CN104844631A - Copper metal complex and compound prepared from copper metal complex and human serum albumin as well as synthesis method and application thereof - Google Patents
Copper metal complex and compound prepared from copper metal complex and human serum albumin as well as synthesis method and application thereof Download PDFInfo
- Publication number
- CN104844631A CN104844631A CN201510248685.6A CN201510248685A CN104844631A CN 104844631 A CN104844631 A CN 104844631A CN 201510248685 A CN201510248685 A CN 201510248685A CN 104844631 A CN104844631 A CN 104844631A
- Authority
- CN
- China
- Prior art keywords
- copper metal
- dimethyl
- thiosemicarbazide
- serum albumin
- metal complex
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000010949 copper Substances 0.000 title claims abstract description 40
- 150000001875 compounds Chemical class 0.000 title claims abstract description 24
- 102000008100 Human Serum Albumin Human genes 0.000 title claims abstract description 18
- 108091006905 Human Serum Albumin Proteins 0.000 title claims abstract description 18
- 229910052802 copper Inorganic materials 0.000 title claims abstract description 18
- -1 Copper metal complex Chemical class 0.000 title claims abstract description 10
- 238000001308 synthesis method Methods 0.000 title abstract 3
- GCSHUYKULREZSJ-UHFFFAOYSA-N phenyl(pyridin-2-yl)methanone Chemical compound C=1C=CC=NC=1C(=O)C1=CC=CC=C1 GCSHUYKULREZSJ-UHFFFAOYSA-N 0.000 claims abstract description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000002904 solvent Substances 0.000 claims abstract description 32
- 239000013078 crystal Substances 0.000 claims abstract description 20
- 239000000463 material Substances 0.000 claims abstract description 11
- 238000005406 washing Methods 0.000 claims abstract description 8
- 239000000376 reactant Substances 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- 239000000203 mixture Substances 0.000 claims description 36
- 229910052751 metal Inorganic materials 0.000 claims description 19
- 239000002184 metal Substances 0.000 claims description 19
- 238000010189 synthetic method Methods 0.000 claims description 17
- 239000002246 antineoplastic agent Substances 0.000 claims description 12
- 229940041181 antineoplastic drug Drugs 0.000 claims description 12
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 10
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 9
- 150000001298 alcohols Chemical class 0.000 claims description 9
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 9
- 102000007562 Serum Albumin Human genes 0.000 claims description 6
- 108010071390 Serum Albumin Proteins 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 239000012467 final product Substances 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 4
- 239000003446 ligand Substances 0.000 abstract 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 18
- 229960004756 ethanol Drugs 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 10
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 4
- 230000022131 cell cycle Effects 0.000 description 4
- 238000002050 diffraction method Methods 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 229910052742 iron Inorganic materials 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000010337 G2 phase Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- QGZCUOLOTMJILH-UHFFFAOYSA-N 2h-tetrazol-2-ium;bromide Chemical compound [Br-].C1=N[NH+]=NN1 QGZCUOLOTMJILH-UHFFFAOYSA-N 0.000 description 1
- ATYGLHGAYOYXRO-UHFFFAOYSA-N 3-amino-1,1-dimethylthiourea;hydrate Chemical class O.CN(C)C(=S)NN ATYGLHGAYOYXRO-UHFFFAOYSA-N 0.000 description 1
- XMYKNCNAZKMVQN-UHFFFAOYSA-N 3-aminopyridine-2-carboxaldehyde thiosemicarbazone Chemical compound NC(=S)NN=CC1=NC=CC=C1N XMYKNCNAZKMVQN-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 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
- 230000018199 S phase Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- XMYKNCNAZKMVQN-NYYWCZLTSA-N [(e)-(3-aminopyridin-2-yl)methylideneamino]thiourea Chemical compound NC(=S)N\N=C\C1=NC=CC=C1N XMYKNCNAZKMVQN-NYYWCZLTSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 150000004699 copper complex Chemical class 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- SRVJKTDHMYAMHA-WUXMJOGZSA-N thioacetazone Chemical compound CC(=O)NC1=CC=C(\C=N\NC(N)=S)C=C1 SRVJKTDHMYAMHA-WUXMJOGZSA-N 0.000 description 1
- 150000003584 thiosemicarbazones Chemical class 0.000 description 1
- 229960005526 triapine Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/38—Albumins
- A61K38/385—Serum albumin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- 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
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/76—Albumins
- C07K14/765—Serum albumin, e.g. HSA
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Toxicology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Inorganic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a copper metal complex and a compound prepared from the copper metal complex and human serum albumin as well as a synthesis method and application thereof. The synthesis method of the copper metal complex comprises the following steps: taking phenyl-2-pyridyl ketone and 4,4'-dimethyl-3-thiosemicarbazide, taking an alcohol material as a solvent, reacting, generating precipitate, collecting the precipitate and washing the precipitate to obtain a ligand; taking the ligand which is phenyl-2-pyridyl ketone and contracting 4,4'-dimethyl-3-thiosemicarbazide and CuC12.2H2O, taking the alcohol material as the solvent, reacting, enabling a reactant to stand, crystallizing and collecting crystals to prepare the copper metal complex. The compound is prepared by incubating the copper metal complex and human serum albumin through a solution process. The structure of the copper metal complex is as shown in the following formula (I) which is as shown in the description.
