CN104478908A - Zinc and cobalt metal complex taking nantenine oxide as ligand as well as synthetic method and application thereof - Google Patents
Zinc and cobalt metal complex taking nantenine oxide as ligand as well as synthetic method and application thereof Download PDFInfo
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- CN104478908A CN104478908A CN201410770874.5A CN201410770874A CN104478908A CN 104478908 A CN104478908 A CN 104478908A CN 201410770874 A CN201410770874 A CN 201410770874A CN 104478908 A CN104478908 A CN 104478908A
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- zinc
- nantenine
- cobalt metal
- metal
- cobalt
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- 239000011701 zinc Substances 0.000 title claims abstract description 35
- WSVWKHTVFGTTKJ-AWEZNQCLSA-N nantenine Chemical compound C1C2=CC=3OCOC=3C=C2C2=C(OC)C(OC)=CC3=C2[C@H]1N(C)CC3 WSVWKHTVFGTTKJ-AWEZNQCLSA-N 0.000 title claims abstract description 34
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 229910052725 zinc Inorganic materials 0.000 title claims abstract description 28
- PXMNUDOKAWZSJH-AWEZNQCLSA-N (+)-Domestine Natural products O(C)c1c(OC)cc2c3[C@@H]([N+](C)CC2)Cc2c(-c13)cc1OCOc1c2 PXMNUDOKAWZSJH-AWEZNQCLSA-N 0.000 title claims abstract description 26
- WSVWKHTVFGTTKJ-UHFFFAOYSA-N O-Methyl domesticine Natural products C1C2=CC=3OCOC=3C=C2C2=C(OC)C(OC)=CC3=C2C1N(C)CC3 WSVWKHTVFGTTKJ-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 229910017052 cobalt Inorganic materials 0.000 title claims abstract description 26
- 239000010941 cobalt Substances 0.000 title claims abstract description 26
- ZMNSHBTYBQNBPV-UHFFFAOYSA-N domesticine Natural products C1C2=CC=3OCOC=3C=C2C2=C(O)C(OC)=CC3=C2C1N(C)CC3 ZMNSHBTYBQNBPV-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000010189 synthetic method Methods 0.000 title claims abstract description 12
- 239000003446 ligand Substances 0.000 title abstract description 7
- -1 cobalt metal complex Chemical class 0.000 title abstract 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229910052751 metal Inorganic materials 0.000 claims abstract description 30
- 239000002184 metal Substances 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 239000002798 polar solvent Substances 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- YPJKMVATUPSWOH-UHFFFAOYSA-N nitrooxidanyl Chemical compound [O][N+]([O-])=O YPJKMVATUPSWOH-UHFFFAOYSA-N 0.000 claims abstract description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 26
- 230000003647 oxidation Effects 0.000 claims description 22
- 238000007254 oxidation reaction Methods 0.000 claims description 22
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 238000013329 compounding Methods 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 6
- 240000007695 Nandina domestica Species 0.000 claims description 5
- 239000003205 fragrance Substances 0.000 claims description 5
- 150000002500 ions Chemical class 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 230000008014 freezing Effects 0.000 claims description 4
- 238000007710 freezing Methods 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 238000007789 sealing Methods 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000004615 ingredient Substances 0.000 claims description 2
- 150000001457 metallic cations Chemical class 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 13
- 230000000259 anti-tumor effect Effects 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 11
- 229910052697 platinum Inorganic materials 0.000 abstract description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract description 6
- 206010028980 Neoplasm Diseases 0.000 abstract description 5
- 210000004881 tumor cell Anatomy 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 230000001093 anti-cancer Effects 0.000 abstract description 2
- 150000004700 cobalt complex Chemical class 0.000 abstract description 2
- 150000001768 cations Chemical class 0.000 abstract 2
- 150000001450 anions Chemical class 0.000 abstract 1
- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 abstract 1
- 238000004729 solvothermal method Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 18
- 239000002904 solvent Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 8
- BZKUYNBAFQJRDM-UHFFFAOYSA-N aporphine Chemical compound C12=CC=CC=C2CC2N(C)CCC3=CC=CC1=C32 BZKUYNBAFQJRDM-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 6
- 239000012467 final product Substances 0.000 description 6
