CN106883251A - A kind of many pyridine copper complexes of amino acid and its preparation method and application - Google Patents
A kind of many pyridine copper complexes of amino acid and its preparation method and application Download PDFInfo
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- CN106883251A CN106883251A CN201710098493.0A CN201710098493A CN106883251A CN 106883251 A CN106883251 A CN 106883251A CN 201710098493 A CN201710098493 A CN 201710098493A CN 106883251 A CN106883251 A CN 106883251A
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- 150000001413 amino acids Chemical class 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title abstract description 7
- IRJGZWIEFFOYJN-UHFFFAOYSA-N copper;pyridine Chemical class [Cu].C1=CC=NC=C1 IRJGZWIEFFOYJN-UHFFFAOYSA-N 0.000 title abstract 2
- 239000010949 copper Substances 0.000 claims abstract description 38
- 235000001014 amino acid Nutrition 0.000 claims abstract description 24
- -1 hydrogen imidazoles Chemical class 0.000 claims abstract description 22
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 claims abstract description 10
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 8
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims abstract description 8
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 7
- 229930182817 methionine Natural products 0.000 claims abstract description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims abstract description 6
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000004471 Glycine Substances 0.000 claims abstract description 4
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims abstract description 4
- 235000004279 alanine Nutrition 0.000 claims abstract description 4
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims abstract description 3
- 150000004699 copper complex Chemical class 0.000 claims description 52
- 239000013078 crystal Substances 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 12
- 150000001879 copper Chemical class 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 claims description 8
- 238000002441 X-ray diffraction Methods 0.000 claims description 7
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 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 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- 229940116318 copper carbonate Drugs 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- 229910000009 copper(II) carbonate Inorganic materials 0.000 claims description 2
- YRNNKGFMTBWUGL-UHFFFAOYSA-L copper(ii) perchlorate Chemical compound [Cu+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O YRNNKGFMTBWUGL-UHFFFAOYSA-L 0.000 claims description 2
- GEZOTWYUIKXWOA-UHFFFAOYSA-L copper;carbonate Chemical compound [Cu+2].[O-]C([O-])=O GEZOTWYUIKXWOA-UHFFFAOYSA-L 0.000 claims description 2
- 239000011646 cupric carbonate Substances 0.000 claims description 2
- 235000019854 cupric carbonate Nutrition 0.000 claims description 2
- 229960003280 cupric chloride Drugs 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000011275 oncology therapy Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 36
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 abstract description 14
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 abstract description 14
- 230000002401 inhibitory effect Effects 0.000 abstract description 12
- 150000001875 compounds Chemical class 0.000 abstract description 11
- 230000001093 anti-cancer Effects 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 8
- 241000024188 Andala Species 0.000 abstract 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 abstract 1
- 238000003556 assay Methods 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 64
- 230000005764 inhibitory process Effects 0.000 description 24
- 206010028980 Neoplasm Diseases 0.000 description 23
- 201000011510 cancer Diseases 0.000 description 17
- 125000004430 oxygen atom Chemical group O* 0.000 description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 description 15
- 210000004881 tumor cell Anatomy 0.000 description 15
- 239000003446 ligand Substances 0.000 description 13
- 239000002246 antineoplastic agent Substances 0.000 description 11
- 229940041181 antineoplastic drug Drugs 0.000 description 11
- 229910052802 copper Inorganic materials 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 125000004429 atom Chemical group 0.000 description 10
- 150000002500 ions Chemical class 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- RKTYLMNFRDHKIL-UHFFFAOYSA-N copper;5,10,15,20-tetraphenylporphyrin-22,24-diide Chemical compound [Cu+2].C1=CC(C(=C2C=CC([N-]2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3[N-]2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 RKTYLMNFRDHKIL-UHFFFAOYSA-N 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- 230000000002 effect on proteasome Effects 0.000 description 4
- 230000001376 precipitating effect Effects 0.000 description 4
- 230000009471 action Effects 0.000 description 3
- 229960001467 bortezomib Drugs 0.000 description 3