Description
Technical field
The present invention relates to and relate to medical art, be specifically related to a kind of copper metal complexes and with the mixture of human serum albumin and their synthetic method and application.
Background technology
Cancer (mainly referring to malignant tumour) is one of harm humans the most serious healthy disease, the most common and endanger serious malignant tumour and mainly contain in China: type (the Farrell N such as mammary cancer, cervical cancer, lymphatic cancer, leukemia, lung cancer, liver cancer, et al.Cancer Res., 1992), antitumor drug is then along with cancer progressively grows up to grave danger of human health.Researcher is through the R&D work of decades, and the antitumor drug of different sorts, different efficacies feature and different mechanism of action goes on the market successively and is applied to clinical treatment and assisting therapy.Wherein, nineteen sixty-five Rosenberg etc. find that cis-platinum has significant antitumour activity (Rosenberg, B L, et al.Nature, 1969), the beginning of inorganic cancer therapy drug has been started, and the serial platinum-containing anticancer drug that to define with cis-platinum, carboplatin, oxaliplatin etc. be representative.Therefore, the novel platinum series antineoplastic medicament of further design and synthesis is a hot research direction, significant.
On the other hand, (thiosemicarbazone) compound has antitumor, antiviral, anti-malarial and many biological activitys such as antibacterial, more existing (thiosemicarbazone) compounds are used in cancer therapy aspect, and such as 3-aminopyridine-2-formaldehyde thiosemicarbazone (Triapine) is for clinical second phase experiment.Yet there are no with phenyl-2-pyridyl ketone contracting 4,4'-dimethyl-3-thiosemicarbazide is the synthesis of copper (II) metal complexes and the open report of pharmacologically active thereof of part.
Summary of the invention
The technical problem to be solved in the present invention be to provide a kind of copper metal complexes and with the mixture of human serum albumin and their synthetic method and application.
Copper metal complexes of the present invention is specifically with phenyl-2-pyridyl ketone contracting 4,4'-dimethyl-3-thiosemicarbazide is copper (II) metal complexes of part, for having compound or its pharmacy acceptable salt of structure shown in following formula (I):
Shown in above-mentioned formula (I), the synthetic method of compound comprises the following steps:
1) get phenyl-2-pyridyl ketone and 4,4'-dimethyl-3-thiosemicarbazide, using alcohols material as solvent, react, have precipitation to generate, collecting precipitation, washing, obtain part phenyl-2-pyridyl ketone contracting 4,4'-dimethyl-3-thiosemicarbazide;
2) part phenyl-2-pyridyl ketone contracting 4,4'-dimethyl-3-thiosemicarbazide and CuCl is got
22H
2o, using alcohols material as solvent, reacts, and reactant leaves standstill, crystallization, collects crystal, namely obtains target compound.
In above-mentioned synthetic method, described raw material 4,4'-dimethyl-3-thiosemicarbazide i.e. 4,4-dimethyl-3-thiosemicarbazide monohydrates.Described alcohols material is preferably methyl alcohol and/or ethanol, and described methyl alcohol preferably adopts volumetric concentration to be the methyl alcohol of 20 ~ 80%, and described ethanol preferably adopts volumetric concentration to be the ethanol of 20 ~ 80%; When alcohols material be chosen as the combination of methyl alcohol and ethanol time, the proportioning between methyl alcohol and ethanol can be any proportioning.