- 238000002329 infrared spectrum Methods 0.000 description 6
- 229910020366 ClO 4 Inorganic materials 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 241000196324 Embryophyta Species 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012265 solid product Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- QCMQEZNBBPGFKQ-UHFFFAOYSA-N Thalisopynine Natural products CN1CCC2=C(OC)C(OC)=C(OC)C3=C2C1CC1=C3C=C(OC)C(O)=C1 QCMQEZNBBPGFKQ-UHFFFAOYSA-N 0.000 description 3
- 239000005388 borosilicate glass Substances 0.000 description 3
- 208000019065 cervical carcinoma Diseases 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- FVRABHGHBLRNNR-UHFFFAOYSA-N liriodenine Natural products O=C1C=CC=c2c1cc3nccc4cc5OCOc5c2c34 FVRABHGHBLRNNR-UHFFFAOYSA-N 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000005515 coenzyme Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 150000003057 platinum Chemical class 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 description 2
- 241001081440 Annonaceae Species 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 229910000906 Bronze Inorganic materials 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000218377 Magnoliaceae Species 0.000 description 1
- 241000218164 Menispermaceae Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 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 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 229930014594 aporphine alkaloid Natural products 0.000 description 1
- 150000008441 aporphines Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000010974 bronze Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- UFMZWBIQTDUYBN-UHFFFAOYSA-N cobalt dinitrate Chemical compound [Co+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O UFMZWBIQTDUYBN-UHFFFAOYSA-N 0.000 description 1
- NVIVJPRCKQTWLY-UHFFFAOYSA-N cobalt nickel Chemical compound [Co][Ni][Co] NVIVJPRCKQTWLY-UHFFFAOYSA-N 0.000 description 1
- 229910001981 cobalt nitrate Inorganic materials 0.000 description 1
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical group [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
- BSUSEPIPTZNHMN-UHFFFAOYSA-L cobalt(2+);diperchlorate Chemical compound [Co+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O BSUSEPIPTZNHMN-UHFFFAOYSA-L 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- KUNSUQLRTQLHQQ-UHFFFAOYSA-N copper tin Chemical compound [Cu].[Sn] KUNSUQLRTQLHQQ-UHFFFAOYSA-N 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000029052 metamorphosis Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229910052761 rare earth metal Inorganic materials 0.000 description 1
- 150000002910 rare earth metals Chemical class 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- RXBXBWBHKPGHIB-UHFFFAOYSA-L zinc;diperchlorate Chemical compound [Zn+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O RXBXBWBHKPGHIB-UHFFFAOYSA-L 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
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/06—Zinc compounds
-
- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/06—Cobalt compounds
- C07F15/065—Cobalt compounds without a metal-carbon linkage
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a zinc and cobalt metal complex taking nantenine oxide as a ligand as well as a synthetic method and application thereof. The synthetic method of the zinc and cobalt metal complex comprises the following step: by taking nantenine oxide as the ligand, performing coordination reaction with metal salts in a polar solvent to obtain the zinc and cobalt metal complex; and specifically, the zinc and cobalt metal complex can be synthesized by virtue of a solution process, and can also be synthesized by virtue of a solvothermal process. Results obtained by investigating the inhibition effects of the zinc and cobalt metal complex on various tumor cell strains by the applicants show that the zinc and cobalt complex plays stronger anti-tumor activity than the nantenine oxide ligand, has the anti-tumor activity on part of tumor strains significantly superior to that of cis-platinum namely a clinical anti-cancer medicine, and has relatively good potential medicinal values. A structural general formula of the zinc and cobalt metal complex is shown in the specification, wherein M represents a bivalent metal cation namely Zn(II) or Co(II); L represents water or methanol; and X represents an anion of a metal salt obtained when the metal cation participates in reaction in a metal salt form, and is a nitrate radical or a perchlorate radical.
