CN112062791A - Novel Pt (IV) complex based on cis-platinum and preparation method and application thereof - Google Patents
Novel Pt (IV) complex based on cis-platinum and preparation method and application thereof Download PDFInfo
- Publication number
- CN112062791A CN112062791A CN202011040300.4A CN202011040300A CN112062791A CN 112062791 A CN112062791 A CN 112062791A CN 202011040300 A CN202011040300 A CN 202011040300A CN 112062791 A CN112062791 A CN 112062791A
- Authority
- CN
- China
- Prior art keywords
- novel
- complex
- cisplatin
- stirring
- preparation
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title abstract description 76
- 229910052697 platinum Inorganic materials 0.000 title abstract description 23
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims abstract description 61
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 57
- 229960004316 cisplatin Drugs 0.000 claims abstract description 54
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000002904 solvent Substances 0.000 claims abstract description 29
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 claims abstract description 27
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 claims abstract description 26
- 229960000951 mycophenolic acid Drugs 0.000 claims abstract description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000012317 TBTU Substances 0.000 claims abstract description 20
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims abstract description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 15
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 9
- 239000012452 mother liquor Substances 0.000 claims abstract description 9
- 238000001556 precipitation Methods 0.000 claims abstract description 8
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 238000001914 filtration Methods 0.000 claims description 26
- 239000007788 liquid Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- 239000012065 filter cake Substances 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 201000008968 osteosarcoma Diseases 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 230000003647 oxidation Effects 0.000 abstract description 4
- 238000007254 oxidation reaction Methods 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 2
- 238000005886 esterification reaction Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229960005399 satraplatin Drugs 0.000 description 4
- 190014017285 satraplatin Chemical compound 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 230000005918 in vitro anti-tumor Effects 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 150000003057 platinum Chemical class 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229910002462 C-Pt Inorganic materials 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 190000008236 carboplatin Chemical compound 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
Images
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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a novel Pt (IV) complex based on cis-platinum and a preparation method and application thereof, belonging to the field of pharmaceutical chemical synthesis. The preparation method takes cis-platinum, hydrogen peroxide and mycophenolic acid as raw materials, and firstly, the cis-platinum is oxidized into dihydroxy cis-platinum (IV) through oxidation and oxidation; carrying out esterification reaction on dihydroxy cisplatin (IV) with TBTU, triethylamine and mycophenolic acid in a DMF (dimethyl formamide) solvent to obtain a novel Pt (IV) complex mother liquor; and carrying out back precipitation on the mother liquor by using methanol, acetone or diethyl ether to obtain the novel Pt (IV) complex. The novel Pt (IV) complex prepared by the invention has certain antitumor activity and can be used for preparing an orally-taken medicine with targeted antitumor. The preparation method is simple and easy to operate, has mild reaction conditions, and has the characteristics of high purity, good stability, high yield and the like.
Description
Technical Field
The invention relates to a novel Pt (IV) complex based on cis-platinum, a preparation method and application thereof, belonging to the field of pharmaceutical chemical synthesis.
Background
With the improvement of living conditions of people, the quality of life and the health of people are increasingly emphasized, but the morbidity and the mortality of cancer are increased rapidly due to environmental problems and poor living habits caused by the excessive economic development, and the search for a specific medicine capable of curing or prolonging the life of a cancer patient is a problem to be solved urgently, and the problem is concerned whether the economic construction and the social development of China can be continuously and well developed.
Chemotherapy is a diagnosis method which is common in treating cancers, less harmful to human bodies and quick in response at present. Among the chemotherapy drugs used in clinic, platinum drugs have the advantages of outstanding anti-tumor effect, wide anti-cancer spectrum, economy and the like and are applied to the treatment of various cancers. At present, platinum anticancer drugs on the market are divalent platinum complexes, all have the defects of large toxic and side effects, drug resistance, dose limitation, injection administration only and the like, and a series of tetravalent platinum complexes with the advantages of low toxicity, oral administration, targeting effect and the like are developed successively for improving the medical quality of patients. The tetravalent platinum complex is formed by connecting ligands with different or same effects in the axial direction of the divalent platinum complex, so that the novel platinum complex not only has better water solubility, fat solubility and targeting property, but also has the specific function of the ligands.
