CN112125933A - Novel Pt (IV) complex based on oxaliplatin and preparation method and application thereof - Google Patents
Novel Pt (IV) complex based on oxaliplatin and preparation method and application thereof Download PDFInfo
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- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 title claims abstract description 57
- 229960001756 oxaliplatin Drugs 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 57
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 37
- 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 27
- 229960000951 mycophenolic acid Drugs 0.000 claims abstract description 27
- 239000012317 TBTU Substances 0.000 claims abstract description 21
- 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 21
- 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 11
- 239000012452 mother liquor Substances 0.000 claims abstract description 10
- 239000003814 drug 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
- 238000003756 stirring Methods 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 238000001914 filtration Methods 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 13
- 239000007788 liquid Substances 0.000 claims description 13
- 239000000706 filtrate Substances 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 239000010413 mother solution Substances 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 5
- 239000001257 hydrogen Substances 0.000 abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 3
- 238000005886 esterification reaction Methods 0.000 abstract description 2
- 229960002163 hydrogen peroxide Drugs 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- 230000001590 oxidative effect Effects 0.000 abstract 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 58
- 238000000926 separation method Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 229910052697 platinum Inorganic materials 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 5
- 229960004316 cisplatin Drugs 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 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
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 229960005399 satraplatin Drugs 0.000 description 3
- 190014017285 satraplatin Chemical compound 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000002401 inhibitory effect 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
- 210000004881 tumor cell Anatomy 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 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
- 230000007547 defect Effects 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000003745 diagnosis 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
- 239000012156 elution solvent Substances 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
- 239000012535 impurity Substances 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 230000005764 inhibitory process 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
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention discloses a novel Pt (IV) complex based on oxaliplatin, a preparation method and application thereof, and belongs to the field of pharmaceutical chemical synthesis. The preparation method comprises the steps of taking oxaliplatin, hydrogen peroxide and mycophenolic acid as raw materials, and oxidizing the oxaliplatin by oxidation hydrogen to form dihydroxy oxaliplatin (IV); carrying out esterification reaction on dihydroxyoxaliplatin (IV) with TBTU, triethylamine and mycophenolic acid in DMF as a 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, easy to operate, mild in reaction conditions, high in purity, good in stability, high in yield and the like.
Description
Technical Field
The invention relates to a novel Pt (IV) complex based on oxaliplatin, a preparation method and application thereof, belonging to the field of pharmaceutical chemical synthesis.
Background
Cancer is a high-risk disease with the fatality rate at the first three in China, and chemotherapy is a diagnosis method which is common in cancer treatment, less harmful to human bodies and quick in effect. 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, mycophenolic acid is organically combined with oxaliplatin oxide to form a novel Pt (IV) complex, and the novel complex is expected to exert antitumor activity on a certain 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 (MPAO-Pt (IV)) based on oxaliplatin, the second purpose of the invention is to provide a preparation method of the novel Pt (IV) complex based on the oxaliplatin, and the third purpose of the invention is to provide the application of the novel Pt (IV) complex based on the oxaliplatin in the preparation of anti-tumor drugs.
The novel Pt (IV) complex prepared by the method has the characteristics of simple synthesis method, easy operation, mild reaction conditions, high purity, good stability, high yield and the like.
The technical scheme adopted for realizing the purpose of the invention is as follows:
a novel Pt (IV) complex based on oxaliplatin is characterized by the following structure:
a preparation method of a novel Pt (IV) complex based on oxaliplatin comprises the following steps:
adding oxaliplatin into water, stirring uniformly, adding 30% hydrogen peroxide, stirring in a dark place, filtering, washing and drying to obtain dihydroxy oxaliplatin (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 oxaliplatin to the water is 1: 50-100; the mass volume ratio of the oxaliplatin to the 30% hydrogen peroxide is 1: 0.8-1.2; the volume ratio of 30% hydrogen peroxide to water is 1: 5-10.
Preferably, in the step two: the mass volume ratio of the dihydroxyoxaliplatin (IV) to the DMF is 1: 4-8; the molar ratio of the dihydroxyoxaliplatin (IV) to any one of TBTU, triethylamine and mycophenolic acid is 1:3 respectively; and adding TBTU, triethylamine and mycophenolic acid, and stirring for 60-80 h in the dark.
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.
Application of a novel Pt (IV) complex based on oxaliplatin in preparation of anti-tumor drugs.
Application of novel Pt (IV) complex based on oxaliplatin in preparation of orally-administrable medicament with targeted antitumor effect.
Further, the tumors include lung cancer, breast cancer, liver cancer and colon cancer.
