at 45 DEG C to polar solvent
Carry out in stream temperature range, react more preferably under the conditions of 60～80 DEG C.Judge whether reaction can adopt thin layer chromatography completely
Tracing detection.Under above-mentioned qualificationss, response time control is more suitable in 24～48h.Reactant is by the way of concentration
Partial solvent is removed, typically concentration removes the 70～90% of polar solvent addition.
When using high pressure solvent full-boiled process, its synthetic method includes：Take compound shown in formula (II) and Copper dichloride dihydrate
It is dissolved in polar solvent, gained mixed liquor is placed in container, vacuum, sealing by fusing, then in heating condition is evacuated to Jing after liquid nitrogen freezing
Lower reaction, obtains target product.
In above-mentioned high pressure solvent full-boiled process, described container is usually heavy wall borosilicate glass tube, reaction temperature generally 60～
Carry out under the conditions of 80 DEG C, under this temperature conditions, the response time is preferably controlled in 48～72h, extend also dependent on practical situation
To more than 72h.
Present invention additionally comprises compound shown in above-mentioned formula (I) or its pharmaceutically acceptable salt are worked as preparing antitumor drug
In application.
Present invention additionally comprises what compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I) were prepared as active component
Antitumor drug.
Compared with prior art, the invention provides a kind of new copper chloride (II) chelate, i.e., with 1- pyridines-B-carboline
Copper chloride (II) chelate for part, and its synthetic method and application.Applicant is thin to kinds of tumors by investigating which
The inhibitory action of born of the same parents' strain, as a result shows that the chelate shows the anti-tumor activity more higher than its part and cisplatin, with preferable
Potential medical value, be expected to be applied to the preparation of various antitumor drug.
Description of the drawings
Hydrogen nuclear magnetic resonance spectrograms of the Fig. 1 for final product obtained in the embodiment of the present invention 1；
Carbon-13 nmr spectra figures of the Fig. 2 for final product obtained in the embodiment of the present invention 1；
Electrospray Mass Spectrometry spectrograms of the Fig. 3 for final product obtained in the embodiment of the present invention 1；
X-ray crystal structure figures of the Fig. 4 for final product obtained in the embodiment of the present invention 1；
X-ray crystal structure figures of the Fig. 5 for final product obtained in the embodiment of the present invention 5；
Electrospray Mass Spectrometry spectrograms of the Fig. 6 for final product obtained in the embodiment of the present invention 5.
Specific 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- pyridines-B-carboline (KL)
1) 1.60g (10mmol) tryptamines is dissolved in 70mL dichloromethane, adds 1.07g (10mmol) pyridine -2- first
Aldehyde, is heated to back flow reaction 8 hours；After reaction terminates, vacuum distillation obtains crude product Compound 1；
2) 2.49g (10mmol) compound 1 is dissolved in 80mL glacial acetic acid, adds 13.4g manganese acetate hydrate (Mn
(Ac)3·nH2O), 80 DEG C are heated to, overnight, solvent evaporated is reacted, 100mL water are added, is extracted with ethyl acetate 3 times, is associated with
Machine phase, solvent evaporated obtain oily crude product, and going up fast liquid chromatography afterwards carries out purification (VPetroleum ether：VDichloromethane=1:1), obtain
Pale yellow crystals compound 2 (yield is about 73%).
Gained pale yellow crystals are carried out with proton nmr spectra, carbon-13 nmr spectra, Electrospray Mass Spectrometry and single crystal diffraction point
Analysis, concrete spectral characteristic are as follows：
(1) proton nmr spectra and carbon spectrum, their spectrogram is respectively as illustrated in fig. 1 and 2.