In above-mentioned synthetic method, described reaction is preferably reacted in 20 DEG C of reflow temperature range to solvent (i.e. alcohols material).The mode that reaction adopts can be reaction under normal temperature condition, conventional reacting by heating or back flow reaction, preferably adopts back flow reaction.Reaction is preferably carried out further in 50 DEG C to the reflow temperature range of solvent, is more preferably and carries out in 60 DEG C of reflow temperature range to solvent (i.e. alcohols material).Whether reaction can adopt thin-layer chromatography (TLC) tracing detection completely.In step 1) in, when carrying out in reaction 50 DEG C to the reflow temperature range of solvent, normally controlling the reaction times is 12 ~ 24h.
The step 1 of above-mentioned synthetic method) in, the precipitation that collection obtains adopts one or more washings in methyl alcohol, ethanol, ether and water usually.In this step, the ratio of the amount of substance of phenyl-2-pyridyl ketone and 4,4'-dimethyl-3-thiosemicarbazide is stoichiometric ratio, is generally 1:1.The consumption of described solvent is advisable can dissolve the raw material participating in reaction, and under normal circumstances, phenyl-2-pyridyl ketone or 4, the 4'-dimethyl-3-thiosemicarbazide solvent of 2 ~ 10mL of 1mmol dissolve.In concrete dissolving step, phenyl-2-pyridyl ketone and 4,4'-dimethyl-3-thiosemicarbazide can be used dissolution with solvents respectively, remix reacts together; Also can by solubilizing agent again after phenyl-2-pyridyl ketone or the mixing of 4,4'-dimethyl-3-thiosemicarbazide.
The step 2 of above-mentioned synthetic method) in, in order to improve product purity, preferably the reactant of reaction gained first being filtered, collecting filtrate, then filtrate carrying out is left standstill, crystallization.In this step, preferably leave standstill under lower temperature condition, usually select to carry out standing crystallization under 0 ~ 8 DEG C of condition.Further, when standing crystallization, at the vessel port upper cover last layer film of splendid attire filtrate, on film, then offer several apertures solvent is slowly volatilized, to obtain better crystallization effect (namely obtaining the crystal of larger grain and higher crystal yield).In this step, part phenyl-2-pyridyl ketone contracting 4,4'-dimethyl-3-thiosemicarbazide and CuCl
22H
2the ratio of the amount of substance of O is stoichiometric ratio, is generally 1:1.The consumption of described solvent is advisable can dissolve the raw material participating in reaction, under normal circumstances, and part phenyl-2-pyridyl ketone contracting 4, the 4'-dimethyl-3-thiosemicarbazide of 1mmol or CuCl
22H
2the O solvent of 2 ~ 10mL dissolves.In concrete dissolving step, can by part phenyl-2-pyridyl ketone contracting 4,4'-dimethyl-3-thiosemicarbazide and CuCl
22H
2o uses dissolution with solvents respectively, and remix reacts together; Also can by part phenyl-2-pyridyl ketone contracting 4,4'-dimethyl-3-thiosemicarbazide and CuCl
22H
2solubilizing agent again after O mixing.
The present invention also comprises compound shown in above-mentioned formula (I) and is preparing the application in antitumor drug.
It is the antitumor drug of active fraction preparation that the present invention comprises with compound above-mentioned formula (I) Suo Shi further.
Copper metal complexes-human serum albumin mixture provided by the invention is hatched by compound above-mentioned formula (I) Suo Shi and human serum albumin (being called for short HAS), then by hatch gained mixture carry out concentrating, wash obtained.
The synthetic method of copper metal complexes-human serum albumin mixture described above is: compound above-mentioned formula (I) Suo Shi and human serum albumin are hatched, and hatches gained mixture and carries out concentrating, washing, to obtain final product.
More specifically synthetic method is: get compound DMSO shown in above-mentioned formula (I) and be configured to solution, get human serum albumin water wiring solution-forming, be that 1:1 mix with the aqueous solution of human serum albumin by amount of substance by the DMSO solution of compound formula (I) Suo Shi, the content of control DMSO is less than or equal to 5%, under 0 ~ 5 DEG C of condition, hatch 20 ~ 24h; Gained mixture concentrates, until the content of DMSO is less than or equal to 0.01%, washing, namely obtains copper metal complexes-human serum albumin mixture.
The present invention also provides above-mentioned mixture preparing the application in antitumor drug.
The antitumor drug that to the present invention further provides with above-mentioned mixture be active fraction preparation.