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical group C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 150000004696 coordination complex Chemical class 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- UVFAEQZFLBGVRM-MSMWPWNWSA-N succinyl-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)CCC(O)=O)CC(C)C)C(=O)NC=1C=C2OC(=O)C=C(C)C2=CC=1)C1=CC=C(O)C=C1 UVFAEQZFLBGVRM-MSMWPWNWSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- QGHDLJAZIIFENW-UHFFFAOYSA-N 4-[1,1,1,3,3,3-hexafluoro-2-(4-hydroxy-3-prop-2-enylphenyl)propan-2-yl]-2-prop-2-enylphenol Chemical group C1=C(CC=C)C(O)=CC=C1C(C(F)(F)F)(C(F)(F)F)C1=CC=C(O)C(CC=C)=C1 QGHDLJAZIIFENW-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 239000012327 Ruthenium complex Substances 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000037012 chymotrypsin-like activity Effects 0.000 description 1
- 229910001431 copper ion Inorganic materials 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 150000003304 ruthenium compounds Chemical class 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07F1/08—Copper compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to many pyridine copper complexes of a kind of amino acid and its preparation method and application.Their chemical formula is respectively [Cu (OH PIP) (Phe) Cl] 3H2O 1、[Cu(OH‑PIP)(Gly)(H2O)]NO3·2H2O 2、[Cu(OH‑PIP)(Ala)(Cl)]3、[Cu(OH‑PIP)(Met)]n(PF6)·2H2O 4、[Cu(OH‑PIP)(Gln)(H2O)](Cl)·3H2O 5.Wherein OH PIP are 4 (base of 1 hydrogen imidazoles [4,5 f] [1,10] phenanthroline 2) phenol, and Phe is phenylalanine, and Gly is glycine, and Met is methionine, and Ala is alanine, and Gln is glutamine.Mtt assay have rated 15 couples of MCF 7 of complex, SMMC 7721, the antitumor activity of the cell of K562, A549 and SGC 7901, it was found that such compound has good active anticancer to above-mentioned cell, and have certain inhibitory action to proteasome activity, can be used as a kind of targeted anticancer medicine of potential using value.
Description
Technical Field
The invention relates to a preparation method and application prospect of an amino acid polypyridine copper complex, wherein the complex has good anticancer activity on selected tumor cell strains and has a certain inhibition effect on proteasome activity, so that the complex can be used as a proteasome-targeted antitumor or anticancer drug with potential application value.
Background
Cancer is a general term for a large group of malignant tumors, and is one of the most major diseases that endanger human life at present. At the end of the last 60 years of the century, cisplatin brings about further intensive research on the pharmacological functions of metal complexes by virtue of excellent antitumor effect. Then a plurality of new metal complexes with high efficiency, low toxicity and anticancer performance are continuously synthesized and gradually put into clinical application. Among them, platinum antitumor drugs such as cisplatin and carboplatin have excellent anticancer properties and are becoming the main anticancer drugs. However, because the action target is DNA, the selectivity to tumor cells is lacked, so that the toxic and side effects of gastrointestinal tracts and blood are caused greatly, and in addition, the cisplatin cannot be taken orally and has serious drug resistance, so that the clinical wide application of the cisplatin is limited. Therefore, medical chemists try to develop other metal-based compounds with targets which are not used for platinum or multiple targets so as to improve the selectivity of the compounds on tumor cells, overcome the defects of platinum drugs and expand the clinical anti-tumor spectrum. The ruthenium complex has low toxicity and is easy to be absorbed by tumor tissues, and is regarded as one of the most promising anticancer drugs. In recent years some ruthenium compounds have been successively introduced into clinical trials. Copper is an important essential element required by human body, and is used as a cofactor of some structures and catalytic centers in the organism to participate in a plurality of biological reaction processes in the organism. In recent years, the metal complex, particularly the copper complex, has strong inhibition effect on proteasomes in tumor cells and can induce apoptosis, and has low toxicity on normal cells, thereby providing a basis for developing the metal complex as a targeted medicament.
The polypyridine ligand has strong sigma electron-donating ability and pi electron-accepting ability, has strong anti-tumor activity, can form a stable complex with various metals, can neutralize the positive charge of metal ions, improves the lipophilicity of the complex, can be inserted into DNA or has redox reaction with protein, and the complex is easy to be absorbed by cells, and has great application prospect in the aspects of DNA structure probes, DNA molecular photoswitches, DNA tracing reagents, DNA breaking reagents, anti-cancer drugs and the like; the amino acid is used as a carrier, the water solubility of the compound can be increased, the toxicity is reduced, and the amino acid requirement of cancer attenuated cells is much greater than that of normal cells, so that the anticancer groups can be carried into the cancer cells by introducing the amino acid molecules, thereby improving the effective dose reaching a target and increasing the selectivity of killing the cancer cells.