1H NMR(500MHz,CDCl3)δ:11.22 (s, 1H), 8.82～8.74 (m, 2H), 8.53 (d, J=5.1Hz,
1H), 7.98 (d, J=5.1Hz, 1H), 7.90 (td, J=7.8,1.8Hz, 1H), 7.60 (d, J=2.4Hz, 1H), 7.54 (d, J
=8.8Hz, 1H), 7.37-7.32 (m, 1H), 7.25 (dd, J=8.8,2.5Hz, 1H), 3.96 (s, J=4.0Hz, 3H).1H
NMR (500MHz, DMSO-d6) δ 11.97 (s, 1H), 8.90 (d, J=4.7Hz, 1H), 8.65 (d, J=8.0Hz, 1H), 8.51
(d, J=5.0Hz, 1H), 8.30 (d, J=7.8Hz, 1H), 8.25 (d, J=5.0Hz, 1H), 8.05 (t, J=7.7Hz, 1H),
7.90 (d, J=8.2Hz, 1H), 7.60 (t, J=7.7Hz, 1H), 7.53 (m, 1H), 7.29 (t, J=7.5Hz, 1H).
13C NMR(126MHz,CDCl3)δ:157.87,154.08,148.25,138.09,137.44,136.83,
135.68,135.30,130.36,122.92,121.41,121.35,118.51,115.36,112.67,103.57,77.30,
77.25,77.04,76.79,56.02 13C NMR(150MHz,DMSO-d6)δ157.10,148.72,141.01,138.08,
137.70,137.24,133.54,129.90,128.36,123.38,121.62,120.83,120.33,119.56,115.68,
112.91。
(2) Electrospray Mass Spectrometry, as shown in figure 3, ESI-MS m/z:246.10[M+H]+.
(3) analysis of X-ray single crystal diffraction, determines that its mono-crystalline structures is as shown in Figure 4.
Accordingly, it can be determined that above-mentioned product as light yellow solid is 1- pyridines-B-carboline, its chemical structural formula such as following formula
(II) shown in：
Embodiment 2：The synthesis of part KL
1) 1.60g (10mmol) tryptamines is dissolved in 70mL toluene, adds 1.07g (10mmol) pyridine-2-formaldehyde, plus
To back flow reaction 6 hours, after reaction terminates, vacuum distillation obtained crude product Compound 1 to heat；
2) 2.49g (10mmol) compound 1 is dissolved in 80mL glacial acetic acid, adds 13.4g manganese acetate hydrate (Mn
(Ac)3·nH2O), 70 DEG C are heated to, overnight, solvent evaporated is reacted, 100mL water are added, is extracted with ethyl acetate 3 times, is associated with
Machine phase, solvent evaporated obtain oily crude product, and going up fast liquid chromatography afterwards carries out purification (VPetroleum ether：VDichloromethane=2:3), obtain
Pale yellow crystals compound 2 (yield is about 55%).
Gained pale yellow crystals are carried out with proton nmr spectra, carbon-13 nmr spectra, Electrospray Mass Spectrometry and single crystal diffraction point
Analysis, is defined as target product 1- pyridines-B-carboline.
Embodiment 3：The synthesis of part KL
1) 1.60g (10mmol) tryptamines is dissolved in the mixed solvent being made up of the ethanol of the methanol and 40mL of 30mL, then
1.07g (10mmol) pyridine-2-formaldehyde is added, backflow 12 hours is heated to, after reaction terminates, vacuum distillation obtains crude product chemical combination
Thing 1；
2) 2.49g (10mmol) compound 1 is dissolved in 80mL glacial acetic acid, adds 20mmol Pb (Ac)4, it is heated to
90 DEG C, overnight, solvent evaporated is reacted, add 100mL water, be extracted with ethyl acetate 3 times, merge organic faciess, solvent evaporated is obtained
Oily crude product, going up fast liquid chromatography afterwards carries out purification (VPetroleum ether：VDichloromethane=3:2), obtain pale yellow crystals chemical combination
Thing 2 (yield is about 67%).
Gained pale yellow crystals are carried out with proton nmr spectra, carbon-13 nmr spectra, Electrospray Mass Spectrometry and single crystal diffraction point
Analysis, is defined as target product 1- pyridines-B-carboline.