The existing research shows that mycophenolic acid has the effects of resisting tumor angiogenesis and tumor, and is a potential therapeutic drug for inhibiting the growth and metastasis of osteosarcoma; mycophenolate mofetil is used as a common immunosuppressant, is widely applied to rheumatic immune diseases such as lupus erythematosus, vasculitis, myositis, dermatomyositis and the like, can effectively control the occurrence of organ transplant rejection, and is also applied to organ transplantation.
Based on the excellent medical efficacy of mycophenolic acid, the mycophenolic acid is organically combined with cisplatin oxide to form a novel Pt (IV) complex which is expected to exert antitumor activity on a specific cancer cell and retain the antitumor advantages of tetravalent platinum and platinum drugs.
Disclosure of Invention
The first purpose of the invention is to provide a novel Pt (IV) complex (MPA C-Pt (IV)) based on cisplatin, the second purpose of the invention is to provide a preparation method of the novel Pt (IV) complex based on cisplatin, and the third purpose of the invention is to provide the application of the novel Pt (IV) complex based on cisplatin in the preparation of antitumor drugs.
The technical scheme adopted for realizing the purpose of the invention is as follows:
a novel Pt (IV) complex based on cisplatin has the following structure:
a preparation method of a novel Pt (IV) complex based on cisplatin comprises the following steps:
adding cisplatin into water, stirring uniformly, adding 30% hydrogen peroxide, stirring in a dark place, filtering, washing and drying to obtain dihydroxy cisplatin (IV);
dissolving the product in DMF, adding TBTU, triethylamine and mycophenolic acid, stirring in the dark, and filtering to obtain a novel Pt (IV) complex mother liquor;
and thirdly, adding methanol or ethanol into the mother liquor, concentrating, adding a reverse precipitation solvent into the residual liquid in a dark environment, and fully stirring, filtering, washing and drying to obtain the novel Pt (IV) complex.
Preferably, in the step (i): the water temperature and the stirring temperature are 50-70 ℃; the adding speed of the hydrogen peroxide solution is 0.1-0.4 mL per second; stirring for 4-8 h in a dark place; the drying temperature is 60-80 ℃; the drying time is 6-8 h.
Preferably, in the step (i): the mass ratio of the cisplatin to the water is 1: 50-100; the mass volume ratio of the cisplatin to the 30% hydrogen peroxide is 1: 0.6-1.0; the volume ratio of 30% hydrogen peroxide to water is 1: 5-10.
Preferably, in the step two: the mass-volume ratio of the dihydroxy cisplatin (IV) to the DMF is 1: 4-8; the molar ratio of the dihydroxycisplatin (IV) to any one of TBTU, triethylamine and mycophenolic acid is 1:3 respectively; and adding TBTU, triethylamine and mycophenolic acid, and stirring for 36-60 h in a dark place.
Preferably, in the third step: the volume ratio of DMF to methanol or ethanol is 1: 1-5; the anti-separation solvent is a mixture of any two solvents of methanol, acetone or diethyl ether, and the volume ratio of any two solvents is 1: 1; the volume ratio of the residual liquid after concentration to the back-elution solvent is 1: 5-10; the water bath temperature of the rotary evaporator is 50-70 ℃; the vacuum degree of the rotary evaporator is 250-200 hPa/mbar; the vacuum drying temperature is 20-50 ℃; the vacuum drying time is 4-8 h.
An application of a novel Pt (IV) complex based on cisplatin in preparing an anti-tumor medicament.
An application of a novel Pt (IV) complex based on cisplatin in preparing an orally-taken medicine with a targeted antitumor effect.
Further, the tumors include lung cancer, human breast cancer, human ovarian cancer and human osteosarcoma.
