CN102942594A - Anti-cancer medicinal aspirin platinum complex and preparation method thereof - Google Patents
Anti-cancer medicinal aspirin platinum complex and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an anti-cancer medicinal aspirin platinum complex and a preparation method thereof. The method comprises the following steps of coordinating amine or heterocyclic amine on a platinum atom through a coordinated N atom and the coordination function of the platinum, introducing halogen or hydroxyl, carboxylate radical or substituted carboxylate radical through the coordination function, and oxidizing the platinum atom into tetravalent platinum, connecting aspirin molecular axially to form tetravalent platinum complex with one aspirin molecular single substitute or two aspirin molecular double substitutes axially. As the tetravalent state of the platinum is relatively inert, the toxic side effect on organs is small, and moreover, the uptake route of drug is changed, the anticancer activity of the drug is improved, the anti-tumor activity which is same to or even more excellent than that of cis-platinum is realized, and the killing function to the drug resistant cells is good. The preparation method provided by the invention is simple in structure, low in cost and suitable for industrial production.
Description
Technical field
The invention belongs to the platinum-based complex for anti-cancer medicament technical field, be specifically related to anticarcinogen acetylsalicylic acid tetravalence platinum complexes and preparation method thereof.
Background technology
Cancer is threatening human health and lives.The data that International Union Against Cancer in 2010 issues the 21st the anticancer conference in the world show that 2008, there were 1,270 ten thousand people's cancer strickens in the whole world, and death toll is up to 7,600,000, account for 13% of whole world death toll then.Number because of cancer mortality in the world wide is also more than suffering from the sick and dead number summation of acquired immune deficiency syndrome (AIDS), malaria and combination.In China, in the Past 30 Years, the mortality ratio of cancer has increased by 80%, and annual therefore dead have 1,800,000 people.Cis-platinum was found to have antitumour activity in 1967, be applied to clinically in 1969, and was used by the FDA approval in 1978.Although cis-platinum has obtained significant success in the treatment of tumour, this two large effects limit of toxic side effect and resistance its use in clinical; " National Cancer Institute " magazine is pointed out in (1988 the 80th phase 1773 pages), the toxic side effect of cis-platinum comprises Toxicity of Kidney, neurotoxicity, ototoxicity, alopecia, feel sick and vomiting etc., and wherein cumulative neurotoxicity is that all platinum medicines all are difficult to overcome at present; Resistance comprises that some patients have geneogenous resistance to cis-platinum, and other patients have then produced resistance gradually in the use procedure of cis-platinum.Although a new generation is platinous to be synthesized to use and to have reduced some toxic side effect, but still exists very large toxic side effect, the resistance problem also still exists.Tetravalence platinum because of the little and fat-soluble increase of its toxic side effect to body by extensive concern; iproplatin and cis-two chloro-are trans-and diacetyl-ammonia-methylamine closes platinum (IV) and (JM216) has been used as oral platinum kind anti-cancer drugs and is used to clinical study; other tetravalence platinum; such as Japanese patent application JP-A61-33192; although the tetravalence platinum of mentioning among JP-A-61-7283 and the JP-A-1-294684 has outstanding water-soluble and low renal toxicity; yet according to what mention among the Chinese patent application publication number CN1193627A; its antitumor action is not very satisfactory, so need to seek new tetravalence platinum-containing anticancer drug.
Summary of the invention
The purpose of this invention is to provide a kind of anticarcinogen with acetylsalicylic acid platinum complex and preparation method thereof, to overcome the defects of prior art, reduce toxic side effect and the resistance of platinum-containing anticancer drug.