Description
Technical field
The present invention relates to metal complex field, be specifically related to be oxidized zinc, cobalt metal compounding and synthetic method thereof and application that nantenine is part.
Background technology
Oxidation nantenine is a kind of typical oxoaporphinoid, extensively be present in the Chinese medicinal plant such as Magnoliaceae, annonaceae, papaveracease, Menispermaceae, (department's end fortune can be obtained by extraction and isolation from these plants, what plain coffee Alkaloid composition of Radix stephaniae tetrandrae over-ground part, Jining Medical College journal, 14th volume the 2nd phase, in June, 1991).Oxidation aporphine alkali is the series alkaloid that a class has remarkable pharmacologically active.Oxidation aporphine alkali, owing to having special rigid plane and heterocycle atom N and ketonic oxygen (C=O) group, makes it have the physiologically active stronger compared with aporphine alkaloid.
On the other hand, along with people's improving constantly the medical level of understanding of metal matrix medicine, domestic and international investigator constantly synthesizes low toxicity, the novel metal title complex that efficient, Antitumor test is wide, the platinum complexes novel comprising some and a large amount of non-platinum complexes, as ruthenium complexe, rhodium complex, gold, silver and bronze title complex and cobalt nickel Zn complex etc.Zinc-Zn (II), cobalt-Co (II) are micro elements needed by human, and their trace existence in human body or organism but extensively distribute, and play crucial or important physiological action with the form of coenzyme in a series of important biological process.As the key coenzymes composition that Zn (II) is tens kinds of enzymes such as archaeal dna polymerase; Co (II) mainly exists with vitamin B12 form, can promote the maturation etc. of erythrocyte.But so far, there is not yet to be oxidized the research report of zinc that nantenine is part, cobalt metal compounding, the research report of its zinc, cobalt metal compounding also belongs to blank.
Summary of the invention
The technical problem to be solved in the present invention is to provide to be oxidized zinc, the cobalt metal compounding that nantenine is part, and their synthetic method and application.
The present invention, itself to have the oxidation nantenine of anti-tumor activity for part, synthesizes with zinc, cobalt positively charged ion, obtains anti-tumor activity generally higher than zinc, the cobalt metal compounding of oxidation nantenine part.
The molecular formula of oxidation nantenine is C
19h
13nO
5, molecular weight is 335.31g/mol, and chemical structural formula is as follows:
In this molecular structure, 7 heterocycle atom N and 8 carbonyl O atoms of oxidation aporphine female ring have stronger chelating ligands ability, can form following coordination mode (ONT of the following stated is the abbreviation of oxidation nantenine part) in coordination reaction:
N, O bidentate chelating mode: to be oxidized 7-N, 8-O two atoms and the central transition metal positively charged ion M chelating ligands of nantenine, forms five-ring chelating body.Based on coordination mode and the ligancy of zinc, cobalt positively charged ion M, the ratio that part ONT can form amount of substance with M is the title complex of 2:1 type, and corresponding coordination structure formula is shown below:
Wherein, M represents a kind of divalent metal, is Zn (II) or Co (II); L represents water (H
2or methyl alcohol (CH O)
3oH); X represents that above-mentioned metallic cation is with the negatively charged ion of this metal-salt during metallic salt form participation reaction, is nitrate radical (NO
3 -) or perchlorate (ClO
4 –).
Above-mentioned to be oxidized zinc, the cobalt metal compounding that nantenine is part, normal pressure solution method or the hot method of high pressure solvent can be adopted to synthesize.
When adopting normal pressure solution method to synthesize, comprise the following steps:
1) stoichiometrically take metal-salt and the luxuriant and rich with fragrance alkali of oxidation Nandina domestica, be dissolved in polar solvent, obtain mixing solutions;
2) gained mixing solutions reacts under 20 ~ 80 DEG C of conditions;
3) gained reacting liquid filtering, throw out, through washing, drying, namely obtains corresponding metal complexes.