The invention has the advantages of
The preparation method takes cis-platinum, hydrogen peroxide and mycophenolic acid as raw materials, firstly the cis-platinum is oxidized into dihydroxy cis-platinum through oxidation and oxidation, and then the dihydroxy cis-platinum, TBTU, triethylamine and mycophenolic acid are subjected to esterification reaction in a DMF solvent to obtain the novel Pt (IV) complex. The novel Pt (IV) complex is respectively connected with mycophenolic acid ligands with targeting effects at two axial ends of Pt, so that the novel Pt (IV) complex has good lipophilicity, and shows anti-tumor activity superior to that of the existing cisplatin, carboplatin and oxaliplatin for some cancer cells, and therefore the novel Pt (IV) complex can become a novel oral specific medicine with targeting effects in the future. In addition, the novel Pt (IV) complex synthesized by the method has the characteristics of simple synthesis, easy operation, mild reaction conditions, high product purity, good stability, high yield and the like.
Drawings
FIG. 1 shows a synthetic route of a novel Pt (IV) complex.
FIG. 2 is a mass spectrum of a novel Pt (IV) complex.
FIG. 3 is a nuclear magnetic hydrogen spectrum of a novel Pt (IV) complex.
Detailed Description
The present invention will be described in further detail with reference to examples, but the scope of the present invention is not limited to the examples.
Example 1
A preparation method of a novel Pt (IV) complex based on cisplatin is shown in figure 1, and specifically comprises the following operations:
(1) synthesis process of dihydroxyl cisplatin (IV)
Adding 1.0 percent of cisplatin into 50 ℃ water, stirring the mixture for 1min at 50 ℃, adding 0.1mL of hydrogen peroxide solution per second, stirring the mixture for 4h in a dark place, filtering the mixture, washing the mixture for 3 times by using proper amount of water, filtering the mixture to be dry, and drying the mixture for 8h at 60 ℃ to obtain 1.05g of dihydroxy cisplatin (IV) with the yield of 94.6 percent. Wherein the cisplatin is 1g of water and 50mL of water, the cisplatin is 30 percent of hydrogen peroxide and is 1g of hydrogen peroxide and 0.6mL of water, and the preparation method of the hydrogen peroxide solution comprises the following steps: 30% hydrogen peroxide was added to 5 volumes of water and stirred.
(2) Process for preparing mother liquor of Pt (IV) complex
Transferring DMF according to the mass-volume ratio of 1g:4mL of dihydroxycisplatin (IV) to DMF, and weighing TBTU, triethylamine and mycophenolic acid according to the molar ratio of 1:3 of dihydroxycisplatin (IV) to TBTU, triethylamine and mycophenolic acid respectively (the molar ratio of TBTU to triethylamine to mycophenolic acid is 1:1: 1). Adding dihydroxycisplatin (IV) into DMF at 20 deg.C, stirring at 20 deg.C for 10min, filtering, transferring the filtrate to 20 deg.C environment, adding TBTU, triethylamine and mycophenolic acid, stirring for 36h in dark place, filtering, and collecting the filtrate.
(3) Process for preparing Pt (IV) complex finished product
Transferring methanol or ethanol according to the volume ratio of DMF to methanol or ethanol of 1:1, and transferring an anti-separation solvent according to the volume ratio of the residual liquid after concentration to the anti-separation solvent of 1:5, wherein the anti-separation solvent is a mixture of any two solvents of methanol, acetone or ether, and the volume ratio of any two solvents is 1: 1. Adding methanol or ethanol into the filtrate collected in the step II, stirring uniformly, evaporating the mixed solution by using a rotary evaporator until no liquid drops drop (the water bath temperature is 50 ℃, the vacuum degree is 250hPa/mbar), taking out the residual liquid, adding a reverse precipitation solvent in a dark environment, stirring for 10min at 20 ℃, filtering, stirring and washing the filter cake for 3 times by using a proper amount of water at 0 ℃, filtering to dry, and drying for 4h at 20 ℃ in vacuum to obtain 2.61g of a novel Pt (IV) complex, wherein the comprehensive yield (calculated by cis-platinum) is 83.4%.
Example 2
A preparation method of a novel Pt (IV) complex based on cisplatin is shown in figure 1, and specifically comprises the following operations:
(1) synthesis process of dihydroxyl cisplatin (IV)
Adding 50.0 of cisplatin into 60 ℃ water, stirring for 15min at 60 ℃, adding 0.2mL of hydrogen peroxide solution per second, stirring for 6h in a dark place, filtering, washing with proper amount of water for 3 times, filtering, and drying at 70 ℃ for 7h to obtain 52.97g of dihydroxycisplatin (IV) with the yield of 95.1%. Wherein the cisplatin is 1g of water and 80mL of water, the cisplatin is 30 percent of hydrogen peroxide and is 1g of hydrogen peroxide and 0.8mL of water, and the preparation method of the hydrogen peroxide solution comprises the following steps: 30% hydrogen peroxide was added to 8 times the volume of water and stirred.