Compared with prior art, the invention provides a kind of newly with phenyl-2-pyridyl ketone contracting 4,4'-dimethyl-3-thiosemicarbazide is copper (II) metal complexes and the synthetic method thereof of part, additionally provides the synthetic method that this title complex and human serum albumin carry out hatching mixture and this mixture obtained; The anti tumor activity in vitro research of applicant to gained title complex and mixture shows, they all have significant anti tumor activity in vitro to HepG-2, A549, NCI-H460 and T24 tumor cell line, there is good potential pharmaceutical use, be expected to the preparation for various antitumor drug.
Accompanying drawing explanation
Fig. 1 is the single crystal structure figure of the final product that the embodiment of the present invention 1 obtains;
Fig. 2 is the final product one-piece construction figure that the embodiment of the present invention 4 obtains;
Fig. 3 is the partial enlargement structure iron of the final product structure iron that the embodiment of the present invention 4 obtains;
Fig. 4 ~ 6 are the cell cycle variation diagram after flow cytometer detection by quantitative drug treating 48h, and wherein, Fig. 4 is blank, and Fig. 5 is Cu (Bp44mT) Cl title complex, and Fig. 6 is Cu (Bp44mT)-HSA mixture.
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.
In following embodiment and experimental example, the meaning of the abbreviation representative related to is as follows:
Cu (Bp44mT) Cl title complex: represent with phenyl-2-pyridyl ketone contracting 4,4'-dimethyl-3-thiosemicarbazide to be copper (II) metal complexes of part, i.e. compound shown in formula (I).
HBp44mT: represent part phenyl-2-pyridyl ketone contracting 4,4'-dimethyl-3-thiosemicarbazide.
HSA: human serum albumin.
DMSO: dimethyl sulfoxide (DMSO).
Cu (Bp44mT)-HSA mixture: represent by 4, the 4'-dimethyl-3-thiosemicarbazide that contracts with phenyl-2-pyridyl ketone to be that copper (II) metal complexes of part and human serum albumin hatch the copper metal complexes-human serum albumin mixture obtained.
The synthesis of embodiment 1:Cu (Bp44mT) Cl title complex
Synthetic route is as follows:
Concrete synthetic method is:
1) phenyl-2-pyridyl ketone (1832.1mg) of 10mmol is dissolved in the ethanol (concentration of etoh solvent is 50v/v%) of 20ml, 15min is stirred in 50 DEG C, obtained solution, above-mentioned dropwise instillation 20ml is added with 10mmol4, in ethanol (concentration of etoh solvent the is 60v/v%) solution of 4'-dimethyl-3-thiosemicarbazide (1191.9mg), light yellow precipitate is obtained in 50 DEG C of return stirring reaction 24h, the above-mentioned gained pale yellow precipitate rear dehydrated alcohol of filtration and ether are respectively washed 3 times, after drying, obtain part phenyl-2-pyridyl ketone contracting 4, 4'-dimethyl-3-thiosemicarbazide,
2) will containing CuCl
22H
2o (170.48mg, 1mmol) methyl alcohol (concentration of solvent methanol the is 60v/v%) solution of 20ml, be added drop-wise to containing 1mmol phenyl-2-pyridyl ketone contracting 4, in 20ml ethanol (concentration of etoh solvent the is 70v/v%) solution of 4'-dimethyl-3-thiosemicarbazide part, in 50 DEG C of return stirring 2h, solution after reaction is filled in 50ml beaker, and seals with preservative film, pinprick 20 holes, in 4 DEG C of volatilization a few days, obtain dark-brown crystal.
The dark-brown crystal of gained is carried out ultimate analysis, infrared spectra and single crystal diffraction analysis, and concrete spectral characteristic is as follows:
(1) ultimate analysis:
The molecular formula of gained mixture is C
15h
15clCuN
4s; Results of elemental analyses is: calculated value: C, 46.87%; H, 4.46%; N, 14.58%; S, 8.34%. analytical value: C, 47.02%; H, 4.99%; N, 14.46%; S, 8.85%.
(2) infrared spectra:
IR(KBr):3436.99s,3024.72m,2915.71s.1591.75m,1514.58s,1392.66s,1299.64s,1246.77,1146.60s,921.01s,789.67s 700.31s,632.75m.