The preparation method of platinum-based complex for anti-cancer medicament of the present invention, it is characterized in that first the divalence platinic compound being oxidized to the tetravalence platinum complex, then axially connect the acetylsalicylic acid molecule with antitumour activity at it, obtain can be used as the acetylsalicylic acid molecule list that axially has that anticarcinogen uses and replace or two disubstituted tetravalence platinum complexes of acetylsalicylic acid molecule; Concrete operation step is as follows:
First by every 1mmol cis-platinum or other divalence platinum, be dissolved in the 1-100mL water, with the 2-100mmol hydrogen peroxide at 30-100 ℃ of stirring reaction 1-48h, then adopt rotary evaporation or lyophilize desolventizing to obtain solid, this solid is used first cold water repetitive scrubbing 3-10 time, with ether washing 3-10 time, obtain divalence platinum oxidation product after the drying again;
With divalence platinum oxidation product obtained above, be dissolved in 1-50mL dimethyl sulfoxide (DMSO) or the dimethyl formamide by every 1mmol, with 1mmol o-acetyl salicylic acid acid anhydride, diacetyl oxide, Succinic anhydried, adipic anhydride or phthalic acid acid anhydrides, at 25-80 ℃ of stirring reaction 5-48h, adopt rotary evaporation or lyophilize desolventizing to obtain solid, the acetone that adds 10-100mL in this solid, centrifugation goes out precipitation, then the gained precipitation is used first washing with acetone 3-10 time, again with ether washing 3-10 time, after the vacuum-drying, a mono-substituted tetravalence platinum complexes of acetylsalicylic acid molecule is arranged axially.
Further, also can a mono-substituted tetravalence platinum complexes of acetylsalicylic acid molecule axially be arranged with obtained above, be dissolved in 1-50mL dimethyl sulfoxide (DMSO) or the dimethyl formamide by every 1mmol, with 2-50mmol o-acetyl salicylic acid acid anhydride at 25-80 ℃ of stirring reaction 5-48h, adopt rotary evaporation or lyophilize desolventizing to obtain solid, the acetone that adds 10-100mL in this solid, centrifugation goes out precipitation, then the gained precipitation is used first acetone repetitive scrubbing 3-10 time, again with ether washing 3-10 time, after the vacuum-drying, two disubstituted tetravalence platinum complexes of acetylsalicylic acid molecule are arranged axially.
The above-mentioned acetylsalicylic acid molecule list that axially has for preparing replaces or two disubstituted tetravalence platinum complexes of acetylsalicylic acid molecule, is all platinum-based complex for anti-cancer medicament of the present invention.
Platinum-based complex for anti-cancer medicament of the present invention is characterised in that it for axially there being an acetylsalicylic acid molecule list to replace or two disubstituted tetravalence platinum complexes of acetylsalicylic acid molecule, has following structure:
Wherein two kinds of group Am and Am ' can be respectively amine NH
3, replace amine or heterocyclic amine, they are by nitrogen-atoms and Pt Atomic coordinate, these two kinds of group Am and Am' can be identical or different; L can be halogen, carboxylate radical or substituted carboxylic acid root; Axially replacing the R of functional group is the acetylsalicylic acid molecule with antitumour activity, and another axially replaces the R` of functional group is acetylsalicylic acid molecule, hydroxyl, Succinic Acid, adipic-or phthalic acid.
Described replacement amine is selected from an ethylamine, diethylamide, a n-propyl amine, di-n-propyl amine, an isopropylamine, diisopropylamine, a n-butylamine, di-n-butyl amine, an isobutylamine, diisobutyl amine, a n-pentyl amine, two n-pentyl amine, an isoamylamine or diisoamyl amine;
Described heterocyclic amine is selected from thiazole, benzothiazole, imidazoles, benzoglyoxaline, quinoline, isoquinoline 99.9, pyridine, 2-picoline, 3-picoline, 4-picoline, 2,6-lutidine, 2 hydroxy pyrimidine, 3-pyridone, 2-4-hydroxymethylpiperidine, 3-4-hydroxymethylpiperidine, pyrazine, 2,3-dimethylpyrazine, 2,5-dimethylpyrazine or piperazine;
Described halogen is selected from Cl, Br or I;
Described carboxylate radical is acetate moiety, propionate, butanic acid root, benzoate anion, toluylic acid root or p-methylbenzoic acid root;
Described substituted carboxylic acid root is Monochloro Acetic Acid root, dichloro acetic acid root or trichoroacetic acid(TCA) root.