The step 1 of above-mentioned solution method) in, described polar solvent can be selected from a kind of in water, methyl alcohol, ethanol and dimethyl sulfoxide (DMSO) or the combination two or more arbitrarily in them.When solvent is the mixture of two kinds, the proportioning between them can be any proportioning.Calculate with the metal-salt of 1mmol, total consumption of whole raw material polar solvent used is generally 20 ~ 100mL.In concrete dissolving step, metal-salt and oxidation nantenine part can be dissolved with polar solvent respectively, remix reacts together; Also can by additive polarity solvent again after metal-salt and the mixing of oxidation nantenine part.
The step 2 of above-mentioned solution method) in, whether reaction can adopt thin-layer chromatography tracing detection completely.Reaction preferably adopts back flow reaction, and back flow reaction is preferably carried out in the reflow temperature range of 65 ~ 80 DEG C, and the time of reacting under above-mentioned optimum condition controls usually at 10 ~ 24h; Also as required the reaction times can be extended to more than 24h.When carrying out under the normal temperature reacted below 65 DEG C or heating condition, reaction is to the time needing more to grow completely.
The step 3 of above-mentioned solution method) in, normally wash with water, methyl alcohol, ether successively during washing.Drying conditions is vacuum-drying under 30 ~ 50 DEG C of conditions or constant pressure and dry.In present method, product generally generates in solid form in a large number, if previous step 1) add-on of Semi-polarity solvent comparatively large (upper limit as close to proportioning) or the solvability of solvent to product better, then after reaction, solution may be clear state, this is because caused by the product precipitation formed dissolved by polar solvent, now can by solution decompression distillation after reaction with remove portion solvent, product is mainly separated out with precipitation forms, after taking out the precipitation separated out, carries out next step operation again.
When adopting solvent structure, specifically comprise the following steps:
A) stoichiometrically take metal-salt and the luxuriant and rich with fragrance alkali of oxidation Nandina domestica, be dissolved in polar solvent, obtain mixing solutions;
B) gained mixing solutions is placed in container, after liquid nitrogen freezing, be evacuated to vacuum, sealing by fusing, then reacts under 25 ~ 150 DEG C of conditions, namely obtains corresponding metal complexes.
The step of above-mentioned solvent-thermal method a) in, described polar solvent can be selected from a kind of in water, methyl alcohol, ethanol and dimethyl sulfoxide (DMSO) or the combination two or more arbitrarily in them.When solvent is the mixture of two kinds, the proportioning between them can be any proportioning.Calculate with the metal-salt of 1mmol, total consumption of whole raw material polar solvent used is generally 10 ~ 30mL.In concrete dissolving step, metal-salt and oxidation nantenine part can be dissolved with polar solvent respectively, remix reacts together; Also can by additive polarity solvent again after metal-salt and the mixing of oxidation nantenine part.
The step b of above-mentioned solvent-thermal method) in, described container is generally heavy wall borosilicate glass tube, and mixing solutions preferably reacts under 80 ~ 110 DEG C of conditions, and the time of reacting under above-mentioned optimum condition controls usually at 12 ~ 72h; Also as required the reaction times can be extended to more than 72h.When carrying out under the normal temperature reacted below 80 DEG C or heating condition, the time that reaction needed is longer just can obtain higher productive rate.
In technical solutions according to the invention, when synthesizing to be oxidized the zinc or cobalt metal compounding that nantenine is part, in above-mentioned 2 kinds of synthetic methods, described metal-salt is respectively zinc nitrate or zinc perchlorate, Jing Ti/Bao Pian COBALT NITRATE CRYSTALS/FLAKES or cobaltous perchlorate; The ratio of the amount of substance of described metal-salt and the luxuriant and rich with fragrance alkali of oxidation Nandina domestica is generally 1:1 ~ 3.
In synthetic method of the present invention, the oxidation nantenine part as raw material can extract from corresponding medicinal plant by prior art.