Based on the research background, the invention introduces an amino acid structure into the polypyridine copper complex, on one hand, the water solubility of the amino acid is utilized, and different molecular frameworks are constructed to regulate the lipid-water distribution coefficient and improve the water solubility of the polypyridine copper complex so as to change the activity of the complex entering cells; on the other hand, the target property of the complex is increased by virtue of the affinity of tumor cells to amino acid. The invention designs and synthesizes amino acid polypyridine copper complex, performs structural representation on the complex, and determines the inhibition effect of the complex on the growth and proliferation of tumor cells and the inhibition effect of the complex on the activity of proteasome so as to obtain the novel metal-based targeted antitumor drug.
Disclosure of Invention
The invention aims to provide an amino acid polypyridine copper complex and a preparation method and application thereof. The invention relates to a novel metal complex type anticancer drug. The target compound has good anticancer activity on MCF-7, SMMC-7721, K562, A549 and SGC-7901 cells, and has certain inhibition effect on proteasome activity.
The chemical formula of the amino acid polypyridine copper complex provided by the invention is [ Cu (OH-PIP) (Phe) Cl]·3H2O 1、[Cu(OH-PIP)(Gly)(H2O)]NO3·2H2O 2、[Cu(OH-PIP)(Ala)(Cl)]3、[Cu(OH-PIP)(Met)](PF6)·2H2O 4、[Cu(OH-PIP)(Gln)(H2O)](Cl)·3H2O5, wherein OH-PIP is 4- (1-hydro-imidazo [4, 5-f)][1,10]Phenanthroline-2-yl) phenol, Phe is phenylalanine, Gly is glycine, Met is methionine, Ala is alanine, Gln is glutamine, PF6Is hexafluorophosphate.
The copper complex 1 crystal belongs to an orthorhombic system, and the space group is P21212, unit cell parameter of α -90 °, β -90 °, γ -90 °, Z-2, unit cell volume
The copper complex 2 crystal belongs to a triclinic system, the space group is P-1, and the unit cell parameter is α 74.112(9) ° β 70.602(8) ° γ 72.277(9) ° Z2, unit cell volume
The copper complex 3 crystal belongs to a triclinic system, the space group is P-1, and the unit cell parameter is α 82.402(6) ° β 75.485(6) ° γ 69.805(5) ° Z2, unit cell volumeThe copper complex 4 crystal belongs to a monoclinic system, the space group is C2/C, the unit cell parameter is α ═ 90.00 °, β ═ 104.930(3 °), γ ═ 90.00 °, Z ═ 8, unit cell volume
The copper complex 5 crystal belongs to a monoclinic system, and the space group is P21C, unit cell parameter of α ═ 90.00(6) ° β ═ 95.958(7) (6) ° γ ═ 90.00(5) ° Z ═ 4, unit cell volume
The preparation method of the copper complex 1-5 provided by the invention comprises the following steps: dissolving equimolar amino acid and alkali in a water and alcohol mixed solution with the same volume, adding equimolar metal copper salt under stirring at normal temperature, refluxing and stirring for 2-5 hours, adding equimolar hexafluorophosphate, stirring at room temperature for 1-4 hours, filtering, slowly volatilizing the filtrate at room temperature, separating out green crystals suitable for X-ray analysis after 2-6 weeks, and collecting and detecting.
The alkali comprises triethylamine, lithium hydroxide, sodium hydroxide and potassium hydroxide.
The alcohol includes methanol, ethanol, propanol, isopropanol and butanol.
The salt comprises cupric chloride, cuprous chloride, cupric carbonate, cupric nitrate and cupric perchlorate.
The hexafluorophosphate comprises lithium hexafluorophosphate, sodium hexafluorophosphate, potassium hexafluorophosphate and ammonium hexafluorophosphate.
The structure of the copper complex 1 is as follows: the basic unit consists of one [ Cu (OH-PIP) (Phe) Cl ] and three free water molecules. One Cu atom forms a penta-coordinate configuration with 2N atoms of one OH-PIP ligand, one O and N atoms of a phenylalanine ligand, and one Cl atom. According to the geometric calculation of Addison-Reediijk, the coordination configuration of Cu ions is a tetragonal cone (tau ═ 0.10). The equatorial plane of which consists of the two N atoms of OH-PIP and the N and O atoms of phenylalanine, the Cl ion occupies the axial position and the unit structure diagram is shown in FIG. 1.