(2) Process for preparing mother liquor of Pt (IV) complex
Transferring DMF according to the mass-volume ratio of 1g:6mL of dihydroxycisplatin (IV) to DMF, and weighing TBTU, triethylamine and mycophenolic acid according to the molar ratio of 1:3 of dihydroxycisplatin (IV) to TBTU, triethylamine and mycophenolic acid respectively (the molar ratio of TBTU to triethylamine to mycophenolic acid is 1:1: 1). Adding dihydroxycisplatin (IV) into DMF at 30 ℃, stirring for 20min at 30 ℃, filtering, transferring the filtrate to the environment at 30 ℃, adding TBTU, triethylamine and mycophenolic acid, stirring for 48h in the dark, filtering, and collecting the filtrate.
(3) Process for preparing Pt (IV) complex finished product
Transferring methanol or ethanol according to the volume ratio of DMF to methanol or ethanol of 1:3, and transferring an anti-separation solvent according to the volume ratio of the residual liquid after concentration to the anti-separation solvent of 1:8, wherein the anti-separation solvent is a mixture of any two solvents of methanol, acetone or ether, and the volume ratio of any two solvents is 1: 1. Adding methanol or ethanol into the filtrate collected in the step (II), stirring uniformly, evaporating the mixed solution by using a rotary evaporator until no liquid drops drop (the water bath temperature is 60 ℃, the vacuum degree is 230hPa/mbar), taking out the residual liquid, adding a reverse precipitation solvent in a dark environment, stirring for 30min at 30 ℃, filtering, stirring and washing the filter cake for 3 times by using a proper amount of water at 10 ℃, filtering to dry, and drying for 6h at 30 ℃ in vacuum to obtain 129.71g of the novel Pt (IV) complex, wherein the comprehensive yield (calculated by cis-platinum) is 83.0%.
Example 3
A preparation method of a novel Pt (IV) complex based on cisplatin is shown in figure 1, and specifically comprises the following operations:
(1) synthesis process of dihydroxyl cisplatin (IV)
100.0 cis-platinum is added into 70 ℃ water and stirred for 30min at 70 ℃, hydrogen peroxide solution is added at the speed of 0.4mL per second, the mixture is stirred for 8h in dark place, filtered, stirred and washed for 3 times by proper amount of water, filtered to be dry and dried for 6h at 80 ℃ to obtain 106.32g of dihydroxy cis-platinum (IV), and the yield is 95.5%. Wherein the cisplatin is 1g of water and 100mL of water, the cisplatin is 1g of 30% hydrogen peroxide and 1.0mL of hydrogen peroxide solution, and the preparation method of the hydrogen peroxide solution comprises the following steps: 30% hydrogen peroxide was added to 10 volumes of water and stirred.
(2) Process for preparing mother liquor of Pt (IV) complex
Transferring DMF according to the mass-volume ratio of 1g:8mL of dihydroxycisplatin (IV) to DMF, and weighing TBTU, triethylamine and mycophenolic acid according to the molar ratio of 1:3 of dihydroxycisplatin (IV) to TBTU, triethylamine and mycophenolic acid respectively (the molar ratio of TBTU to triethylamine to mycophenolic acid is 1:1: 1). Adding dihydroxycisplatin (IV) into DMF at 40 ℃, stirring at 40 ℃ for 30min, filtering, transferring the filtrate to the environment at 40 ℃, adding TBTU, triethylamine and mycophenolic acid, stirring for 60h in the dark, filtering, and collecting the filtrate.