The present invention also comprise above-mentioned to be oxidized zinc that nantenine is part, cobalt metal compounding preparing the application in antitumor drug.
The present invention comprises with above-mentioned further with the antitumor drug being oxidized zinc that nantenine is part, cobalt metal compounding is prepared for effective ingredient.
The present invention is oxidized nantenine for active ligand with the effective constituent in medicinal plant, oxidation nantenine zinc, the cobalt metal compounding with anti-tumor activity has been synthesized with zinc, cobalt metal ion, by investigating their restraining effect to various tumor cell strains, result shows zinc, cobalt complex shows the anti-tumor activity stronger than oxidation nantenine part, clinical anticancer medication cis-platinum is obviously better than to the anti-tumor activity of Partial tumors strain, there is good potential pharmaceutical use, be expected to the preparation for various antitumor drug.
Accompanying drawing explanation
Fig. 1 is the infrared spectra spectrogram of the final product that the embodiment of the present invention 1 obtains;
Fig. 2 is the electrospray ionization mass spectrum spectrogram of the final product that the embodiment of the present invention 1 obtains;
Fig. 3 is the crystalline structure figure of the final product that the embodiment of the present invention 1 obtains;
Fig. 4 is the infrared spectra spectrogram of the final product that the embodiment of the present invention 2 obtains;
Fig. 5 is the electrospray ionization mass spectrum spectrogram of the final product that the embodiment of the present invention 2 obtains;
Fig. 6 is the crystalline structure figure of the final product that the embodiment of the present invention 2 obtains.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail, and to understand content of the present invention better, but the present invention is not limited to following examples.
Embodiment 1: with normal pressure solution method synthesis ONT-Zn (II) title complex
1mmol Zn (NO
3)
2.6H
2the ONT of O and 2mmol is dissolved in 20mL methanol solution, and under 65 DEG C of (condensing reflux) conditions, react 10h, solution becomes reddish-brown from yellow gradually, has a large amount of title complex solid to generate; Treat this solution of its cold filtration, filter with water, washing with alcohol the solid obtained successively, dry, finally obtain red solid product, productive rate: 67%.Product is analyzed (spectrogram as shown in Figure 3) through infrared spectra (spectrogram as shown in Figure 1), electrospray ionization mass spectrum (spectrogram as shown in Figure 2) and X-ray single crystal diffraction and is carried out structure determination, is defined as title complex [Zn (ONT)
2(CH
3oH) (NO
3)] NO
3.
Embodiment 2: with normal pressure solution method synthesis ONT-Co (II) title complex
1mmol Co (ClO
4)
2.6H
2the ONT of O and 2mmol is dissolved in (volume ratio is 4:5) in the mixing solutions of 40mL ethanol and dimethyl sulfoxide (DMSO), reacts 24h, obtains red suspension after reaction, have a large amount of title complex solid to generate under 80 DEG C of (condensing reflux) conditions; Filter this solution, filter with water, washing with alcohol the solid obtained successively, dry, finally obtain red solid product, productive rate: 71%.Product is analyzed (spectrogram as shown in Figure 6) through infrared spectra (spectrogram as shown in Figure 4), electrospray ionization mass spectrum (spectrogram as shown in Figure 5) and X-ray single crystal diffraction and is carried out structure determination, is defined as title complex [Co (ONT)
2(H
2o)
2] (ClO
4)
2.
Embodiment 3: with solvent structure ONT-Zn (II) title complex
Take 0.1mmol Zn (NO
3)
2.6H
2o and 0.2mmol ONT is in the heavy wall borosilicate glass tube of one end open, add the ethanol of 1.5mL and the mixed solvent (volume ratio is 1:2) of water again, under the condition that liquid nitrogen freezing vacuumizes, by opening end sealing by fusing, then under 110 DEG C of conditions, fully 12h is reacted, red colored crystalline type solid product can be obtained, productive rate: 53%.Product carries out structure determination through infrared spectra, electrospray ionization mass spectrum and the analysis of X-ray single crystal diffraction, is defined as title complex [Zn (ONT)
2(CH
3oH) (NO
3)] NO
3.