The present invention is coordinated to amine or heterocyclic amine on the pt atom by the N atom of part and the coordination of platinum, introduce halogen or hydroxyl, carboxylate radical or substituted carboxylic acid root by coordination again, then be oxidized to tetravalence platinum, axially connecting the acetylsalicylic acid molecule, obtained axially having an acetylsalicylic acid molecule list to replace or two disubstituted tetravalence platinum complexes of acetylsalicylic acid molecule, they all are platinum-based complex for anti-cancer medicaments.After the platinum complexes that adopts the inventive method to prepare enters cancer cells, because the divalence platinum complex that reduction generates in the presence of the reducing substance in cell of tetravalence platinum complex wherein, can act on DNA, thereby suppress copying of DNA, cause cancer cell-apoptosis; The platinum complexes of the present invention preparation is because of the tetravalent state comparison inertia of platinum wherein, body only there is very little toxic side effect, and changed the picked-up approach of medicine, improve the antitumour activity of medicine, have the anti-tumor activity equal even more superior with cis-platinum, and mdr cell is also had good lethal effect.What employing the inventive method prepared axially has an acetylsalicylic acid molecule list replacement or two disubstituted tetravalence platinum complexes of acetylsalicylic acid molecule is axially arranged, lung carcinoma cell, cervical cancer cell, ovarian cancer cell and breast cancer cell to the people all have the growth in vitro restraining effect, can be used as the medicine for the treatment of cancer.Preparation method of the present invention is fairly simple, and is with low cost, is fit to suitability for industrialized production.
Embodiment
Embodiment 1:c, c, t-[Pt (NH
3)
2Cl
2(OH) (Aspirin) preparation]
The 1mmol cis-platinum is dissolved in the 5mL water, adds the 10mmol hydrogen peroxide, at 50 ℃ of stirring reaction 1.5h, then stirring reaction 12h at room temperature, the rotary evaporation desolventizing obtains solid, and this solid is used first the cold water repetitive scrubbing 3 times, with ether washing 3 times, vacuum-drying gets the cis-platinum oxidation products again; By electrospray ionization mass spectrum it is characterized, data are MW=332.80, can confirm that products therefrom is that the gained material is c, c, t-[Pt (NH
3)
2Cl
2(OH)
2];
Get this material 1mmol, be dissolved in the 10mL dimethyl sulfoxide (DMSO), add 1mmol o-acetyl salicylic acid acid anhydride, at 30 ℃ of stirring reaction 12h, the lyophilize desolventizing obtains solid, adds the acetone of 10-100mL in this solid, centrifugation goes out precipitation, gained precipitation first with acetone wash 3 times, again with ether washing 3 times, vacuum-drying obtains the light yellow solid product.
By proton nmr spectra the above-mentioned light yellow solid product that obtains is characterized, resulting data are as follows: D
2O. δ (ppm): 7.90 (d, H
1), δ (ppm): 7.67 (ter, H
2), δ (ppm): 7.45 (ter, H
3), δ (ppm): 7.23 (d, H
4), δ (ppm): 2.47 (s, CH
3); By electrospray ionization mass spectrum it is characterized, the data that obtain are MW=496.86.Can confirm thus: the preparation-obtained light yellow solid of present embodiment is target product c, c, t-[Pt (NH
3)
2Cl
2(OH) (Aspirin)].
The preparation of embodiment 2:Oxaliplatin (IV)-aspirin compound
The 1mmol potassium hexachloroplatinate is dissolved in the 10mL water, add 0.5mmol hydrochloric acid buzane, 55 ℃ of stirring reactions are 3h at least, then behind 85 ℃ of reaction 6min, reaction soln is placed frozen water water-bath 30min, then carry out centrifugation, take out supernatant liquor, the desolventizing of supernatant rotary evaporation, obtain potassium tetrachloroplatinate;
The 1mmol potassium tetrachloroplatinate is dissolved in the 5mL water, and it is trans 1 to add 1mmol, the 2-cyclohexanediamine, stirring at room reaction 24h, centrifugation obtains solid, and this solid is dissolved in the 5mL water, and then the Silver Nitrate of adding 2mmol, stirring at room reaction 24h carries out centrifugation, take out supernatant liquor, add again excessive KI, reaction 12h, supernatant liquor is taken out in centrifugation again, add equimolar oxalic acid, stirring reaction 24h, centrifugation goes out solid; This solid is used first cold wash 3 times, with ether washing 3 times, obtain solid product again;
Solid product 1mmol obtained above is dissolved in the 5ml water, adds the 50mmol hydrogen peroxide, at 50 ℃ of reaction 1.5h, the stirring at room reaction is spent the night, and the rotary evaporation desolventizing obtains solid; This solid is used first cold wash 3 times, and with ether washing 3 times, vacuum-drying obtains another kind of solid product again;
Get obtained above should another kind solid product 1mmol, be dissolved in the 10mL dimethyl sulfoxide (DMSO), add 1mmol o-acetyl salicylic acid acid anhydride, stirring at room reaction 24h adopts the lyophilize desolventizing, the acetone of 10-100mL will be added in the resulting lyophilized products solid, centrifugation goes out precipitation, and the gained precipitation is washed 3 times with acetone first, again with ether washing 3 times, then vacuum-drying obtains final product.