(3) Process for preparing Pt (IV) complex finished product
Transferring methanol or ethanol according to the volume ratio of DMF to methanol or ethanol of 1:5, and transferring an anti-separation solvent according to the volume ratio of the residual liquid after concentration to the anti-separation solvent of 1:10, wherein the anti-separation solvent is a mixture of any two solvents of methanol, acetone or ether, and the volume ratio of any two solvents is 1: 1. Adding methanol or ethanol into the filtrate collected in the step (II), stirring uniformly, evaporating the mixed solution by using a rotary evaporator until no liquid drops drop (the water bath temperature is 70 ℃, the vacuum degree is 200hPa/mbar), taking out the residual liquid, adding a reverse precipitation solvent in a dark environment, stirring for 60min at 40 ℃, filtering, stirring and washing the filter cake for 3 times by using a proper amount of water at 20 ℃, filtering to dry, and drying for 8h at 50 ℃ in vacuum to obtain 262.38g of the novel Pt (IV) complex, wherein the comprehensive yield (calculated by cis-platinum) is 83.9%.
It can be seen from the results of the above examples that the method for preparing the novel Pt (IV) complex of the present invention has the advantages of simple operation, stable yield and high yield, so that the process is suitable for mass production.
FIG. 2 shows the mass spectrum of the novel Pt (IV) complex obtained in example 2, in which:
HR-MS(m/z):[C34H44Cl2N2O12Pt+Na]+961.2 (100%), 960.2 (83.5%), 962.2 (63.9%), 963.2 (57.2%), 959.2 (55.6%), 964.2 (16.8%), 965.2 (13.7%), consistent with the molecular weight of the target compound.
FIG. 3 shows the nuclear magnetic hydrogen spectrum of the novel Pt (IV) complex, which shows that:
1H-NMR(400MHz,DMSO):(ppm)=9.37~9.45(s,2H,2C-OH),6.46(br s,6H,2CO-CH 3),55.13~5.35(s,4H,2COO-CH 2),5.00~5.11(t,2H,2C-CH),3.67~3.76(t,6H,2C-CH 3),3.29~3.30(s,4H,2CH-CH 2),2.24~2.28(d,4H,2CO-CH 2),2.19(q,4H,2C-CH 2),1.63~2.14(s,6H,2NH3),1.24(d,6H,2C-CH 3) Groups of hydrogen signals assigned to the target compound C34H44Cl2N2O12The hydrogen spectrum signals belong to the same category, which shows that the product prepared by the method is the target product, and the spectrum only contains trace impurity peaks, thus showing that the purity of the prepared product is higher.
Table 1 shows a cisplatin-based formulationIC of the novel Pt (IV) complexes in individual cancer cells50The value (mu M) is tested by adopting an MTT method to test the in-vitro anti-tumor activity of the novel Pt (IV) complex prepared by the invention on human lung cancer cells A549, human breast cancer cells MCF-7 and MDA-MB-231, human ovarian cancer cells Caov-3 and human osteosarcoma cells U-2OS, cisplatin and satraplatin are selected as positive controls, and the half maximum inhibition concentration (IC50) of the novel Pt (IV) complex in 48h is shown in Table 1.
TABLE 1 comparison of IC50 values for the novel Pt (IV) complexes, cisplatin and satraplatin in individual cancer cells
As can be seen from the results in Table 1, the complexes of the invention all show better in vitro anti-tumor activity, wherein the inhibition activity on MDA-MB-231 and Caov-3 tumor cell lines is better than that of cisplatin and satraplatin. In addition, the inhibition activity of the compound on U-2OS tumor cell strains is far better than that of satraplatin. Therefore, the complex of the invention shows potential application prospect on MCF-7, MDA-MB-231, Caov-3 and U-2OS tumor cells.
Claims (12)
2. a method for producing a novel cisplatin-based Pt (iv) complex according to claim 1, characterized by comprising the steps of:
step 1, synthesizing dihydroxy cisplatin (IV): adding cisplatin into water, stirring, adding hydrogen peroxide, stirring in dark place, filtering, washing, and drying to obtain dihydroxy cisplatin (IV);
step 2, preparing a novel Pt (IV) complex mother liquor: adding the dihydroxycisplatin (IV) into DMF (dimethyl formamide) at the temperature of 20-40 ℃, stirring for 10-30 min at the temperature of 20-40 ℃, filtering, transferring the filtrate to an environment at the temperature of 20-40 ℃, adding TBTU, triethylamine and mycophenolic acid, stirring for 36-60 h in the dark, filtering, and collecting the filtrate;
step 3, preparing a novel Pt (IV) complex finished product: adding methanol or ethanol into the filtrate collected in the step 2, stirring uniformly, evaporating the mixed solution by using a rotary evaporator until no liquid drops drip, taking out the residual liquid, adding a reverse precipitation solvent in a dark environment, stirring for 10-60 min at 20-40 ℃, filtering, washing a filter cake for 3 times by using a proper amount of water at 0-20 ℃, filtering, and drying in vacuum for 4-8 h at 20-50 ℃ to obtain the novel Pt (IV) complex.