Embodiment 4：The synthesis of part KL
1) 1.6g (10mmol) tryptamines, 1.1g (10mmol) pyridine-2-formaldehydes and 50ml chloroform are added into 150ml circles
Bottom flask, is heated to back flow reaction 4 hours, and question response terminates rear solvent evaporated, residue 100ml being recrystallized to give of normal hexane
(2.3g, yield is 92%) for compound 1；
2) 2.5g (10mmol) compound 1,2.5g palladium carbons (10%Pd/C) and 100ml xylol are added into 250ml circles
Bottom flask, is heated to backflow, and is terminated to reaction with thin layer chromatography tracing detection, stands sucking filtration and is simultaneously evaporated filtrate, and gained is residual
Silicagel column (chromatography purification (V petroleum ether on slag：V dichloromethane=1:1) pale yellow crystals compound 2 (2.1g, yield, are obtained
86%).
Gained pale yellow crystals are carried out with proton nmr spectra, carbon-13 nmr spectra, Electrospray Mass Spectrometry and single crystal diffraction point
Analysis, is defined as target product 1- pyridines-B-carboline.
Embodiment 5：Chelate [CuII(KL)Cl2] synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.1mmol Copper dichloride dihydrates and 0.1mmol parts are directly added into
KL, (volume ratio of methanol and acetonitrile is 4 to add the mixed solvent that 1.5mL is made up of methanol and dimethyl sulfoxide:1)；Jing liquid
Vacuum is evacuated to after chilled nitrogen, by opening sealing by fusing, the then fully reaction 72h under the conditions of 80 DEG C；After reaction terminates, drop per hour
5 DEG C of temperature, until dropping to room temperature, that is, has the bar-shaped crystalline solids product of yellow green to separate out.
By above-mentioned gained yellow green product Jing Electrospray Mass Spectrometry (as shown in Figure 6) and X-ray single crystal diffraction analytical structure (such as
Shown in Fig. 5) determine, it is defined as copper chloride (II) chelate with 1- pyridines-B-carboline as part, i.e. target chelate [CuII
(KL)Cl2], shown in its structural formula such as following formula (I)：
Embodiment 6：Chelate [CuII(KL)Cl2] synthesis
Repeat embodiment 5, except for the difference that：
Polar solvent is changed to the mixed solvent that is made up of first alcohol and water, and (volume ratio of first alcohol and water is 8:2), reaction temperature
60 DEG C are changed to, the response time is 72h, after reaction terminates, directly cooling (yield 76%).
Separating out yellow green product Jing Electrospray Mass Spectrometry and the analysis of X-ray single crystal diffraction carries out structure determination, is defined as target
Chelate [CuII(KL)Cl2]。
Embodiment 7：Chelate [CuII(KL)Cl2] synthesis
Repeat embodiment 5, except for the difference that：
Polar solvent is changed to the mixed solvent that is made up of methanol and chloroform, and (volume ratio of methanol and chloroform is 5:1), react
Temperature is still 80 DEG C, and the response time is 72h, after reaction terminates, directly cooling (yield 68%).
Separating out yellow green product Jing Electrospray Mass Spectrometry and the analysis of X-ray single crystal diffraction carries out structure determination, is defined as target
Chelate [CuII(KL)Cl2]。
Embodiment 8：Chelate [CuII(KL)Cl2] synthesis
Part KL 0.1mmol, Copper dichloride dihydrate 0.1mmol are weighed respectively, and part KL is dissolved in 25mL methanol,
Copper dichloride dihydrate is dissolved in the DMF of 10mL, uniformly two kinds of solution of mixing；React at 80 DEG C
24h, vacuum distillation remove most of solvent (the 80% of solvent adding amount), are cooled to room temperature, stand, and separate out green solid, point
Solid is separated out, washed with water, be dried, obtain greenish solid product (yield 79%).
Separating out yellow green product carries out structure determination with reference to the analysis of X-ray single crystal diffraction through Electrospray Mass Spectrometry, is defined as
Target chelate [CuII(KL)Cl2]。
Embodiment 9：Chelate [CuII(KL)Cl2] synthesis
Repeat embodiment 8, except for the difference that：
DMF in polar solvent is changed to into acetone, the wherein volume ratio of methanol and acetone is 10:1, instead
Temperature is answered for 75 DEG C, the response time is 48h (yield 71%).