The invention has the advantages of
According to the preparation method, oxaliplatin, hydrogen peroxide and mycophenolic acid are used as raw materials, oxaliplatin is oxidized to dihydroxy oxaliplatin, and then the dihydroxy oxaliplatin is subjected to esterification reaction with TBTU, triethylamine and mycophenolic acid 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 oxaliplatin specifically comprises the following operations:
(1) synthesis of dihydroxyoxaliplatin (IV)
Adding 1.0 part of oxaliplatin into 50 ℃ water, stirring the mixture for 1min at 50 ℃, adding 0.1mL of hydrogen peroxide solution per second, stirring the mixture for 4 hours in a dark place, filtering the mixture, washing the mixture for 3 times by using proper amount of water, draining the mixture, and drying the mixture for 8 hours at 60 ℃ to obtain 1.01g of dihydroxyoxaliplatin (IV), wherein the yield is 92.7%. Wherein, the ratio of oxaliplatin to water is 1g:50mL, the ratio of oxaliplatin to 30% hydrogen peroxide is 1g:0.8mL, 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 dihydroxyoxaliplatin (IV) to DMF, and weighing TBTU, triethylamine and mycophenolic acid according to the molar ratio of 1:3 of the dihydroxyoxaliplatin (IV) to the TBTU, the triethylamine to the mycophenolic acid respectively (the molar ratio of the TBTU to the triethylamine to the mycophenolic acid is 1:1: 1). Adding dihydroxyoxaliplatin (IV) into DMF at 20 ℃, stirring for 10min at 20 ℃, filtering, transferring the filtrate to an environment at 20 ℃, 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 1:1, 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 2.21g of the novel Pt (IV) complex, wherein the comprehensive yield (calculated by oxaliplatin) is 84.7%.
Example 2
A preparation method of a novel Pt (IV) complex based on oxaliplatin specifically comprises the following operations:
(1) synthesis of dihydroxyoxaliplatin (IV)
Adding 50.0 parts of oxaliplatin into 60 ℃ water, stirring for 15min at 60 ℃, adding 0.2mL of hydrogen peroxide solution per second, stirring for 6h in the dark, filtering, stirring and washing with proper amount of water for 3 times, filtering, and drying at 70 ℃ for 7h to obtain 51.93g of dihydroxyoxaliplatin (IV), wherein the yield is 95.6%. Wherein, the ratio of oxaliplatin to water is 1g:80mL, the ratio of oxaliplatin to 30% hydrogen peroxide is 1g:1.0mL, 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 dihydroxyoxaliplatin (IV) to DMF, and weighing TBTU, triethylamine and mycophenolic acid according to the molar ratio of 1:3 of the dihydroxyoxaliplatin (IV) to the TBTU, the triethylamine to the mycophenolic acid respectively (the molar ratio of the TBTU to the triethylamine to the mycophenolic acid is 1:1: 1). Adding dihydroxyoxaliplatin (IV) into DMF at 30 ℃, stirring for 20min at 30 ℃, filtering, transferring the filtrate to an environment at 30 ℃, adding TBTU, triethylamine and mycophenolic acid, stirring for 70h 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 112.62g of the novel Pt (IV) complex, wherein the comprehensive yield (calculated by oxaliplatin) is 86.3%.
Example 3
A preparation method of a novel Pt (IV) complex based on oxaliplatin specifically comprises the following operations:
(1) synthesis of dihydroxyoxaliplatin (IV)
Adding 100.0 parts of oxaliplatin into 70 ℃ water, stirring the mixture for 30min at 70 ℃, adding 0.4mL of hydrogen peroxide solution per second, stirring the mixture for 8h in a dark place, filtering the mixture, washing the mixture for 3 times by using proper amount of water, draining the mixture, and drying the mixture for 6h at 80 ℃ to obtain 99.91g of dihydroxyoxaliplatin (IV), wherein the yield is 92.0%. Wherein, the ratio of oxaliplatin to water is 1g to 100mL, the ratio of oxaliplatin to 30% hydrogen peroxide is 1g to 1.2mL, 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 dihydroxyoxaliplatin (IV) to DMF, and weighing TBTU, triethylamine and mycophenolic acid according to the molar ratio of 1:3 of the dihydroxyoxaliplatin (IV) to the TBTU, the triethylamine to the mycophenolic acid respectively (the molar ratio of the TBTU to the triethylamine to the mycophenolic acid is 1:1: 1). Adding dihydroxyoxaliplatin (IV) into DMF at 40 ℃, stirring at 40 ℃ for 30min, filtering, transferring the filtrate to a 40 ℃ environment, adding TBTU, triethylamine and mycophenolic acid, stirring for 80h in a 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 1:5, 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, drying at 50 ℃ in vacuum for 8h to obtain 225.62g of the novel Pt (IV) complex, wherein the comprehensive yield (calculated by oxaliplatin) is 86.5%.
From the results, the method for preparing the novel Pt (IV) complex has the advantages of simple operation, stable yield and high yield, so the process is more suitable for mass production.
As shown in fig. 2, the mass spectrum of the novel Pt (iv) complex obtained in example 2 shows:
HR-MS(m/z):[C42H52N2O16Pt+Na]+1058.3 (100%), 1059.3 (94.6%), 1057.3 (63.2%), 1060.3 (37.7%), 1061.3 (21.9%), 1062.3 (11.6%), consistent with the molecular weight of the target compound.