Resulting final product is characterized it by proton nmr spectra, and the data obtained is as follows: D
2O. δ (ppm): 3.35 (d, H
1), δ (ppm): 3.70 (m, H
2), δ (ppm): 3.81 (ter, H
3), δ (ppm): 7.92 (d, H
1), δ (ppm): 7.68 (ter, H
2), δ (ppm): 7.46 (ter, H
3), δ (ppm): 7.25 (d, H
4), δ (ppm): 2.48 (s, CH
3); Be MW=593.96 by electrospray ionization mass spectrum to its characterization data.Confirm thus: the preparation-obtained final product of present embodiment is Oxaliplatin (IV)-aspirin compound.
Embodiment 3:c, c, t-[Pt (NH
3)
2Cl
2(Aspirin)
2] preparation
The 1mmol cis-platinum is dissolved in the 5mL water, adds the 10mmol hydrogen peroxide, at 50 ℃ of stirring reaction 1.5h, then stirring reaction 12h at room temperature, adopt the rotary evaporation desolventizing to obtain solid, this solid is used first cold wash 3 times, again with ether washing 3 times, vacuum-drying obtains the cis-platinum oxidation products, by electrospray ionization mass spectrum it is characterized, data are MW=332.80, can confirm that products therefrom is c, c, t-[Pt (NH
3)
2Cl
2(OH)
2];
Get this material 1mmol, be dissolved in the 10mL dimethyl sulfoxide (DMSO), add 5mmol o-acetyl salicylic acid acid anhydride, 70 ℃ of stirring reaction 12h, lyophilize desolventizing, the acetone that adds 10-100mL in the gained solid, centrifugation goes out precipitation, this precipitation is washed 3 times with acetone first, again with ether washing 3 times, vacuum-drying obtains the light yellow solid product.
By proton nmr spectra resulting light yellow solid product is characterized, resulting data are as follows: D
2O. δ (ppm): 7.90 (d, H
1), δ (ppm): 7.67 (ter, H
2), δ (ppm): 7.45 (ter, H
3), δ (ppm): 7.23 (d, H
4), δ (ppm): 2.47 (s, CH
3); By electrospray ionization mass spectrum it is characterized, the data obtained is MW=657.02.Can confirm thus: the preparation-obtained light yellow solid product of present embodiment is c, c, t-[Pt (NH
3)
2Cl
2(Aspirin)
2].
Embodiment 4:c, c, t-[Pt (NH
3)
2Cl
2(succinate) (Aspirin) preparation]
The 1mmol cis-platinum is dissolved in the 5mL water, adds the 10mmol hydrogen peroxide, at 50 ℃ of stirring reaction 1.5h, stirring reaction 12h at room temperature then, vacuum is spin-dried for to get solid, and this solid is used first cold wash 3 times, washed 3 times vacuum-drying with ether again, the gained material is c, c, t-[Pt (NH
3)
2Cl
2(OH)
2];
Get this material 1mmol, be dissolved in the 10mL dimethyl sulfoxide (DMSO), add the 1mmol Succinic anhydried, in 30 ℃ of stirring reaction 12h, lyophilize desolventizing, the acetone that adds 10-100mL in the gained solid, centrifugation goes out precipitation, this precipitation is washed 3 times with acetone first, again with ether washing 3 times, vacuum-drying gets the light yellow solid product;
Getting above-mentioned light yellow solid product 1mmol is dissolved in the 10mL dimethyl sulfoxide (DMSO), add 1mmol o-acetyl salicylic acid acid anhydride, 30 ℃ of stirring reaction 12h, the lyophilize desolventizing, use the acetone precipitation lyophilized products, the gained precipitation is washed 3 times with acetone first, again with ether washing 3 times, vacuum-drying obtains another kind of light yellow solid product.