The structure of the copper complex 2 is as follows: the basic unit is composed of [ Cu (OH-PIP) (Gly) (H)2O)]+A cation, one nitrate anion and two free water molecules. A Cu atom forms a penta-coordinate configuration with 2N atoms of an OH-PIP ligand, one O and N atoms of a glycine ligand, and one O atom of a water molecule. According to the Addison-Reedijk geometric calculation, the coordination configuration of the Cu ion is a tetragonal cone (tau ═ 0.02). The equatorial plane of which consists of the two N atoms of OH-PIP and the N and O atoms of the amino acids, the O atom of water occupies the axial position, and the unit structure diagram is shown in FIG. 2.
The structure of the copper complex 3 is as follows: the basic unit consists of one [ Cu (OH-PIP) (Ala) (Cl) ]. One Cu atom forms a penta-coordinate configuration with 2N atoms of one OH-PIP ligand, one O and N atoms of an alanine ligand, and one Cl atom. According to the Addison-Reedijk geometric calculation, the coordination configuration of the Cu ion is a tetragonal cone (tau ═ 0.08). The equatorial plane of which consists of the two N atoms of OH-PIP and the N and O atoms of the amino acids, the Cl atom occupies the axial position and the unit structure diagram is shown in FIG. 3.
The structure of the copper complex 4 is as follows: the basic unit consists of one [ Cu (OH-PIP) (Met)]+A cation, one hexafluorophosphate anion and two free water molecules. One Cu atom forms a penta-coordinate configuration with 2N atoms of one OH-PIP ligand, one O and N atoms of a methionine ligand, and the O atom of another methionine. According to the Addison-Reedijk geometry, the coordination configuration of Cu ions is a tetragonal pyramid (tau. is 0.003). The equatorial plane of the strain is composed of two N atoms of OH-PIP and N and O atoms of methionine, and the O atom of the other methionine occupies an axial position, and the unit structure diagram is shown in FIG. 4.
The structure of the copper complex 5 is as follows: the basic unit is composed of one [ Cu (OH-PIP) (Gln) (H)2O)]+Cation, one Cl ion and three free water molecules. One Cu atom forms a penta-coordinate configuration with 2N atoms of one OH-PIP ligand, one O and N atoms of a glutamine ligand, and one O atom. According to the Addison-Reedijk geometric calculation, the coordination configuration of the Cu ion is a tetragonal cone (tau ═ 0.08). The equatorial plane of which consists of the two N atoms of OH-PIP and the N and O atoms of the amino acids, the O atom occupying the axial position, the unit structure diagram is shown in FIG. 5.
The amino acid polypyridine copper complex provided by the invention is used in the field of anti-tumor or cancer treatment.
The invention uses OH-PIP as main ligand, contains rich pi electron and N coordination site, uses amino acid with different structure as auxiliary ligand, can be chelated and coordinated with copper ion, and uses conventional solvent synthesis method to obtain target complex. The copper complex has good anticancer activity on MCF-7, SMMC-7721, K562, A549 and SGC-7901 cells, and has a certain inhibition effect on proteasomes, so that the copper complex is a targeted anticancer drug with potential application value, and the preparation method is simple and reliable.
Drawings
FIG. 1: the unit structure of copper complex 1.
FIG. 2: the unit structure of copper complex 2.
FIG. 3: the unit structure of the copper complex 3.
FIG. 4: the unit structure of copper complex 4.
FIG. 5: the unit structure of the copper complex 5.
FIG. 6: fluorescence of action on proteasome at concentrations of 10. mu. mol/L of copper complex 1-5.
FIG. 7: the inhibition rate of the action of the copper complex on proteasome at the concentration of 10 mu mol/L.
Detailed Description
Example 1
Synthesis of copper Complex 1:
dissolving 0.5mmol of amino acid and 0.5mmol of base in a mixed solution of 20mL of water and 20mL of alcohol, adding 0.5mmol of copper chloride under stirring at normal temperature, refluxing and stirring for 3 hours, filtering, adding 0.5mmol of ammonium hexafluorophosphate, continuing to react at room temperature for 1 hour, filtering, slowly volatilizing the filtrate at room temperature, and precipitating green crystals suitable for X-ray analysis after 3 weeks with the yield of about 48% (calculated by copper salt). Elemental analysis results (%), experimental values: c, 54.80; h, 4.62; n,11.40 theoretical value (C)28H28N5O5ClCu): c, 54.81; h, 4.60; n,11.41, the result is basically consistent with the theoretical value.
Example 2
Synthesis of copper complex 2:
dissolving 0.5mmol of amino acid and 0.5mmol of base in a mixed solution of 20mLl water and 20mL of alcohol, adding 0.5mmol of copper nitrate under stirring at normal temperature, refluxing and stirring for 3 hours, filtering, adding 0.5mmol of ammonium hexafluorophosphate, continuing to react at room temperature for 1 hour, filtering, slowly volatilizing the filtrate at room temperature, and precipitating green crystals suitable for X-ray analysis after 3 weeks, wherein the yield is about 41 percent (calculated by copper salt), the elemental analysis result (%), the experimental value: c, 44.54; h, 3.95; n,14.85 theoretical value (C)21H22N6O9Cu): c, 44.56; h, 3.92; n,14.85, the results are essentially in accordance with the theoretical values.
Example 3
Synthesis of copper complex 3:
dissolving 0.5mmol of amino acid and 0.5mmol of base in a mixed solution of 20mL of water and 20mL of alcohol, adding 0.5mmol of copper chloride under stirring at normal temperature, refluxing and stirring for 3 hours, filtering, adding 0.5mmol of ammonium hexafluorophosphate, continuing to react at room temperature for 1 hour, filtering, slowly volatilizing the filtrate at room temperature, and precipitating green crystals suitable for X-ray analysis after 3 weeks with the yield of about 43 percent (calculated by copper salt). Elemental analysis results (%), experimental values: c, 52.90; h, 3.65; n,14.01 theoretical value (C)22H18N5O3ClCu): c, 52.91; h, 3.63; n,14.02, and the result is basically consistent with the theoretical value.
Example 4
Synthesis of copper Complex 4:
dissolving 0.5mmol amino acid and 0.5mmol base in 20mL water and 20mL alcohol mixed solution, adding 0.5mmol copper nitrate under stirring at room temperature, refluxing and stirring for 3 hr, filtering, adding 0.5mmol hexafluoro fluorideAmmonium phosphate, continued reaction at room temperature for 1 hour, filtration, slow evaporation of the filtrate at room temperature, 3 weeks later, precipitation of green crystals suitable for X-ray analysis, with a yield of about 38% (calculated as copper salt). Elemental analysis results (%), experimental values: c, 52.90; h, 3.65; n,14.01 theoretical value (C)24H26N5O5SPF6Cu): c, 40.88; h, 3.71; n,9.93, the results are substantially in accordance with the theoretical values.
Example 5
Synthesis of copper complex 5:
dissolving 0.5mmol of amino acid and 0.5mmol of base in a mixed solution of 20mL of water and 20mL of alcohol, adding 0.5mmol of copper chloride under stirring at normal temperature, refluxing and stirring for 3 hours, filtering, adding 0.5mmol of ammonium hexafluorophosphate, continuing to react at room temperature for 1 hour, filtering, slowly volatilizing the filtrate at room temperature, and precipitating green crystals suitable for X-ray analysis after 3 weeks with the yield of about 38% (calculated by copper salt). Elemental analysis results (%), experimental values: c, 52.90; h, 3.65; n,14.01 theoretical value (C)24H29N6O8ClCu): c, 45.86; h, 4.65; n,13.37, and the result is basically consistent with the theoretical value.
The structural parameters of the copper complexes 1 to 5 are shown in tables 1 to 6.
Example 6
Selective experiments with copper complexes 1-5 on several cancer cells:
the MTT (Thiazolum blue) method is a method for detecting the survival and growth of cells. The basic principle of the experiment is as follows: the thiazole blue can penetrate through a live cell membrane to enter a cell, the amber dehydrogenase in mitochondria of the live cell can reduce exogenous MTT into blue-purple Formazan crystals which are difficult to dissolve in water and precipitate in the cell, the crystals can be dissolved by DMSO, and an enzyme-labeling instrument is used for detecting the absorbance value at 570nm, thereby indirectly reflecting the number of the live cells. The method is commonly used for screening a large number of antitumor drugs, cytotoxicity tests, tumor radiosensitivity determination and the like. Has the advantages of high sensitivity, economy and the like.