Separating out yellow green product carries out structure determination with reference to the analysis of X-ray single crystal diffraction through Electrospray Mass Spectrometry, is defined as
Target chelate [CuII(KL)Cl2]。
Embodiment 10：Chelate [CuII(KL)Cl2] synthesis
Part KL 0.1mmol, Copper dichloride dihydrate 0.1mmol are weighed respectively, and part KL and Copper dichloride dihydrate are dissolved
In the mixed solvent being made up of 10mL methanol, 1mL acetonitriles and 1mL water, 48h is reacted at 70 DEG C, vacuum distillation removes big portion
Divide solvent (the 90% of solvent adding amount), be cooled to room temperature, stand, separate out green solid.Solid is isolated, washed with water, done
It is dry, obtain greenish solid product (yield 75%).
Separating out yellow green product carries out structure determination with reference to the analysis of X-ray single crystal diffraction through Electrospray Mass Spectrometry, is defined as
Target chelate [CuII(KL)Cl2]。
In order to absolutely prove copper chloride (II) chelate with 1- pyridines-B-carboline as part of the present invention in pharmacy
In purposes, applicant carried out anti-tumor activity experiment to the chelate and its part KL.
Experimental example 1：Copper chloride (II) chelate with 1- pyridines-B-carboline as part (presses 5 methods described system of embodiment
) and part KL (prepared by 1 methods described of embodiment) vitro inhibition activity experiment is carried out to various human tumor strains
1st, cell strain and cell culture
NCI-H-460 (human large cell lung cancer), SK-OV-3 (people's ovary adenocarcinoma cells strain), Hep G2 (people are selected in this experiment
Hepatoma carcinoma cell), MGC803 (gastric carcinoma cells), T24 (human bladder cancer cell) etc..
All cell strains are cultivated the fetal blood of cattle containing 10%FBS is clear, in the DMEM culture fluid of 1% mycillin mixed liquor,
Put 37 DEG C of 5%CO containing volumetric concentration2Cultivate in incubator.
2nd, primary dcreening operation
Serum-free DMEM is changed after 96 orifice plates of each strain cell kind are adherent, dosing after 12 to 18 hours.This experiment is (pure with compound
Degree >=95%), compound is configured to into 200 μm of ol/L intermediate concentrations, 20 μ L intermediate concentration compound solutions are taken, is added existing
In 96 orifice plates of 180 μ L Cell saps, final compound concentration is 20 μm of ol/L.DMSO final concentration≤1%, tests chemical combination under the concentration
Inhibition level of the thing to growth of tumour cell.Every suppression ratio is more than 50%, and meets cell under light microscopic suppressed (or impaired)
Metamorphosis (such as cell shrinkage, crushing, floating etc.), then it is judged to that primary dcreening operation effectively, tries to achieve suppression ratio result such as table 1 below institute
Show.
3rd, cell growth inhibition test (mtt assay)
After test-compound to be measured is dissolved with DMSO, serum-free medium dilution intermediate concentration is 200 μm of ol/L,
100 μm of ol/L, 50 μm of ol/L, 25 μm of ol/L, 12.5 μm of ol/L, then it is degerming with the filtering with microporous membrane of d=0.22 μm of diameter, put
Preserve at 4 DEG C.