Embodiment 4: with solvent structure ONT-Co (II) title complex
Take 0.1mmol Co (ClO
4)
2.6H
2o and 0.2mmol ONT is in the heavy wall borosilicate glass tube of one end open, add the methyl alcohol of 2mL and the mixed solvent (volume ratio is 1:1) of water again, under the condition that liquid nitrogen freezing vacuumizes, by opening end sealing by fusing, then under 80 DEG C of conditions, fully 72h is reacted, red colored crystalline type solid product can be obtained, productive rate: 59%.Product carries out structure determination through infrared spectra, electrospray ionization mass spectrum and the analysis of X-ray single crystal diffraction, is defined as title complex [Co (ONT)
2(H
2o)
2] (ClO
4)
2.
Experimental example 1: oxidation nantenine, title complex obtained by embodiment 1 ~ 4 are to the vitro inhibition activity experiment of multiple mankind's tumor line
1, cell strain and cell cultures
BEL-7404 human hepatocellular cells and HepG2, human stomach cancer cell line MGC80-3, Human cervical carcinoma cell line HeLa, human bladder cancer cell's strain T-24 are selected in this experiment.
All cells strain is all cultivated in the RPMI-1640 nutrient solution containing the little ox blood of 10wt%, 100U/mL penicillin, 100U/mL Streptomycin sulphate, puts 37 DEG C containing volumetric concentration 5%CO
2cultivate in incubator.
2, primary dcreening operation
The purity of compound used herein all >=95%; All compounds are mixed with the DMSO liquid storage of 20 μm of ol/L, solubility promoter DMSO final concentration≤1%, test the suppression degree of compound on tumor Growth of Cells under this concentration.
Under testing this concentration, each compound is to the inhibiting rate of cancer cells, all inhibiting rates are greater than 50% and (as cell shrinkage, fragmentation, floating etc.) of cell suppressed (or impaired) metamorphosis under meeting light microscopic, and be not very large compound to normal cytotoxicity, then preliminary judgement is that this compound primary dcreening operation is effective.
3, cell growth inhibition test (mtt assay)
Get the cell being in logarithmic phase, every hole 180 μ L (an about 4500-5000 cell) celliferous culture medium inoculated in 96 well culture plates, in 37 DEG C, 5%CO
224h is cultivated under abundant humidifying condition.After cell attachment, add sample by the amount of every hole 20 μ L, 6 multiple holes established by each sample, set corresponding blank simultaneously.After continuing to cultivate 48h, every hole adds 10 μ L MTT reagent (concentration is 5mg/mL), and after continuing to hatch 4h, inhale and abandon supernatant liquor, every hole adds 150 μ L DMSO again, and slight concussion reaction 5-8min, makes crystalline particle fully dissolve.Blank group returns to zero, and measures the absorbance after removing bias light absorption value by microplate reader with 490nm wavelength
calculate cell proliferation inhibition rate, the test-compound good to primary dcreening operation antitumous effect, continue to continue by 5 concentration gradients the IC doing corresponding cell strain
50value, all experiments are averaged after all repeating 3 times.According to the optical density value recorded (OD value), judge viable cell quantity, OD value is larger, and cytoactive is stronger.Utilize formula:
Measuring and calculating title complex to the inhibiting rate of growth of tumour cell, then calculates the IC of each rare earth compounding to above-mentioned tumor cell line respectively with Bliss method
50value, its result is as shown in table 1 below:
Table 1:
From upper table data, under same experimental conditions, two kinds of zinc (II) of being synthesized by embodiment 1 ~ 4, Co (II) transition metal complex Zn
iI-ONT and Co
iI-ONT all shows significant in-vitro multiplication inhibit activities to surveyed 5 kinds of human tumor cell lines, and activity is all better than part, wherein, and Zn
iIthe activity comparatively part enhancing 2 ~ 3 times of-ONT, Co
iIthe activity comparatively part enhancing more than 2 ~ 4 times of-ONT.The inhibit activities of two kinds of title complexs to HeLa human cervical carcinoma cell lines is the highest, IC
50value is all about 11 μMs.On the other hand, two kinds of title complexs are compared with classical cancer therapy drug-cis-platinum, its anti tumor activity in vitro also shows clear superiority generally, except to the inhibit activities of HeLa human cervical carcinoma cell lines a little less than cis-platinum, to the inhibit activities of other four kinds of tumor lines all higher than cis-platinum, wherein zinc (II), Co (II) title complex to the activity of MGC80-3 human stomach cancer cell line then respectively higher than cis-platinum 4 times and 8 times.