3. A method for preparing a novel cisplatin-based Pt (iv) complex as claimed in claim 2, wherein said step 1 dihydroxycisplatin (iv) synthesis process comprises:
adding 1.0-100.0 g of cisplatin into 50-70 ℃ water, and stirring for 1-30 min at 50-70 ℃; adding hydrogen peroxide solution at the speed of 0.1-0.4 mL per second, and stirring for 4-8 h in a dark place; filtering, and washing with appropriate amount of water for 3 times; and (5) filtering, and drying at 60-80 ℃ for 6-8 h.
4. A method for producing a novel cisplatin-based Pt (iv) complex as claimed in claim 3, characterized in that:
the mass-volume ratio of the cisplatin to the water is 1g: 50-100 mL; the mass volume ratio of the cisplatin to the 30% hydrogen peroxide is 1g to 0.6-1.0 mL; the preparation method of the hydrogen peroxide solution comprises the following steps: adding 30% of hydrogen peroxide into water with the volume 5-10 times of that of the mixture, and uniformly stirring.
5. The method for preparing a novel cisplatin-based Pt (iv) complex as claimed in claim 2, wherein the preparation process of the novel Pt (iv) complex mother liquor in step 2 comprises:
the mass volume ratio of the dihydroxy cisplatin (IV) to the DMF is 1g: 4-8 mL;
the molar ratio of the dihydroxycisplatin (IV) to any one of TBTU, triethylamine and mycophenolic acid is 1:3 respectively.
6. The method for producing a novel cisplatin-based Pt (iv) complex according to claim 5, characterized in that:
the molar ratio of TBTU to triethylamine to mycophenolic acid is 1:1: 1.
7. The method for preparing a novel cisplatin-based Pt (iv) complex as claimed in claim 2, wherein the step 3 of preparing the novel Pt (iv) complex finished product comprises:
the volume ratio of DMF to methanol or ethanol is 1: 1-5;
the volume ratio of the anti-precipitation solvent to the residual liquid after concentration is 5-10: 1.
8. A method for producing a novel cisplatin-based Pt (iv) complex as claimed in claim 2 or 7, characterized in that:
the anti-precipitation solvent is a mixture of any two solvents of methanol, acetone or diethyl ether, and the volume ratio of any two solvents is 1: 1.
9. A process for producing a novel cisplatin-based Pt (iv) complex as claimed in claim 2 or 7 or 8, characterized in that:
the water bath temperature of the rotary evaporator is 50-70 ℃, and the vacuum degree is 250-200 hPa/mbar.
10. Use of the novel Pt (iv) complex based on cisplatin according to claim 1 in the preparation of an antitumor drug.
11. Use of the novel Pt (iv) complex based on cisplatin according to claim 1 for the preparation of an orally administrable drug having a targeted antitumor effect.