The panel of tumor cell strain in exponential phase is inoculated in into 96 orifice plates, edge respectively with 180 μ L of every hole respectively
Hole adds 200 μ L PBS (phosphoric acid buffer salt powder prepares solution), cell concentration about 1 × 104/ hole, cultivates 12 hours, treats cell
After adherent, serum-free DMEM is changed, 12 to 18 hours compound intermediate concentration liquid, each concentration of compound is parallel to set 5 multiple holes,
Wherein DMSO final concentration≤1%, while setting corresponding negative control group (in culture fluid only cell and equivalent DMSO, without medicine)
With blank control group (there was only the medicine of equivalent in culture fluid, acellular), each group is also parallel to set 5 multiple holes, when medicine is acted on
Between be 48h.Culture terminates 10 μ L MTT (5mg/mL PBS) to be added per hole in first 4 hours, and after continuing culture 4h, incline culture fluid,
100 μ L/ holes of DMSO, plate shaker vibration 7min is added crystal is fully dissolved, microplate reader is used in blank control group zeroing
Absorbance (A) value removed after background absorbance value is determined with 570nm/630nm dual wavelengths, suppression ratio, IC is measured50, its test
As a result as shown in the following Table 2：
Table 1：
Table 2：
Claims (10)
1. compound shown in formula (I) or its pharmaceutically acceptable salt are descended:
2. the synthetic method of compound described in claim 1, it is characterised in that：Take compound and two hydrations as shown in following formula (II)
Copper chloride, is dissolved in polar solvent, carries out complexation reaction, that is, obtain target product；
3. synthetic method according to claim 2, it is characterised in that：Described polar solvent be methanol with selected from water, third
One kind or arbitrarily two or more combinations in ketone, chloroform, dimethyl sulfoxide, DMF and acetonitrile.
4. the synthetic method according to Claims 2 or 3, it is characterised in that：Take compound shown in formula (II) and two hydration chlorine
Change copper, be dissolved in polar solvent, gained mixed liquor is reacted under heating condition, reactant removes partial solvent, stand, separate out,
Solid is isolated, target product is obtained final product.
5. synthetic method according to claim 4, it is characterised in that：React the reflux temperature model at 60 DEG C to polar solvent
Carry out in enclosing.
6. the synthetic method according to Claims 2 or 3, it is characterised in that：Take compound shown in formula (II) and two hydration chlorine
Change copper, be dissolved in polar solvent, gained mixed liquor is placed in container, and vacuum, sealing by fusing, then in heating are evacuated to Jing after liquid nitrogen freezing
Under the conditions of react, obtain target product.
7. synthetic method according to claim 6, it is characterised in that：Reaction is carried out under the conditions of 60～80 DEG C.
8. the synthetic method according to Claims 2 or 3, it is characterised in that：Compound shown in the formula (II) presses following sides
Method is prepared：With tryptamines and pyridine-2-formaldehyde as raw material, react in the first organic solvent, through dehydrating condensation
Compound 1；Then compound 1 is placed in the second organic solvent, adds oxidant cyclization dehydrogenation, obtain final product；Wherein：
The first described organic solvent be in toluene, methanol, ethanol, dichloromethane and chloroform one or two with
On combination；
The second described organic solvent be in benzene, toluene, xylol, glacial acetic acid and dichloromethane one or two with
On combination；
Described oxidant is palladium carbon, manganese acetate hydrate, bis- chloro- 5,6- dicyan 1,4-benzoquinone of lead tetraacetate or 2,3-.
9. the application of compound described in claim 1 or its pharmaceutically acceptable salt in antitumor drug is prepared.
10. the antitumor drug for being prepared with compound described in claim 1 or its pharmaceutically acceptable salt as active component.
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| CN110950896A (en) * | 2019-10-28 | 2020-04-03 | 广西师范大学 | Copper (II) complex with 9-aldehyde-10-pyrimidinehydrazone as ligand and synthetic method and application thereof |
| CN110950895A (en) * | 2019-10-28 | 2020-04-03 | 广西师范大学 | Binuclear copper complex with 9-aldehyde-10-benzothiazole anthracene hydrazone as ligand and synthetic method and application thereof |
| CN110950895B (en) * | 2019-10-28 | 2021-05-14 | 广西师范大学 | Binuclear copper complex with 9-aldehyde-10-benzothiazole anthracene hydrazone as ligand and synthetic method and application thereof |
| CN110950896B (en) * | 2019-10-28 | 2021-05-14 | 广西师范大学 | Copper (II) complex with 9-aldehyde-10-pyrimidinehydrazone as ligand and synthetic method and application thereof |
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