Should characterize by the another kind light yellow solid resulting by proton nmr spectra, it is as follows to obtain data: D
2O. δ (ppm): 7.90 (d, H
1), δ (ppm): 7.67 (ter, H
2), δ (ppm): 7.45 (ter, H
3), δ (ppm): 7.23 (d, H
4), δ (ppm): 2.47 (s, CH
3), δ (ppm): 2.64 (m, CH
2), δ (ppm): 2.55 (m, CH
2); By electrospray ionization mass spectrum it is characterized, the data that obtain are MW=595.85.Can confirm thus: the preparation-obtained another kind of light yellow solid of present embodiment is target product c, c, t-[Pt (NH
3)
2Cl
2(succinate) (Aspirin)].
Embodiment 5:trans-Pt (Cl)
2(NH
3) (Py) (OH) (aspirin) preparation of compound
1mmol cis-platinum and 3mmol pyridine are dissolved in the 1mL water, 30 ℃ of reactions 1 hour; Then the concentrated hydrochloric acid that adds 1mL 10M, refluxed 5 hours, there is faint yellow solid to separate out, filter and collect product, wash 3 times with ethanol, get solid with ether washing 3 times, vacuum-drying again, by electrospray ionization mass spectrum this solid is characterized, the data that obtain are MW=360.85, can confirm thus: resulting solid chemical compound is trans-Pt (Cl)
2(NH
3) (Py);
Get solid chemical compound trans-Pt obtained above (Cl)
2(NH
3) (Py) 1mmol be dissolved in the 5ml water, add the 50mmol hydrogen peroxide, at 50 ℃ of reaction 1.5h, the stirring at room reaction is spent the night, and adopts the rotary evaporation desolventizing to obtain solid, this solid is first through cold wash 3 times, with ether washing 3 times, vacuum-drying gets oxidation products, by electrospray ionization mass spectrum this oxidation products is characterized again, the data that obtain are MW=394.96, can confirm thus: resulting oxidation products is trans-Pt (Cl)
2(NH
3) (Py) (OH)
2
With oxidation products trans-Pt obtained above (Cl)
2(NH
3) (Py) (OH)
2Getting 1mmol is dissolved in the 10mL dimethyl sulfoxide (DMSO), add 1mmol o-acetyl salicylic acid acid anhydride, stirring at room reaction 24h, the lyophilize desolventizing adds the acetone of 10-100mL in the gained solid, and centrifugation goes out precipitation, this precipitation is washed 3 times with acetone first, with ether washing 3 times, vacuum-drying namely obtains the purpose product again.
By proton nmr spectra the above-mentioned purpose product for preparing is characterized, the data that obtain are as follows: D
2O. δ (ppm): 8.67 (m, α H), 7.88 (m, γ H), 7.58 (m, β H), δ (ppm): 7.90 (d, H
1), δ (ppm): 7.67 (ter, H
2), δ (ppm): 7.45 (ter, H
3), δ (ppm): 7.23 (d, H
4), δ (ppm): 2.47 (s, CH
3); By electrospray ionization mass spectrum it is characterized, obtaining data is MW=557.95.Can confirm thus: the preparation-obtained purpose product of present embodiment is trans-Pt (Cl)
2(NH
3) (Py) (OH) (aspirin).
Preparation-obtained platinum complexes all has following structure in the above embodiment of the present invention:
Wherein two kinds of group Am and Am ' can be amine NH
3, replace amine or heterocyclic amine, they are by nitrogen-atoms and Pt Atomic coordinate, these two kinds of group Am and Am ' can be identical or different; L can be halogen, carboxylate radical or substituted carboxylic acid root; Axially replacing the R of functional group is the acetylsalicylic acid molecule with antitumour activity, and another axially replaces the R` of functional group is acetylsalicylic acid molecule, hydroxyl, Succinic Acid, adipic-or phthalic acid.Described replacement amine is selected from an ethylamine, diethylamide, a n-propyl amine, di-n-propyl amine, an isopropylamine, diisopropylamine, a n-butylamine, di-n-butyl amine, an isobutylamine, diisobutyl amine, a n-pentyl amine, two n-pentyl amine, an isoamylamine or diisoamyl amine; Described heterocyclic amine can be selected from thiazole, benzothiazole, imidazoles, benzoglyoxaline, quinoline, isoquinoline 99.9, pyridine, 2-picoline, 3-picoline, 4-picoline, 2,6-lutidine, 2 hydroxy pyrimidine, 3-pyridone, 2-4-hydroxymethylpiperidine, 3-4-hydroxymethylpiperidine, pyrazine, 2,3-dimethylpyrazine, 2,5-dimethylpyrazine or piperazine; Described halogen is selected from Cl, Br or I; Described carboxylate radical is acetate moiety, propionate, butanic acid root, benzoate anion, toluylic acid root or p-methylbenzoic acid root; Described substituted carboxylic acid root is Monochloro Acetic Acid root, dichloro acetic acid root or trichoroacetic acid(TCA) root.