The experimental process comprises the following steps:
the MTT method is used to measure the inhibition ability of the complex on the growth of MCF-7, SMMC-7721, K562, A549 and SGC-7901 cells in vitro, and the basic step is to inoculate the cells into 96-well culture plates, each well of which is 2 × 105Individual cells, 6 duplicate wells. 5% CO2After incubation for 24h at 37 ℃, drugs with different concentrations were added to the corresponding well plates to act on tumor cells for 48h, while control wells (cells, drug lysis medium of the same concentration, culture solution, MTT, dimethyl sulfoxide) were set, and 3 wells per group were set. MTT (5 mg. mL) was added to each well-1)20 μ L, further culturing for 4h, carefully aspirating the supernatant, adding dimethyl sulfoxide (100 μ L/well), gently shaking, reacting at room temperature for 0.5h, detecting the absorbance at 570nm with a microplate reader, and then analyzing the data.
The experimental results are as follows:
after the complex 1 with different concentrations acts on the cancer cells for 48 hours, the inhibition effect on the cancer cells is found to be remarkably different, the complex acts on SGC-7901 cells strongly, and the half inhibition rate IC is50The value was 3.50. mu.g.mL-1Has equivalent effect on MCF-7 and A549 cells, but has weaker effect on SMMC-7 and K562 cells, and IC50The values are all more than 100 mu g/mL-1The data are shown in Table 7.
After the complex 2 with different concentrations acts on the cancer cells for 48 hours, the inhibitory action on the cancer cells is found to be remarkably different, and the IC on MCF-7, SMMC-7721, K562, A549 and SGC-7901 cells is found to be remarkably different50The value is 2.69 to 65.25. mu.g.mL-1The data are shown in Table 8, wherein the effect on SGC-7901 is strongest, the effect on MCF-7 and A549 cells is equivalent, and the effect on SMMC-7721 is relatively weakest.
After the complex 3 with different concentrations acts on the cancer cells for 48 hours, the inhibitory action on the cancer cells is found to be remarkably different, and the IC on MCF-7, SMMC-7721, K562, A549 and SGC-7901 cells is found to be remarkably different50The value is 2.18 to 22.26. mu.g.mL-1The data are shown in Table 9, wherein the effect on SGC-7901 cells is strongest, and the effect on SMMC-7721 cells is relatively weakest.
After the complex 4 with different concentrations acts on the cancer cells for 48 hours, obvious difference is found in the inhibition effect on the cancer cells, and the IC of the complex on MCF-7, SMMC-7721, K562, A549 and SGC-7901 cells50The value is 2.49 to 65.97. mu.g/mL-1The data are shown in Table 10, wherein the effect on SGC-7901 cells is strongest, and the effect on SMMC-7721 cells is relatively weakest.
After the complex 5 with different concentrations acts on the cancer cells for 48 hours, the inhibitory action on the cancer cells is found to be remarkably different, and the IC on MCF-7, SMMC-7721, K562, A549 and SGC-7901 cells is found to be remarkably different50The value is 0.08 to 19.80. mu.g.mL-1Among them, the effect was strongest on K562 cells, followed by SGC-7901 cells, and relatively weakest on SMMC-7721 cells, as shown in Table 11.
As seen from the above evaluation results, complex 5 has strong effects on the above five tumor cells, especially on K562 cells, and its IC is the strongest50The value reaches 0.083 mug. mL-1(ii) a The activity of the complex 3 on MCF-7 cells is the highest, and the activity of other four complexes on MCF-7 cells is equivalent; the complex 1 has the worst activity on SMMC7721 and K562 cells, and the half inhibition rate exceeds 100 mu g/mL-1(ii) a Complexes 2 and 4 were comparable in activity on MCF-7 and SMMC-7721 cells, whereas complex 2 was more active than complex 4 on K562 cells. IC of complexes 1-5 on SGC-7901 cells50All values are lower than 4 mug. multidot.mL-1And relatively weakest on SMMC-7721 cells, which indicates that the compounds have selectivity on tumor cells.
Example 7
In vitro evaluation experiment of copper complex 1-5 for inhibition of proteasome activity:
the experimental method comprises the following steps: the chymotrypsin-like activity of the proteasome is calculated by measuring the amount of AMC groups released by the cells. Adding different concentrations of complex or no drug into 100 μ L buffer (20mM Tris-HCl, pH 7.5) containing a certain amount of 20S proteasome, and adding 10 μmol. L-1Chymotrypsin-like active substrate Suc-LLVY-AMC, incubation for 2 hours at 37 ℃, fluorescence activity (excitation wavelength is 365nm, emission wavelength is 460nm) monitored by a microplate reader, and bortezomib group is used as a positive control group.