(3) X-ray single crystal diffraction is analyzed, and determines its single crystal structure figure as shown in Figure 1; Gained complex crystal structured data and part bond distance bond angle are respectively as shown in following table 1 and table 2:
Table 1:
Table 2:
Therefore, can determine that the dark brown solid product of gained is is copper (II) metal complexes of part with phenyl-2-pyridyl ketone contracting 4,4'-dimethyl-3-thiosemicarbazide, and its structural formula is as shown in the formula shown in (I):
The synthesis of embodiment 2:Cu (Bp44mT) Cl title complex
1) phenyl-2-pyridyl ketone (1832.1mg) of 10mmol is dissolved in the methyl alcohol (concentration of solvent methanol is 80v/v%) of 20ml, 15min is stirred in 60 DEG C, obtained solution, above-mentioned dropwise instillation 20ml is added with 10mmol4, in methyl alcohol (concentration of solvent methanol the is 20v/v%) solution of 4'-dimethyl-3-thiosemicarbazide (1191.9mg), light yellow precipitate is obtained in 50 DEG C of return stirring reaction 24h, the above-mentioned gained pale yellow precipitate rear dehydrated alcohol of filtration and ether are respectively washed 3 times, after drying, obtain part phenyl-2-pyridyl ketone contracting 4, 4'-dimethyl-3-thiosemicarbazide,
2) will containing CuCl
22H
2o (170.48mg, 1mmol) methyl alcohol (concentration of solvent methanol the is 40v/v%) solution of 20ml, be added drop-wise to containing 1mmol phenyl-2-pyridyl ketone contracting 4, in 20ml methyl alcohol (concentration of solvent methanol the is 30v/v%) solution of 4'-dimethyl-3-thiosemicarbazide part, in 90 DEG C of return stirring 2h, solution after reaction is filled in 50ml beaker, and seals with preservative film, pinprick 10 holes, in 2 DEG C of volatilization a few days, obtain dark-brown crystal.
The dark-brown crystal of gained is carried out ultimate analysis, infrared spectra and single crystal diffraction analysis, and being defined as of the present invention take phenyl-2-pyridyl ketone contracting 4,4'-dimethyl-3-thiosemicarbazide as copper (II) metal complexes of part.
The synthesis of embodiment 3:Cu (Bp44mT) Cl title complex
1) phenyl-2-pyridyl ketone (1832.1mg) of 10mmol is dissolved in the ethanol (concentration of etoh solvent is 40v/v%) of 20ml, 20min is stirred in 30 DEG C, obtained solution, above-mentioned dropwise instillation 20ml is added with 10mmol4, in ethanol (concentration of etoh solvent the is 70v/v%) solution of 4'-dimethyl-3-thiosemicarbazide (1191.9mg), under 35 DEG C of conditions, stirring reaction 72h obtains light yellow precipitate, 3 times are washed with water after being filtered by above-mentioned gained pale yellow precipitate, after drying, obtain part phenyl-2-pyridyl ketone contracting 4, 4'-dimethyl-3-thiosemicarbazide,
2) will containing CuCl
22H
2o (170.48mg, 1mmol) ethanol (concentration of etoh solvent the is 80v/v%) solution of 20ml, be added drop-wise to containing 1mmol phenyl-2-pyridyl ketone contracting 4, in 20ml ethanol (concentration of etoh solvent the is 50v/v%) solution of 4'-dimethyl-3-thiosemicarbazide part, stirring reaction 2h under 40 DEG C of conditions, is filled into solution after reaction in 50ml beaker, and seals with preservative film, pinprick 30 holes, in 8 DEG C of volatilization a few days, obtain dark-brown crystal.
The dark-brown crystal of gained is carried out ultimate analysis, infrared spectra and single crystal diffraction analysis, and being defined as of the present invention take phenyl-2-pyridyl ketone contracting 4,4'-dimethyl-3-thiosemicarbazide as copper (II) metal complexes of part.
The synthesis of embodiment 4:Cu (Bp44mT)-HSA mixture
Shown in the formula (I) that Example 1 is obtained, compound DMSO is configured to solution, get human serum albumin water wiring solution-forming, be that 1:1 mix with the aqueous solution of human serum albumin by amount of substance by the DMSO solution of compound formula (I) Suo Shi, the content controlling DMSO in gained mixed solution is 4%, under 4 DEG C of conditions, hatch 24h; Gained mixture concentrates, until wherein the content of DMSO is less than 0.01%, washing, namely obtains copper metal complexes-human serum albumin mixture.Gained mixture through single crystal diffraction analysis, its structure iron as shown in Figure 2, the partial enlargement structure iron of Fig. 3 gained mixture one-piece construction figure.The crystal structural data of gained mixture is as described in Table 3:
Table 3:
Experimental example: the anti-tumor activity experiment of Cu of the present invention (Bp44mT) Cl title complex (obtaining by method described in embodiment 1), Cu (Bp44mT)-HSA mixture (obtaining by method described in embodiment 4), part HBp44mT etc.