As shown in FIG. 3, it is a nuclear magnetic hydrogen spectrum diagram of the novel Pt (IV) complex, and can be seen that:
1H-NMR(400MHz，DMSO)：(ppm)＝9.36～9.37(s，2H，2C-OH)，8.20～8.31(d，4H，2COO-CH 2)，5.24(s，4H，2CH-CH 2)，5.11～5.13(t，2H，2CH-NH2)，3.69(s，6H，2CO-CH 3)，3.27～3.28(d，4H，2CO-CH 2)，2.28～2.31(t，4H，2C-CH 2)，2.09～2.11(t，4H，2CH-CH 2)，2.07～2.08(s，6H，2C-CH 3)，1.70(s，6H，2C-CH 3)，1.47～1.48(s，2H，2C-CH)，1.23～1.38(d，4H，2NH2)，1.08～1.18(m，4H，2CH2-CH 2) Groups of hydrogen signals assigned to the target compound C42H52N2O16The Pt 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 the IC of novel Pt (IV) complexes based on oxaliplatin in various cancer cells50Value (. mu.M). The MTT method is adopted 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, human liver cancer cells HEPG-2 and human colon cancer cells SW480, 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 the table.
TABLE 1 IC of the above-mentioned novel Pt (IV) complexes with cisplatin and satraplatin in various cancer cells50Value comparison table
The results in Table 1 show that the complex has far better inhibitory activity on HEPG-2 and SW480 tumor cell lines than cisplatin but slightly lower than satraplatin, and shows potential application prospects on two tumor cells.
Claims (12)
1. A novel Pt (IV) complex based on oxaliplatin is characterized by the following structure:
2. a method for preparing a novel oxaliplatin-based Pt (iv) complex according to claim 1, characterized by comprising the steps of:
step 1, synthesizing dihydroxyoxaliplatin (IV): adding oxaliplatin into water, stirring uniformly, adding 30% hydrogen peroxide, stirring in a dark place, filtering, washing and drying to obtain dihydroxyoxaliplatin (IV);
step 2, preparing a novel Pt (IV) complex mother liquor: dissolving the dihydroxyoxaliplatin (IV) product in DMF, adding TBTU, triethylamine and mycophenolic acid, stirring in a dark place, and filtering to obtain a novel Pt (IV) complex mother solution;
step 3, preparing a novel Pt (IV) complex finished product: adding methanol or ethanol into the novel Pt (IV) complex mother liquor, concentrating, adding a reverse precipitation solvent into the concentrated residual liquid in a dark environment, stirring for 10-60 min at 20-40 ℃, filtering, washing a filter cake for 3 times with 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. The method for preparing oxaliplatin-based novel Pt (IV) complex according to claim 2, wherein the step 1 dihydroxyoxaliplatin (IV) synthesis process comprises:
adding 1.0-100.0 g of oxaliplatin into 40-80 ℃ water, stirring for 1-30 min at 50-70 ℃, adding 0.1-0.4 mL of hydrogen peroxide solution per second, stirring for 4-8 h in a dark place, filtering, washing with appropriate amount of water for 3 times, draining, and drying for 6-8 h at 60-80 ℃.
4. The method for the preparation of novel oxaliplatin-based Pt (IV) complexes according to claim 3, characterized in that:
the mass volume ratio of oxaliplatin to water is 1g: 50-100 mL, the mass volume ratio of oxaliplatin to 30% hydrogen peroxide is 1g: 0.8-1.2 mL, and 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 Pt (IV) complex based on oxaliplatin according to claim 2, wherein the preparation process of the novel Pt (IV) complex mother liquor of the step 2 comprises the following steps:
adding dihydroxyoxaliplatin (IV) into DMF at the temperature of 20-40 ℃, stirring for 10-30 min at the temperature of 20-40 ℃, filtering, transferring the filtrate to the environment at the temperature of 20-40 ℃, adding TBTU, triethylamine and mycophenolic acid, stirring for 60-80 h in the dark, filtering, and collecting the filtrate;
the mass volume ratio of the dihydroxyoxaliplatin (IV) to the DMF is 1g: 4-8 mL;
the molar ratio of the dihydroxyoxaliplatin (IV) to any one of TBTU, triethylamine and mycophenolic acid is 1:3 respectively.
6. The method for preparing a novel oxaliplatin-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 Pt (IV) complex based on oxaliplatin according to claim 2, wherein the preparation process of the novel Pt (IV) complex finished product in the step 3 comprises the following steps:
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. The method for preparing a novel oxaliplatin-based Pt (IV) complex according to 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. The process for the preparation of novel Pt (iv) complexes based on oxaliplatin according to 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 a novel oxaliplatin-based Pt (IV) complex according to claim 1 for the preparation of an anti-tumour medicament.
11. Use of the novel oxaliplatin-based Pt (IV) complexes according to claim 1 for the preparation of orally administrable medicaments with targeted antitumor properties.
12. Use of a novel oxaliplatin-based Pt (IV) complex according to claim 10 for the preparation of an antitumor medicament or of a novel oxaliplatin-based Pt (IV) complex according to claim 11 for the preparation of an orally administrable medicament having a targeted antitumor effect, characterized in that:
the tumors include liver cancer and colon cancer.
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| 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)》 * |
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