After this platinum complexes enters cancer cells, its axial R of functional group and R` are sloughed by reducing substances reduction in the cell, the ligand L hydrolysis, allow to act on DNA, thereby suppress copying of DNA, cause cancer cell-apoptosis, and the acetylsalicylic acid molecule of sloughing also has lethal effect to cancer cells, so that adopts the inventive method preparation axially has an acetylsalicylic acid molecule list to replace or two tetravalence platinum complexes that the acetylsalicylic acid molecule replaces, they can be as the medicine of all kinds of cancers for the treatment of.
Embodiment 6: adopt the preparation-obtained medicinal effect test that an acetylsalicylic acid molecule list replacement or two disubstituted tetravalence platinum complexes of acetylsalicylic acid molecule are axially arranged of the inventive method
One, cell cultures
With human lung carcinoma cell, human cervical carcinoma cell, Proliferation of Human Ovarian Cell or human breast cancer cell in containing the RPMI-1640 substratum that volume ratio is 10% calf serum in 37 ℃, CO
2Volume ratio is to cultivate in 5% the incubator.The logarithmic phase cell is selected in experiment.
Two, mtt assay is measured cytoactive
Cytotoxicity experiment is selected logarithmic phase cell 2 * 10
4Individual/mL is seeded in 96 orifice plates, and every hole 100 μ L cultivate the fresh substratum of replacing after 24 hours, experimental group, control group and blank group are set, experimental group adds the medicine of different concns gradient, and control group does not add medicine, and blank group does not have inoculating cell and do not add medicine; Continue to cultivate tetrazolium bromide (MTT) method mensuration cytoactive after 72 hours, calculate the cell survival rate of experimental group, thereby obtain the cytotoxicity of medicine.
1, collect the logarithmic phase cell, adjust concentration of cell suspension, every hole adds 100 μ L, and it is 2000/hole that bed board makes cell density to be measured, (marginal pore is filled with aseptic PBS).
2, at CO
2Volume ratio is to hatch in 5%, 37 ℃ the incubator, be paved with the hole to cell monolayer at the bottom of (96 hole flat underside), add the medicine of concentration gradient, each concentration is established 3 multiple holes.
3, at CO
2Volume ratio is to hatch 72 hours in 5%, 37 ℃ the incubator, observes under the inverted microscope.
4, discard old substratum and add fresh culture 100 μ L, then to add 25 μ L concentration be the MTT solution of 5mg/ml in every hole, continues to cultivate 2 hours.
6, every hole adds 100 μ L cell pyrolysis liquids, at CO
2Volume ratio is overnight incubation in 5%, 37 ℃ the incubator, and crystallisate is fully dissolved.Measure the absorbance A value in each hole at enzyme-linked immunosorbent assay instrument 490nm place.
Survival rate (%)=[the A value of experimental group (S)-blank (B) A value]/[the A value of the A value of control group (C)-blank (B)].
Experimental result shows: the acetylsalicylic acid molecule list that axially has that adopts method of the present invention to prepare replaces or two disubstituted tetravalence platinum complexes of acetylsalicylic acid molecule, human lung carcinoma cell, human cervical carcinoma cell, Proliferation of Human Ovarian Cell and human breast cancer cell to human lung carcinoma cell, resistance have significant restraining effect, and effect all slightly is better than cis-platinum.Experiment showed, that by picked-up the intake of this compounds in cancer cells is all very high.Tetravalent state comparison inertia because of platinum, body there is very little toxic side effect, changed the picked-up approach of medicine, increased the amount that medicine enters cell, and axial acetylsalicylic acid has antitumour activity, acetylsalicylic acid and platinum medicine can act synergistically and kill and wound cancer cells, improve the antitumour activity of medicine, having the anti-tumor activity equal even more superior with cis-platinum, and mdr cell is also had good lethal effect, is the new multi-functional platinum complex of a class.Can be used as the medicine for the treatment of cancer, have the antitumous effect of wide spectrum.Preparation method of the present invention is simple, and is with low cost, is fit to suitability for industrialized production.