1) cell strain and cell cultures
Tumor cell line HepG-2, A549, NCI-H460, T24, HL-7702, all come from theAmerican Type Culture Collection (Rockville, MD, USA), cell is in 5% incubator 37 DEG C of volumetric concentrations, with being added with 10% foetal calf serum and 100 μ gmL
-1streptomycin sulphate, the DMEM culture medium culturing of 100 units per ml penicillin
2) cell growth inhibition test (mtt assay)
Note: MTT full name is 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide, Chinese chemistry 3-(4 by name, 5-mtt.html'target='_blank'> dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt, trade(brand)name: mtt.html'target='_blank'> tetrazolium bromide.It is a kind of dyestuff of yellow color.
By Cu (Bp44mT) Cl title complex with after DMSO hydrotropy, use perfect medium be diluted to five gradients successively, 20 times to the working fluid of final concentration, between each gradient except drug level difference, solubility promoter DMSO equal size is all consistent.Being that the filtering with microporous membrane of 0.22um is degerming with diameter is again placed in 4 DEG C of preservations.By the tumor cell line HepG2 of logarithmic phase, MCF-7, NCI-H460, A549, be inoculated in 96 orifice plates respectively with every hole 0.18ml, cell concn is about 0.4-0.5 × 10
4/ hole, cultivate 12h after cell attachment, add the test-compound of different concns respectively, every hole 20ul, final concentration is made to be respectively 0 μM, 0.2 μM, 0.4 μM, 0.8 μM of each gradient establishes 4 multiple holes, wherein DMSO final concentration is less than 0.5%, corresponding negative control group is set simultaneously and (in nutrient solution, only has cell and equivalent DMSO, without medicine), often organize and 4 multiple holes are also set, after drug effect 48h, incline nutrient solution, add 100ulDMSO, plate shaker concussion 10min, crystallisate is fully dissolved, blank group returns to zero, absorbancy (A) value after removing end absorbance value is measured with 550nm/655nm dual wavelength by microplate reader, with Bliss method difference computerized compound to tumor cell line HepG-2, A549, NCI-H460, T24, the IC of HL-7702
50value, all experiment repetitions 3 times.Experimental result, in table 4, can find out the part HBp44mT of cytoactive apparently higher than correspondence of Cu (Bp44mT) Cl title complex tumour cell HepG-2, A549, NCI-H460, T24; Cu (Bp44mT)-HSA mixture to the cytoactive of tumour cell HepG-2, A549, NCI-H460, T24 apparently higher than Cu (Bp44mT) Cl title complex.But for normal cell, the toxicity of Cu (Bp44mT)-HSA mixture is starkly lower than the toxicity of Cu (Bp44mT) Cl title complex, this just illustrates the toxicity that obviously can reduce metal complexes after human serum albumin and part phenyl-2-pyridyl ketone contracting 4,4'-dimethyl-3-thiosemicarbazide form mixture.
Table 4:
Note: HepG2 is human liver cancer cell, NCI-H460 is maxicell lung cancer, A549 is human lung carcinoma cell, T24 human colon cancer cell, HL-7702 are people's liver cell.
3) cell cycle experimental analysis
After Flow cytometry tests Cu (Bp44mT) the Cl title complex effect HepG-248h of 1 μM, the cell of PI dyeing; Shown in following Fig. 4 ~ 6 of result, title complex Cu (Bp44mT) Cl is relative to blank, and S issue amount is increased to 40.41% from 30.87%, and the G2 phase obviously reduces, and illustrates that this copper complex can affect the cell cycle by the S phase; Albumin complex Cu (the Bp44mT)-HSA of comparable sodium is relative to Cu (Bp44mT) Cl, S issue amount is increased to 44.17% from 40.41%, and the G2 phase obviously reduces, illustrate that the ability in Cu (Bp44mT)-HSA T suppression cell cycle is higher than Cu (Bp44mT) Cl title complex.
Claims (10)
1. compound shown in following formula (I) or its pharmacy acceptable salt:
2. the synthetic method of compound according to claim 1, comprises the following steps:
1) get phenyl-2-pyridyl ketone and 4,4'-dimethyl-3-thiosemicarbazide, using alcohols material as solvent, react, have precipitation to generate, collecting precipitation, washing, obtain part phenyl-2-pyridyl ketone contracting 4,4'-dimethyl-3-thiosemicarbazide;
2) part phenyl-2-pyridyl ketone contracting 4,4'-dimethyl-3-thiosemicarbazide and CuCl is got
22H
2o, using alcohols material as solvent, reacts, and reactant leaves standstill, crystallization, collects crystal, namely obtains target compound.
3. synthetic method according to claim 2, is characterized in that: described alcohols material is methyl alcohol and/or ethanol.
4. synthetic method according to claim 2, is characterized in that: react and react to the reflow temperature range of solvent at 20 DEG C.
5. compound described in claim 1 is preparing the application in antitumor drug.
6. with the antitumor drug that compound described in claim 1 is active fraction preparation.
7. copper metal complexes-human serum albumin mixture, is characterized in that: it is hatched by compound according to claim 1 and human serum albumin, hatch gained mixture carry out concentrating, wash obtained.
8. the synthetic method of mixture described in claim 7, is characterized in that: compound described in claim 1 and human serum albumin are hatched, and hatches gained mixture and carries out concentrating, washing, to obtain final product.
9. mixture described in claim 7 is preparing the application in antitumor drug.
10. with the antitumor drug that mixture described in claim 7 is active fraction preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510248685.6A CN104844631A (en) | 2015-05-15 | 2015-05-15 | Copper metal complex and compound prepared from copper metal complex and human serum albumin as well as synthesis method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510248685.6A CN104844631A (en) | 2015-05-15 | 2015-05-15 | Copper metal complex and compound prepared from copper metal complex and human serum albumin as well as synthesis method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104844631A true CN104844631A (en) | 2015-08-19 |
Family
ID=53844662
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510248685.6A Pending CN104844631A (en) | 2015-05-15 | 2015-05-15 | Copper metal complex and compound prepared from copper metal complex and human serum albumin as well as synthesis method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104844631A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105396142A (en) * | 2015-12-14 | 2016-03-16 | 广西师范大学 | Human serum albumin-medicine compound, synthetic method and applications |
| CN107698609A (en) * | 2017-09-15 | 2018-02-16 | 广西师范大学 | Method and application based on human serum albumins IB subdomain synthesizing antitumor metal prodrugs |
| CN108912149A (en) * | 2018-06-25 | 2018-11-30 | 广西师范大学 | It is a kind of using 2- acetyl group -3- ethyl pyrazine thiosemicarbazones as the copper compound of ligand and its synthetic method and application |
| CN109796501A (en) * | 2019-03-28 | 2019-05-24 | 广西师范大学 | Using human serum albumins as the synthetic method and application of platinum (II) metal composite of carrier |
| CN110698511A (en) * | 2019-11-15 | 2020-01-17 | 广西师范大学 | Tin complex with 2-pyridinecarboxaldehyde thiosemicarbazone as ligand and synthesis method thereof |
| CN110713500A (en) * | 2019-11-15 | 2020-01-21 | 广西师范大学 | Palladium complex using 2-benzoylpyridine thiosemicarbazone and synthetic method thereof |
| CN112079851A (en) * | 2020-09-22 | 2020-12-15 | 广西师范大学 | Gold complex of FTO (fluorine-doped tin oxide) small-molecule inhibitor and synthetic method thereof |
-
2015
- 2015-05-15 CN CN201510248685.6A patent/CN104844631A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105396142A (en) * | 2015-12-14 | 2016-03-16 | 广西师范大学 | Human serum albumin-medicine compound, synthetic method and applications |
| CN105396142B (en) * | 2015-12-14 | 2018-04-10 | 广西师范大学 | Human serum albumins medicinal composition and its synthetic method and application |
| CN107698609A (en) * | 2017-09-15 | 2018-02-16 | 广西师范大学 | Method and application based on human serum albumins IB subdomain synthesizing antitumor metal prodrugs |
| CN107698609B (en) * | 2017-09-15 | 2020-01-31 | 广西师范大学 | Method for synthesizing anti-tumor metal prodrug based on human serum albumin IB subdomain and application |