The experimental results are as follows:
as shown in FIG. 6, the fluorescence intensity released by the complexes 1-5 is obviously reduced compared with that of the positive control, wherein the fluorescence intensity of bortezomib is the lowest, which indicates that the proteasome inhibition activity of the compound is weaker than that of the positive drug, but the reduction amplitude of the released fluorescence is more than 50% from the results, which indicates that the IC of the complexes 1-5 is50All values are less than 10 mu mol.L-1The compounds have certain proteasome inhibition activity.
As a result of quantitative calculation, as shown in FIG. 7, the positive drug inhibited the proteasome activity by more than 90%, whereas the complex 1-5 was administered at a concentration of 10. mu. mol. L-1The inhibition rate exceeds 60%, and the results prove that the designed and synthesized compound has a considerable inhibitory activity on the enzyme and can be used as a proteasome inhibitor to develop antitumor drugs.
Example 8
Evaluation experiment of copper complexes 1 to 5 for inhibition of intracellular proteasome Activity:
the experimental method comprises the following steps:
after MCF-7 tumor cells are treated by the corresponding coordination compound, the cells are washed by PBS, cell lysate is added, the cells are vibrated and lysed, centrifugation is carried out, and supernatant is collected. Mixing 10 μ g of cell extract with 20 μmol/L at 37 deg.C-1The fluorescent polypeptide substrate Suc-LLVY-AMC was incubated in 100. mu.L of buffer for 1 hour and the fluorescence of the product of the hydrolyzed AMC group was measured using a microplate reader. The excitation wavelength was 365nm and the emission wavelength was 460 nm. Wherein,the negative control group is DMSO, and the positive control group is bortezomib.
The experimental results are as follows:
as shown in Table 12, the final concentration of the complex 1-5 was 6.67. mu.g/mL-1The inhibition rate is more than 50%, and the compound is preliminarily considered to have the effect of inhibiting the proteasome activity, and has significant difference (P is less than 0.01) in the proteasome activity inhibition effect in MCF-7 cells compared with a negative control group.
TABLE 1 Main data on the crystal structures of copper complexes 1 to 5
TABLE 2 major bond lengths and bond angles of the copper complex 1 crystals
TABLE 3 major bond lengths and bond angles of the copper complex 2 crystals
TABLE 4 major bond lengths and bond angles of copper complex 3 crystals
TABLE 5 major bond lengths and bond angles of copper complex 4 crystals
TABLE 6 major bond lengths and bond angles of the copper complex 5 crystals
TABLE 7 inhibition of five tumor cell lines by copper Complex 1 at different concentrations and IC thereof50Value of
“-”indicates the complex has no inhibitory effect on the tumor cellproliferation.
TABLE 8 inhibition of five tumor cell lines by copper complex 2 at different concentrations and IC thereof50Value of
“-”indicates the complex has no inhibitory effect on the tumor cellproliferation.
TABLE 9 inhibition of five tumor cell lines by copper complex 3 at different concentrations and IC thereof50Value of
“-”indicates the complex has no inhibitory effect on the tumor cellproliferation.
TABLE 10 inhibition of five tumor cell lines by copper complex 4 at different concentrations and IC thereof50Value of
“-”indicates the complex has no inhibitory effect on the tumor cellproliferation.
TABLE 11 inhibition of five tumor cell lines by copper complex 5 at different concentrations and IC thereof50Value of
“-”indicates the complex has no inhibitory effect on the tumor cellproliferation.
TABLE 12 inhibitory Effect of copper complexes 1-5 on proteasome Activity
**compared to NS p＜0.01。
Claims (8)
1. An amino acid polypyridine copper complex, characterized in that: they have the chemical formula [ Cu (OH-PIP) (Phe) Cl]·3H2O 1、[Cu(OH-PIP)(Gly)(H2O)]NO3·2H2O 2、[Cu(OH-PIP)(Ala)(Cl)]3、[Cu(OH-PIP)(Met)]n(PF6)·2H2O 4、[Cu(OH-PIP)(Gln)(H2O)](Cl)·3H2O5, wherein OH-PIP is 4- (1-hydro-imidazo [4, 5-f)][1,10]Phenanthroline-2-yl) phenol, Phe is phenylalanine, Gly is glycine, Met is methionine, Ala is alanine, and Gln is glutamine.