Claims (8)
1. platinum-based complex for anti-cancer medicament is characterised in that it for axially there being an acetylsalicylic acid list to replace or two disubstituted tetravalence platinum complexes of acetylsalicylic acid molecule, has following structure:
Wherein two kinds of group Am and Am ' are respectively amine NH
3, replace amine or heterocyclic amine, they are by nitrogen-atoms and Pt Atomic coordinate, these two kinds of group Am are identical with Am ' or different; L is halogen, carboxylate radical or substituted carboxylic acid root; Axially replacing the R of functional group is the acetylsalicylic acid molecule, and another axially replaces the R` of functional group is acetylsalicylic acid molecule, hydroxyl, Succinic Acid, adipic-or phthalic acid.
2. platinum-based complex for anti-cancer medicament as claimed in claim 1 is characterised in that described replacement amine is selected from an ethylamine, diethylamide, a n-propyl amine, di-n-propyl amine, an isopropylamine, diisopropylamine, a n-butylamine, di-n-butyl amine, an isobutylamine, diisobutyl amine, a n-pentyl amine, two n-pentyl amine, an isoamylamine or diisoamyl amine.
3. platinum-based complex for anti-cancer medicament as claimed in claim 1, be characterised in that described heterocyclic amine is selected from thiazole, benzothiazole, imidazoles, benzoglyoxaline, quinoline, isoquinoline 99.9, pyridine, 2-picoline, 3-picoline, 4-picoline, 2,6-lutidine, 2 hydroxy pyrimidine, 3-pyridone, 2-4-hydroxymethylpiperidine, 3-4-hydroxymethylpiperidine, pyrazine, 2,3-dimethylpyrazine, 2,5-dimethylpyrazine or piperazine.
4. platinum-based complex for anti-cancer medicament as claimed in claim 1 is characterised in that described halogen is selected from Cl, Br or I.
5. platinum-based complex for anti-cancer medicament as claimed in claim 1 is characterised in that described carboxylate radical is acetate moiety, propionate, butanic acid root, benzoate anion, toluylic acid root or p-methylbenzoic acid root.
6. platinum-based complex for anti-cancer medicament as claimed in claim 1 is characterised in that described substituted carboxylic acid root is Monochloro Acetic Acid root, dichloro acetic acid root or trichoroacetic acid(TCA) root.
7. the preparation method of a platinum-based complex for anti-cancer medicament is characterized in that concrete operation step is as follows:
First by every 1mmol cis-platinum or other divalence platinum, be dissolved in the 1-100mL water, with the 2-100mmol hydrogen peroxide at 30-100 ℃ of stirring reaction 1-48h, then adopt rotary evaporation or lyophilize desolventizing to obtain solid, this solid is used first cold water repetitive scrubbing 3-10 time, with ether washing 3-10 time, obtain divalence platinum oxidation product after the drying again;
With divalence platinum oxidation product obtained above, be dissolved in 1-50mL dimethyl sulfoxide (DMSO) or the dimethyl formamide by every 1mmol, with 1mmol o-acetyl salicylic acid acid anhydride, diacetyl oxide, Succinic anhydried, adipic anhydride or phthalic acid acid anhydrides, at 25-80 ℃ of stirring reaction 5-48h, adopt rotary evaporation or lyophilize desolventizing to obtain solid, the acetone that adds 10-100mL in this solid, centrifugation goes out precipitation, then the gained precipitation is used first washing with acetone 3-10 time, again with ether washing 3-10 time, after the vacuum-drying, a mono-substituted tetravalence platinum complexes of acetylsalicylic acid molecule is arranged axially.