| CN108912149A (en) * | 2018-06-25 | 2018-11-30 | 广西师范大学 | It is a kind of using 2- acetyl group -3- ethyl pyrazine thiosemicarbazones as the copper compound of ligand and its synthetic method and application |
| CN108912149B (en) * | 2018-06-25 | 2020-12-22 | 广西师范大学 | Copper compound with 2-acetyl-3-ethylpyrazine thiosemicarbazone as ligand and synthetic method and application thereof |
| CN109796501A (en) * | 2019-03-28 | 2019-05-24 | 广西师范大学 | Using human serum albumins as the synthetic method and application of platinum (II) metal composite of carrier |
| CN110698511A (en) * | 2019-11-15 | 2020-01-17 | 广西师范大学 | Tin complex with 2-pyridinecarboxaldehyde thiosemicarbazone as ligand and synthesis method thereof |
| CN110713500A (en) * | 2019-11-15 | 2020-01-21 | 广西师范大学 | Palladium complex using 2-benzoylpyridine thiosemicarbazone and synthetic method thereof |
| CN110698511B (en) * | 2019-11-15 | 2021-09-14 | 广西师范大学 | Tin complex with 2-pyridinecarboxaldehyde thiosemicarbazone as ligand and synthesis method thereof |
| CN112079851A (en) * | 2020-09-22 | 2020-12-15 | 广西师范大学 | Gold complex of FTO (fluorine-doped tin oxide) small-molecule inhibitor and synthetic method thereof |
| CN112079851B (en) * | 2020-09-22 | 2021-09-10 | 广西师范大学 | Gold complex of FTO (fluorine-doped tin oxide) small-molecule inhibitor and synthetic method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104844631A (en) | Copper metal complex and compound prepared from copper metal complex and human serum albumin as well as synthesis method and application thereof | |
| CN100528886C (en) | Metal complex with liriodenine as ligand and its synthesis process and use | |
| CN101701024B (en) | Ruthenium complex, preparation method thereof and application thereof | |
| CN104844632A (en) | Copper metal complex and compound of copper metal complex and human serum albumin, as well as synthesis methods and application of copper metal complex and compound | |
| CN111116667B (en) | Iridium complex constructed based on 8-hydroxyquinoline derivative and 1-phenylpyrazole iridium dimer as well as synthetic method and application thereof | |
| CN114149470B (en) | Ruthenium nitrosyl (II) complex and preparation method and application thereof | |
| CN107043345B (en) | 4-acetylbiphenyl hydrazone-indoline -2,3- diketone Schiff base preparation, structure and purposes | |
| CN111138372A (en) | Preparation and application of acetylpyrazine thiosemicarbazone metal chelating agent and metal complex thereof | |
| CN109776623A (en) | The preparation method and application of a kind of fluorine-containing oxamides with/heteronuclear compound | |
| CN107501303B (en) | Copper (II) complex and its synthetic method and application that a kind of brufen and quinoline-8-formaldehyde schiff bases are constructed | |
| CN109232703A (en) | Containing 16- (1 '-aromatic radical -1 ', 2 ', 3 '-triazoles) methylene-androstane -17- ketone derivatives | |
| CN100391451C (en) | Application of cantharidin derivative in preparation of antitumour medicine | |
| CN106967146B (en) | Oleanolic acid terazole derivatives and its preparation method and application | |
| CN109293727A (en) | 1- methyl purine -4- methylenandrosta-triazole derivatives, its synthetic method and application | |
| CN109666047B (en) | Ruthenium fluorescent probe, and preparation method, application and application product thereof | |
| CN111747889B (en) | NNO type quinoline Fe (II) complex containing multiple coordination sites and preparation method and application thereof | |
| CN105440085A (en) | 9-benzothianthrene hydrazine-ruthenium (II) complex as well as synthetic method and application thereof | |
| CN107868063A (en) | A kind of acetone 9 oxime derivate of tetrahydro benzothiazol 2 and its preparation method and application | |
| CN109627210B (en) | Gallium fluorescent probe, preparation method, application and application product thereof | |
| CN104086597B (en) | With platinum (II) antineoplastic compound that 3-oxo-tetramethylene-1,1-dicarboxylic acid radical is part | |
| CN103467497A (en) | Double-ligand copper complex with salicylidene-taurine and imidazole as ligands as well as synthesis method and application thereof | |
| CN108276394A (en) | Daidzein derivative, preparation method and application | |
| CN106883271A (en) | ONS tridentate ligands Pt (II) complex of antitumor activity and its preparation method and application | |
| CN103860564A (en) | Application of ruthenium pyridine (II) complexes as antitumor drugs | |
| CN114230616B (en) | Cancer cell targeted anticancer Pt complex and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150819 |