2. The copper complex 1 crystal according to claim 1 belonging to the orthorhombic system, space group being P21212, unit cell parameter ofα -90 °, β -90 °, γ -90 °, Z-2, unit cell volumeThe copper complex 2 crystal belongs to a triclinic system, the space group is P-1, and the unit cell parameter is α 74.112(9) ° β 70.602(8) ° γ 72.277(9) ° Z2, unit cell volumeThe copper complex 3 crystal belongs to a triclinic system, the space group is P-1, and the unit cell parameter isα 82.402(6) ° β 75.485(6) ° γ 69.805(5) ° Z2, unit cell volumeThe copper complex 4 crystal belongs to a monoclinic system, the space group is C2/C, the unit cell parameter isα ═ 90.00 °, β ═ 104.930(3 °), γ ═ 90.00 °, Z ═ 8, unit cell volumeThe copper complex 5 crystal belongs to monoclinic systemThe cluster is P21C, unit cell parameter of α ═ 90.00(6) ° β ═ 95.958(7) (6) ° γ ═ 90.00(5) ° Z ═ 4, unit cell volume
3. A method for producing the copper complex 1 to 5 according to claim 1 to 2, characterized in that: it comprises the following steps: dissolving equimolar amino acid and alkali in a mixed solution of water and alcohol with the same volume, adding equimolar metal copper salt under stirring at normal temperature, refluxing and stirring for 2-5 hours, adding equimolar hexafluorophosphate, stirring at room temperature for 1-4 hours, filtering, slowly volatilizing the filtrate at room temperature, separating out green crystals suitable for X-ray analysis after 2-6 weeks, and collecting the crystals.
4. The method according to claim 3, wherein the base comprises triethylamine, lithium hydroxide, sodium hydroxide, or potassium hydroxide.
5. The method according to claim 3, wherein the alcohol comprises methanol, ethanol, propanol, isopropanol, butanol.
6. The method according to claim 3, wherein the copper salt comprises cupric chloride, cuprous chloride, cupric carbonate, cupric nitrate, and cupric perchlorate.
7. The method according to claim 3, wherein the hexafluorophosphate salt comprises lithium hexafluorophosphate, sodium hexafluorophosphate, potassium hexafluorophosphate, ammonium hexafluorophosphate.
8. Use of the copper complexes according to claims 1-2 in the field of antitumor or cancer therapy.
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|---|---|---|---|---|
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| CN111978336A (en) * | 2020-08-05 | 2020-11-24 | 温州大学新材料与产业技术研究院 | Preparation method and application of 5-fluorouracil-1-yl-acetic acid o-phenanthroline copper tetrafluoroborate anticancer functional complex |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014003541A1 (en) * | 2012-06-28 | 2014-01-03 | Universiti Tunku Abdul Rahman | Copper(ii) -mixed ligand complexes with anticancer properties |
| CN103788118A (en) * | 2014-02-21 | 2014-05-14 | 南开大学 | Mononuclear copper complex and preparation method and application thereof |
| CN105440059A (en) * | 2014-06-11 | 2016-03-30 | 首都师范大学 | Copper complexes of amino acids and phenanthroline or phenanthroline derivative and preparation method and application thereof |
-
2017
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014003541A1 (en) * | 2012-06-28 | 2014-01-03 | Universiti Tunku Abdul Rahman | Copper(ii) -mixed ligand complexes with anticancer properties |
| CN103788118A (en) * | 2014-02-21 | 2014-05-14 | 南开大学 | Mononuclear copper complex and preparation method and application thereof |
| CN105440059A (en) * | 2014-06-11 | 2016-03-30 | 首都师范大学 | Copper complexes of amino acids and phenanthroline or phenanthroline derivative and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| L.WANG ET AL.: "Syntheses, structures, fluorescent properties and natural bond orbital analyses of metal-organic complexes based on 5,6-substituted1,10-phenanthroline derivatives", 《POLYHEDRON》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111875623A (en) * | 2020-08-05 | 2020-11-03 | 温州大学新材料与产业技术研究院 | Preparation method and application of 5-fluorouracil-1-yl acetic acid bipyridyl copper tetrafluoroborate anticancer functional complex |
| CN111978336A (en) * | 2020-08-05 | 2020-11-24 | 温州大学新材料与产业技术研究院 | Preparation method and application of 5-fluorouracil-1-yl-acetic acid o-phenanthroline copper tetrafluoroborate anticancer functional complex |
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