8. the preparation method of a platinum-based complex for anti-cancer medicament is characterized in that concrete operation step is as follows:
First by every 1mmol cis-platinum or other divalence platinum, be dissolved in the 1-100mL water, with the 2-100mmol hydrogen peroxide at 30-100 ℃ of stirring reaction 1-48h, then adopt rotary evaporation or lyophilize desolventizing to obtain solid, this solid is used first cold water repetitive scrubbing 3-10 time, with ether washing 3-10 time, obtain divalence platinum oxidation product after the drying again;
With divalence platinum oxidation product obtained above, be dissolved in 1-50mL dimethyl sulfoxide (DMSO) or the dimethyl formamide by every 1mmol, with 1mmol o-acetyl salicylic acid acid anhydride, diacetyl oxide, Succinic anhydried, adipic anhydride or phthalic acid acid anhydrides, at 25-80 ℃ of stirring reaction 5-48h, adopt rotary evaporation or lyophilize desolventizing to obtain solid, the acetone that adds 10-100mL in this solid, centrifugation goes out precipitation, then the gained precipitation is used first washing with acetone 3-10 time, again with ether washing 3-10 time, after the vacuum-drying, a mono-substituted tetravalence platinum complexes of acetylsalicylic acid molecule is arranged axially;
With obtained above a mono-substituted tetravalence platinum complexes of acetylsalicylic acid molecule arranged axially again, be dissolved in 1-50mL dimethyl sulfoxide (DMSO) or the dimethyl formamide by every 1mmol, with 2-50mmol o-acetyl salicylic acid acid anhydride at 25-80 ℃ of stirring reaction 5-48h, adopt rotary evaporation or lyophilize desolventizing to obtain solid, the acetone that adds 10-100mL in this solid, centrifugation goes out precipitation, then the gained precipitation is used first acetone repetitive scrubbing 3-10 time, again with ether washing 3-10 time, after the vacuum-drying, two disubstituted tetravalence platinum complexes of acetylsalicylic acid molecule are arranged axially.
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Cited By (5)
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| CN103554187A (en) * | 2013-09-18 | 2014-02-05 | 中国科学技术大学 | Platinum complexes, protein complexes prepared from same, and preparation method of protein complexes |
| US20170190726A9 (en) * | 2013-12-12 | 2017-07-06 | University Of Georgia Research Foundation, Inc. | Prodrug for release of cisplatin and cyclooxygenase inhibitor |
| CN108395537A (en) * | 2018-03-13 | 2018-08-14 | 合肥工业大学 | A kind of tetravalence platinum macromolecular prodrug PDA, tetravalence platinum macromolecular calcium phosphate nanoparticles and its application |
| CN113527368A (en) * | 2021-08-12 | 2021-10-22 | 中国科学技术大学 | Preparation method and application of compound and anticancer drug |
| WO2023015526A1 (en) * | 2021-08-12 | 2023-02-16 | 中国科学技术大学 | Compound, preparation method for anti-cancer drug, and use |
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| CN102503984A (en) * | 2011-09-27 | 2012-06-20 | 中国科学技术大学 | Platinum-based complex for anti-cancer medicament and preparation method thereof |
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| CN102503984A (en) * | 2011-09-27 | 2012-06-20 | 中国科学技术大学 | Platinum-based complex for anti-cancer medicament and preparation method thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554187A (en) * | 2013-09-18 | 2014-02-05 | 中国科学技术大学 | Platinum complexes, protein complexes prepared from same, and preparation method of protein complexes |
| CN103554187B (en) * | 2013-09-18 | 2016-03-30 | 中国科学技术大学 | Platinum complexes, protein complex of being obtained by this platinum compound and preparation method thereof |
| US20170190726A9 (en) * | 2013-12-12 | 2017-07-06 | University Of Georgia Research Foundation, Inc. | Prodrug for release of cisplatin and cyclooxygenase inhibitor |
| EP3080137A4 (en) * | 2013-12-12 | 2017-07-19 | The University Of Georgia Research Foundation, Inc | Prodrug for release of cisplatin and cyclooxygenase inhibitor |
| CN108395537A (en) * | 2018-03-13 | 2018-08-14 | 合肥工业大学 | A kind of tetravalence platinum macromolecular prodrug PDA, tetravalence platinum macromolecular calcium phosphate nanoparticles and its application |
| CN113527368A (en) * | 2021-08-12 | 2021-10-22 | 中国科学技术大学 | Preparation method and application of compound and anticancer drug |
| WO2023015526A1 (en) * | 2021-08-12 | 2023-02-16 | 中国科学技术大学 | Compound, preparation method for anti-cancer drug, and use |
| CN113527368B (en) * | 2021-08-12 | 2023-03-10 | 中国科学技术大学 | Preparation method and application of compound and anti-cancer drug |
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