CN112062791B - 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
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
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- 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
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 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
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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 the antitumor activity on a certain 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:
(1) adding cisplatin into water, stirring, adding 30% hydrogen peroxide, stirring in dark place, filtering, washing, and drying to obtain dihydroxy cisplatin (IV);
(2) 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;
(3) adding methanol or ethanol into the mother liquor, concentrating, adding an anti-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 (1): 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 (1): the mass ratio of the cisplatin to the water is 1; the mass volume ratio of the cisplatin to the 30% hydrogen peroxide is 1; the volume ratio of the 30% hydrogen peroxide to the water is 1.
Preferably, in the step (2): the mass volume ratio of the dihydroxycisplatin (IV) to the DMF is 1; the molar ratio of dihydroxycisplatin (IV) to any one of TBTU, triethylamine and mycophenolic acid is 1; adding TBTU, triethylamine and mycophenolic acid, and stirring for 36-60 h in the dark.
Preferably, in the step (3): the volume ratio of DMF to methanol or ethanol is 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; the volume ratio of the residual liquid after concentration to the back-elution solvent is 1; 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 comprises the following specific operations:
(1) Synthesis process of dihydroxyl cisplatin (IV)
Adding 1.0 part of cisplatin into 50 ℃ water, stirring the solution at 50 ℃ for 1min, adding 0.1mL of hydrogen peroxide solution per second, stirring the solution for 4h in a dark place, filtering the solution, washing the solution with proper amount of water for 3 times, draining the solution, and drying the solution at 60 ℃ for 8h to obtain 1.05g of dihydroxycisplatin (IV), wherein the yield is 94.6%. Wherein the cisplatin is 1g of water and 50mL, the cisplatin is 1g of 30% hydrogen peroxide and is 1.6 mL, 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
DMF was removed according to a mass volume ratio of dihydroxycisplatin (iv) to DMF of 1g. 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
Removing the methanol or the ethanol according to a volume ratio of the DMF to the methanol or the ethanol of 1, and removing the anti-precipitation solvent according to a volume ratio of the residual liquid after concentration in the step (3) to the anti-precipitation solvent of 1. 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 drop (the water bath temperature is 50 ℃, the vacuum degree is 250 hPa/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, drying at 20 ℃ in vacuum for 4h 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 weight ratio of the cis-platinum to the water is 1g: 30% hydrogen peroxide was added to 8 times the volume of water and stirred.
(2) Process for preparing mother liquor of Pt (IV) complex
The mass volume ratio of dihydroxycisplatin (iv) to DMF is 1g. 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
Removing methanol or ethanol according to a volume ratio of DMF to methanol or ethanol of 1. 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 drop (the water bath temperature is 60 ℃, the vacuum degree is 230 hPa/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, drying at 30 ℃ in vacuum for 6h 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 a 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 water of 1g 100mL, the cisplatin is 30% hydrogen peroxide of 1g: 30% hydrogen peroxide was added to 10 volumes of water and stirred.
(2) Process for preparing mother liquor of Pt (IV) complex
The mass-to-volume ratio of dihydroxycisplatin (iv) to DMF was 1g, DMF was removed, and TBTU, triethylamine and mycophenolic acid were weighed as 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
Removing the methanol or the ethanol according to a volume ratio of the DMF to the methanol or the ethanol of 1. 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 drop (the water bath temperature is 70 ℃, the vacuum degree is 200 hPa/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 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):[C 34 H 44 Cl 2 N 2 O 12 Pt+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:
1 H-NMR(400MHz，DMSO)：δ(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，2NH 3 )，1.24(d，6H，2C-CH 3 ) Groups of hydrogen signals assigned to the target compound C 34 H 44 Cl 2 N 2 O 12 The 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 IC of a novel Pt (IV) complex based on cisplatin in various cancer cells 50 The 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 inhibitory concentration (IC 50) of the novel Pt (IV) complex in 48h is shown in Table 1.
TABLE 1 comparison of IC50 values of 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 (11)
1. A Pt (IV) complex based on cisplatin is characterized by having the following structure:
2. a method for producing a Pt (iv) complex based on cisplatin 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 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 the 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 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 Pt (IV) complex.
3. A method for preparing a Pt (iv) complex based on cisplatin according to claim 2, wherein the synthesis process of dihydroxy cisplatin (iv) in step 1 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; filtering and drying at 60-80 ℃ for 6-8 h.
4. A method for producing a Pt (iv) complex based on cisplatin according to claim 3 characterized in that:
the mass volume ratio of the cisplatin to the water is 1g; the mass volume ratio of the cisplatin to the 30% hydrogen peroxide is 1g; the preparation method of the hydrogen peroxide solution comprises the following steps: adding 30% hydrogen peroxide into water with 5-10 times volume, and stirring uniformly.
5. The method for preparing a Pt (IV) complex based on cisplatin as claimed in claim 2, wherein the Pt (IV) complex mother liquor preparation process of step 2 comprises:
the mass volume ratio of the dihydroxycisplatin (IV) to the DMF is 1g;
the molar ratio of dihydroxycisplatin (iv) to TBTU, triethylamine and mycophenolic acid was 1.
6. The method for preparing a Pt (iv) complex based on cisplatin according to claim 2, characterized in that:
the volume ratio of DMF to methanol or ethanol is 1-5;
the volume ratio of the anti-precipitation solvent to the residual liquid after concentration is 5-10.
7. A method for preparing a Pt (IV) complex based on cisplatin as claimed in claim 2 or 6 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.
8. A process for preparing a Pt (IV) complex based on cisplatin as claimed in claim 2 or 6 characterized in that:
the rotary evaporator has a water bath temperature of 50-70 ℃ and a vacuum degree of 250-200 hPa.
9. Use of a Pt (IV) complex based on cisplatin according to claim 1 in the preparation of an anti-tumor medicament.
10. Use of a Pt (iv) complex based on cisplatin according to claim 1 in the preparation of an orally administrable medicament having a targeted antitumor effect.
11. Use of a cisplatin-based Pt (iv) complex as defined in claim 9 for the preparation of an antitumor medicament or use of a cisplatin-based Pt (iv) complex as defined in claim 10 for the preparation of an orally administrable medicament having a targeted antitumor effect, characterized in that:
the tumor is human breast cancer, human ovarian cancer and human osteosarcoma.
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