Visible, of the present invention to be oxidized zinc (II), Co (II) metal complexes that nantenine is part, all show the anti-tumor activity stronger than oxidation nantenine part, there is good potential pharmaceutical use, be expected to the preparation for various antitumor drug.
Claims (7)
1., to be oxidized zinc, the cobalt metal compounding that nantenine is part, their general structure is shown below:
Wherein, M represents a kind of divalent metal, is Zn (II) or Co (II); L represents water or methyl alcohol; X represents that above-mentioned metallic cation is with the negatively charged ion of this metal-salt during metallic salt form participation reaction, is nitrate radical or perchlorate.
2. according to claim 1 with the synthetic method being oxidized zinc that nantenine is part, cobalt metal compounding, comprise the following steps:
1) stoichiometrically take metal-salt and the luxuriant and rich with fragrance alkali of oxidation Nandina domestica, be dissolved in polar solvent, obtain mixing solutions;
2) gained mixing solutions reacts under 20 ~ 80 DEG C of conditions;
3) gained reacting liquid filtering, throw out, through washing, drying, namely obtains corresponding metal complexes.
3. synthetic method according to claim 2, is characterized in that: step 1) in, described polar solvent is be selected from a kind of in water, methyl alcohol, ethanol and dimethyl sulfoxide (DMSO) or the combination two or more arbitrarily in them.
4. according to claim 1 with the synthetic method being oxidized zinc that nantenine is part, cobalt metal compounding, comprise the following steps:
A) stoichiometrically take metal-salt and the luxuriant and rich with fragrance alkali of oxidation Nandina domestica, be dissolved in polar solvent, obtain mixing solutions;
B) gained mixing solutions is placed in container, after liquid nitrogen freezing, be evacuated to vacuum, sealing by fusing, then reacts under 25 ~ 150 DEG C of conditions, namely obtains corresponding metal complexes.
5. synthetic method according to claim 2, is characterized in that: step a) in, described polar solvent is be selected from a kind of in water, methyl alcohol, ethanol and dimethyl sulfoxide (DMSO) or the combination two or more arbitrarily in them.
6. according to claim 1 to be oxidized zinc that nantenine is part, cobalt metal compounding preparing the application in antitumor drug.
7. with according to claim 1 with the antitumor drug being oxidized zinc that nantenine is part, cobalt metal compounding is prepared for effective ingredient.
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| CN101020699A (en) * | 2006-02-16 | 2007-08-22 | 广西师范大学 | Metal complex with liriodenine as ligand and its synthesis process and use |
| CN102260293A (en) * | 2011-05-04 | 2011-11-30 | 广西师范大学 | Transition metal coordination compounds with oxoglaucine as ligand, synthesizing method thereof, and application thereof |
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| CN101020699A (en) * | 2006-02-16 | 2007-08-22 | 广西师范大学 | Metal complex with liriodenine as ligand and its synthesis process and use |
| CN102260293A (en) * | 2011-05-04 | 2011-11-30 | 广西师范大学 | Transition metal coordination compounds with oxoglaucine as ligand, synthesizing method thereof, and application thereof |
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| CN104844635A (en) * | 2015-04-17 | 2015-08-19 | 广西师范大学 | Manganese and zinc metal complexes taking alocasia amazonica alkali as ligand as well as synthesis method and application of manganese and zinc metal complexes |
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