12. Use of a novel cisplatin-based Pt (iv) complex as described in claim 10 or a novel cisplatin-based Pt (iv) complex as described in claim 11 for the preparation of an orally-administrable drug having a targeted antitumor activity, characterized in that:
the tumor comprises human breast cancer, human ovarian cancer and human osteosarcoma.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011040300.4A CN112062791B (en) | 2020-09-28 | 2020-09-28 | Novel Pt (IV) complex based on cis-platinum and preparation method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011040300.4A CN112062791B (en) | 2020-09-28 | 2020-09-28 | Novel Pt (IV) complex based on cis-platinum and preparation method and application thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112062791A true CN112062791A (en) | 2020-12-11 |
CN112062791B CN112062791B (en) | 2023-03-24 |
Family
ID=73684381
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202011040300.4A Active CN112062791B (en) | 2020-09-28 | 2020-09-28 | Novel Pt (IV) complex based on cis-platinum and preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN112062791B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113698435A (en) * | 2021-08-25 | 2021-11-26 | 中国人民解放军空军军医大学 | Tetravalent platinum complex containing p53-MDM2 inhibitor and preparation method and application thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105622674A (en) * | 2016-02-29 | 2016-06-01 | 东南大学 | Tetravalent platinum complex with bioactive group and preparation method of tetravalent platinum complex |
-
2020
- 2020-09-28 CN CN202011040300.4A patent/CN112062791B/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105622674A (en) * | 2016-02-29 | 2016-06-01 | 东南大学 | Tetravalent platinum complex with bioactive group and preparation method of tetravalent platinum complex |
Non-Patent Citations (2)
Title |
---|
张新忠等: "抗肿瘤铂(Ⅳ)配合物靶向给药系统研究进展", 《昆明理工大学学报(自然科学版)》 * |
谭晓晓等: "作为抗肿瘤药物的小分子四价铂", 《化学进展》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113698435A (en) * | 2021-08-25 | 2021-11-26 | 中国人民解放军空军军医大学 | Tetravalent platinum complex containing p53-MDM2 inhibitor and preparation method and application thereof |
CN113698435B (en) * | 2021-08-25 | 2023-09-29 | 中国人民解放军空军军医大学 | Tetravalent platinum complex containing p53-MDM2 inhibitor and preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN112062791B (en) | 2023-03-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111171080B (en) | High-efficiency low-toxicity anticancer compound synthesized by autocatalysis in cells and living bodies and synthesis method thereof | |
AU595827B2 (en) | Novel platinum complexes | |
CN111205331B (en) | Anti-tumor tetravalent platinum complex with anti-drug resistance function and preparation method thereof | |
KR900003513B1 (en) | Organic-platinum complexes and method of theating tumors | |
CN112062791B (en) | Novel Pt (IV) complex based on cis-platinum and preparation method and application thereof | |
CN110183494B (en) | Preparation method and application of novel orally-administrable anti-tumor Pt (IV) complex | |
CN109675053B (en) | Targeted preparation of podophyllotoxin and its derivative and its preparing method | |
CN113845551B (en) | Pt (II) complex with photodynamic anti-triple-negative breast cancer activity and preparation method and application thereof | |
CN101787051B (en) | Water-soluble carboxyl-bridge dicaryon Pt (II) anti-tumor complex | |
CN110128482B (en) | Preparation method and application of novel Pt (IV) complex with tumor targeting function | |
CN112125933B (en) | Novel Pt (IV) complex based on oxaliplatin and preparation method and application thereof | |
CN114573598A (en) | White leaf vine zinc (II) complex with high activity in vivo and in vitro and synthesis method and application thereof | |
CN113416216B (en) | High-activity Pt complex and preparation method and application thereof | |
CN113786411A (en) | Oxaliplatin prodrug for oral administration, preparation method and application of oxaliplatin prodrug as antitumor drug | |
CN110172075B (en) | Novel coumarin-quinoline-platinum (II) complex and synthesis method and application thereof | |
CN100445293C (en) | Supermolecular carboplatinum derivatives, their preparation method, and pharmaceutical composition containing them as active ingredient and applications of the composition | |
CN108484661B (en) | Hexavanadic acid- β -alanine tert-butyl ester derivative and preparation method and application thereof | |
CN106608898B (en) | The complex of water-soluble platinum containing deoxyglucose and Preparation method and use | |
CN103772435A (en) | Water-soluble stable lobaplatin derivative | |
CN101967163A (en) | Platinum (II) anti-cancer compound with selectivity for cancer cells | |
JPS61267595A (en) | Novel platinum complex | |
CN114409707B (en) | 8-hydroxyquinoline-N-oxide manganese complex and synthetic method and application thereof | |
CN114409712B (en) | Pt (IV) complex containing cannabidiol, and preparation method and application thereof | |
CN104230997B (en) | A kind of platinum (II) coordination compound, its preparation method, pharmaceutical composition and application | |
CN114230616B (en) | Cancer cell targeted anticancer Pt complex and preparation method and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |