CN112961190A - Veratric acid tetravalent platinum and preparation method and application thereof - Google Patents
Veratric acid tetravalent platinum and preparation method and application thereof Download PDFInfo
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- 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
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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 belongs to the technical field of medicines, and particularly relates to veratric acid tetravalent platinum, a preparation method and application thereof, wherein the structural formula of the veratric acid tetravalent platinum is as follows:
the preparation method comprises the following steps: (1) synthesizing hydroxyl platinum; (2) synthesizing veratric acid tetravalent platinum; (3) purifying veratric acid tetravalent platinum. The veratric acid tetravalent platinum provided by the invention belongs to a tetravalent platinum prodrug, is a novel high-efficiency antitumor active compound, has a broad-spectrum anticancer effect, has small killing effect on normal cells of a human body, is high-efficiency and low-toxicity, has a high medicinal value, and is simple in preparation method, low in cost and easy for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to veratric tetravalent platinum and a preparation method and application thereof.
Background
Since the approval of cisplatin, a bivalent platinum anticancer drug, into clinical use, it has been widely used in various cancer treatments, and is now a first-line drug for cancer treatment. Cisplatin mainly acts on guanine N7 position of DNA, and forms Pt-DNA adduct through crosslinking with DNA, so that the cisplatin affects the replication and transcription of DNA, and finally induces apoptosis. At present, toxic and side effects and tumor drug resistance caused by platinum drugs are key problems for limiting the development of the platinum drugs in the clinical use process.
The molecular mechanisms of cisplatin resistance are broadly divided into four categories: (1) pre-target drug resistance, which is related to the degree of metabolism of cisplatin before reaching the DNA, including reduction of intracellular platinum content and intracellular detoxification, such as increase of sulfur-containing proteins like glutathione; (2) target resistance, associated with the recognition and repair of cisplatin DNA damage; (3) post-target drug resistance, associated with post-cisplatin DNA damage effects; (4) non-target drug resistance, and has no direct connection with the cisplatin DNA target effect. Among them, pre-target drug resistance is an extremely important reason for causing cisplatin drugs to develop drug resistance: only less than 1% of bivalent cisplatin molecules entering the cytoplasm can enter the nucleus and act with DNA in the nucleus due to the deactivation of platinum drugs by sulfur-containing proteins such as GSH.
The tetravalent platinum complex plays a role in a prodrug mode, and compared with a divalent platinum complex, the tetravalent platinum complex is in an octahedral configuration and has substitution inertia, so that the tetravalent platinum complex has good stability, reduces the reaction with nucleophilic substances in a body, can relatively completely reach cancer cells, and plays an anticancer role. In addition, the tetravalent platinum complex is easy to carry out chemical modification, and a bioactive group can be introduced into the axial position of the tetravalent platinum complex to realize synergistic interaction, so that the anticancer activity of the tetravalent platinum complex is improved. Thus, tetravalent platinum prodrugs are an ideal choice for improving cisplatin deficiency.
Veratric acid (Veratric acid) is a simple benzoic acid obtained from vegetables and fruits and has antioxidant, cardiovascular protective and anti-inflammatory activities. Studies indicate that veratric acid can inhibit COX-2 expression. COX-2 is a key enzyme catalyzing arachidonic acid to generate various Prostaglandins (PGs), is expressed in various tumors and participates in the generation of tumor drug resistance, and reduces the curative effect of chemotherapy. After the COX-2 inhibitor and the chemotherapeutic drug are combined for use, the generation of drug resistance can be reduced by reducing the expression of various tumor drug-resistant proteins, so that the sensitivity of the chemotherapeutic drug to tumors is enhanced, and the curative effect of the chemotherapeutic drug is enhanced.
Disclosure of Invention
The invention aims to provide veratric acid quadrivalent platinum which has small killing effect on normal cells of a human body, high efficiency and low toxicity and has obvious inhibition effect on tumor cells so as to solve the problems in the background technology.
In order to achieve the technical purpose, the technical scheme of the invention is as follows:
veratric acid tetravalent platinum has the following structural formula:
the invention also aims to provide a preparation method of veratric acid tetravalent platinum, which comprises the following steps:
(1) synthesis of hydroxyplatinum: weighing cisplatin, slowly adding hydrogen peroxide, keeping out of the sun, heating and refluxing at 40-100 ℃ for 1-24h, standing at 0-10 ℃ for crystallization after reaction is finished, centrifuging, washing centrifuged solids twice with distilled water, ethanol and diethyl ether respectively, and drying to obtain light yellow solid hydroxyl platinum;
(2) synthesis of veratric acid platinum: weighing the hydroxyl platinum, adding DMF (dimethyl formamide) for dissolving, sequentially adding veratric acid, triethylamine and TBTU, keeping out of the sun, protecting with nitrogen, stirring at normal temperature until a reaction solution is clear, adding ice water into the reaction solution, and separating out a yellow precipitate;
(3) purification of platinum benzydate: and purifying the yellow precipitate by a silica gel column, and performing gradient elution by using a mixed solution of dichloromethane and methanol to obtain yellow solid platinum benzydate.
As an improvement, in the step (1), the molar ratio of the cisplatin to the hydrogen peroxide is 1: 5-200.
As an improvement, in the step (1), the mass concentration of the hydrogen peroxide is 30%.
As a modification, in the step (1), the heating reflux temperature is preferably 70 ℃ and the time is preferably 5 hours.
As a modification, in the step (1), the temperature for the crystallization is preferably 4 ℃.
As an improvement, in the step (2), the ratio of the platinum hydroxide: veratric acid: triethylamine: the TBTU molar ratio was 1:3:3: 3.
As a modification, the stirring time at normal temperature in the step (2) is 12 to 96 hours, preferably 48 hours.
As an improvement, in the step (3), the volume ratio of the dichloromethane to the methanol is 60: 1.
The invention also aims to provide the application of veratric acid tetravalent platinum in preparing anti-cancer and anti-tumor drugs. The cancer or tumor includes, but is not limited to, non-small cell lung cancer, cervical cancer, breast cancer, pharyngeal squamous carcinoma.
Due to the adoption of the technical scheme, the invention has the beneficial effects that:
the veratric platinum provided by the invention belongs to a tetravalent platinum prodrug, firstly, a divalent platinum drug cisplatin is oxidized into a tetravalent platinum complex, the tetravalent platinum complex is easy to carry out chemical modification, and then veratric acid molecules with synergistic effect are introduced at the axial position of the tetravalent platinum complex to obtain the veratric acid disubstituted tetravalent platinum antitumor prodrug, so that the synergistic effect is realized, and the anticancer activity of the tetravalent platinum antitumor prodrug is improved. The multiplication inhibition activity of the veratric acid tetravalent platinum on various human tumor cells is higher than that of a clinical anticancer drug cisplatin and combined administration of the cisplatin and the veratric acid, so that the veratric acid tetravalent platinum has good selectivity, small killing effect on normal cells of a human body, high efficiency and low toxicity, and has higher medicinal value. The preparation method of the invention has the advantages of simplicity, low cost, high yield and easy industrial production. Cisplatin is used as octahedral bottom surface, and small molecular target or medicine active group is introduced to the axial position to provide antitumor quadrivalent platinum complex for obtaining high efficiency and low toxicity quadrivalent platinum medicine.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of veratric acid tetravalent platinum;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of veratric acid tetravalent platinum;
figure 3 is a mass spectrum of veratric acid tetravalent platinum.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only. Reagents, consumables and the like used in the following examples are commercially available unless otherwise specified.
Example 1
Refluxing 200mg (0.67mmol) of cisplatin and 2mL of hydrogen peroxide (the hydrogen peroxide content is 30 wt%) at 70 ℃ for 5 hours, standing the reaction solution at 4 ℃ after the reaction is finished to separate out a solid, centrifuging, collecting the solid, washing the solid twice by using distilled water, ethanol and diethyl ether in sequence, and drying to obtain 189mg of a light yellow solid product, wherein the yield is 84.7%.
The yellowish solid product was characterized by infrared spectroscopy to obtain the following data: IR 3461(s, OH stretch),1075(m, Pt-OH bend),539(m, Pt-N (O) stretch). The results confirmed that hydroxyplatine (Oxoplatin) which is an oxidation product of cisplatin was obtained.
100mg (0.3mmol) of hydroxyplatinum is dissolved in 2mL of DMF, and 164mg (0.9mmol) of veratric acid, 130. mu.L (0.9mmol) of triethylamine and 288mg (0.9mmol) of TBTU are sequentially added, and the mixture is stirred at normal temperature for 48 hours under nitrogen protection. Adding 20mL of ice water into the reaction solution to separate out a light yellow precipitate, dissolving the light yellow precipitate in methanol, and then carrying out silica gel column chromatography separation, wherein the eluent is a mixed solvent of dichloromethane and methanol, the volume ratio of the dichloromethane to the methanol is 20:1, and after elution, 81mg of light yellow solid product veratric platinum veratric acid is obtained.
Example 2
Refluxing 200mg (0.67mmol) of cisplatin and 0.35mL of hydrogen peroxide (the content of hydrogen peroxide is 30%) at 40 ℃ for 20 hours, standing the reaction solution at 0 ℃ after the reaction is finished to separate out a solid, centrifuging, collecting the solid, washing the solid twice by using distilled water, ethanol and diethyl ether in sequence, and drying to obtain 191mg of a light yellow solid product, wherein the yield is 85.3%.
100mg (0.3mmol) of hydroxyplatinum is dissolved in 2mL of DMF, and 164mg (0.9mmol) of veratric acid, 130. mu.L (0.9mmol) of triethylamine and 288mg (0.9mmol) of TBTU are sequentially added, and the mixture is stirred at normal temperature for 24 hours under nitrogen protection. Adding 20mL of ice water into the reaction solution to separate out a light yellow precipitate, dissolving the light yellow precipitate in methanol, and then carrying out silica gel column chromatography separation, wherein the eluent is a mixed solvent of dichloromethane and methanol, the volume ratio of the dichloromethane to the methanol is 20:1, and after elution, a light yellow solid product, namely veratric platinum (83 mg) veratric acid is obtained.
Example 3
Refluxing 200mg (0.67mmol) of cisplatin and 13.7mL of hydrogen peroxide (the content of hydrogen peroxide is 30%) at 100 ℃ for 1 hour, standing the reaction solution at 10 ℃ after the reaction is finished to separate out a solid, centrifuging, collecting the solid, washing the solid twice by using distilled water, ethanol and diethyl ether in sequence, and drying to obtain a light yellow solid product 188mg, wherein the yield is 84.0%.
100mg (0.3mmol) of hydroxyplatinum is dissolved in 2mL of DMF, and 164mg (0.9mmol) of veratric acid, 130. mu.L (0.9mmol) of triethylamine and 288mg (0.9mmol) of TBTU are sequentially added, and the mixture is stirred at normal temperature for 96 hours under the protection of nitrogen. And adding 20mL of ice water into the reaction solution to separate out a light yellow precipitate, dissolving the light yellow precipitate in methanol, and separating by silica gel column chromatography, wherein the eluent is a mixed solvent of dichloromethane and methanol, the volume ratio of the dichloromethane to the methanol is 20:1, and 80mg of light yellow solid product veratric platinum veratric acid is obtained after elution.
Identification of chemical structure of veratric acid tetravalent platinum by nuclear magnetic resonance hydrogen spectrum (1H-NMR)
About 3mg of veratric platinum prepared in example 1 was weighed, deuterated dimethyl sulfoxide (DMSO-d6) was dissolved and placed in a nuclear magnetic tube, a nuclear magnetic resonance hydrogen spectrum of the tube was measured by a 400MHz nuclear magnetic resonance hydrogen spectrum, tetramethylsilane was used as an internal standard, and a chemical shift value (ppm) of the compound was recorded. As shown in FIG. 1, the nuclear magnetic results of FIG. 1 confirmed that each peak was assigned to the newly synthesized purified molecule. The successful synthesis of veratric acid tetravalent platinum can be confirmed by a 1H-NMR spectrum.
Identification of veratric acid tetravalent platinum chemical structure by nuclear magnetic resonance carbon spectrum (C-NMR)
About 3mg of veratric platinum prepared in example 1 was weighed, and deuterated dimethyl sulfoxide (DMSO-d6) was dissolved and placed in a nuclear magnetic tube, and a nuclear magnetic resonance carbon spectrum was measured by a 101MHz nuclear magnetic resonance hydrogen spectrum, and a chemical shift value (ppm) of the compound was recorded. As shown in FIG. 2, the nuclear magnetic results of FIG. 2 confirmed that each peak was assigned to the newly synthesized purified molecule. The successful synthesis of veratric acid tetravalent platinum can be confirmed by C-NMR spectrum.
Identification of veratric acid tetravalent platinum chemical structure by Mass Spectrum (MS)
About 1mg of the veratric platinum prepared in example 1 was weighed, dissolved in methanol, and subjected to mass spectrometry. The results are shown in FIG. 3, and the mass spectrum result of FIG. 3 shows that the molecular ion peak [ M-H ] + (861.63) appears, which proves the success of the synthesis of veratric platinum.
Observation of in vitro anti-tumor effect of veratric acid tetravalent platinum
The method is completed by adopting an MTT method (tetramethylazoazolate colorimetric method), and five tumor cell strains of A549 (human non-small cell lung cancer cells), HeLa (human cervical cancer cells), MCF-7 (human breast cancer cells), Fadu (human pharyngeal squamous cells), 4T1 (mouse breast cancer cells) and MRC-5 (human embryonic lung fibroblast) normal cell strains are selected. Cells in the logarithmic growth phase were collected, adjusted for cell concentration, and seeded in 96-well plates (about 3000 cells/well) at 200. mu.L per well. The outermost peripheral edge wells of the 96-well plate were filled with sterile PBS to reduce the effect of edge effects. Cells were incubated at 37 ℃ with 5% CO2Culturing overnight under the condition, adding a compound with a concentration gradient when the cells adhere to the wall, and setting 3 multiple wells for each concentration. After 48 hours of action, 10. mu.L of 5mg/mL MTT was addedIncubation was continued for 4 hours. The culture broth was then discarded and 100 μ L DMSO was added per well to solubilize the formazan crystals. The absorbance A of each well was measured at 570nm in an ELISA detector. Three independent replicates were performed. IC50 was calculated and the results are shown in table 1:
table 1 shows that the tetravalent platinum complex prodrug with a veratric acid disubstituted axially prepared by the method of the present invention has significant inhibitory effects on the above five tumor cells, not only has better effects than cisplatin, but also is better than the combined administration form of cisplatin and veratric acid, and simultaneously has small killing effect on normal cells and good selectivity, which proves that the form of the prodrug formed by cisplatin and veratric acid is different from the pure combined administration form essentially. Veratric acid has certain anticancer activity, and can form a prodrug with platinum drug to kill cancer cells under synergistic action, improve the antitumor activity of the drug, and have better antitumor activity than cisplatin and veratric acid. The veratric acid tetravalent platinum is a novel high-efficiency anti-tumor drug, has a broad-spectrum anti-cancer effect, and is simple in preparation method, low in cost and easy for industrial production.
The above-described embodiments of the present invention should not be construed as limiting the scope of the present invention. Any other corresponding changes and modifications made according to the technical idea of the present invention should be included in the protection scope of the claims of the present invention.
Claims (10)
1. The veratric acid tetravalent platinum is characterized by having a structural formula shown as follows:
2. the method of preparing veratric platinum veratric acid of claim 1 comprising the steps of:
(1) synthesis of hydroxyplatinum: weighing cisplatin, slowly adding hydrogen peroxide, keeping out of the sun, heating and refluxing at 40-100 ℃ for 1-24h, standing at 0-10 ℃ for crystallization after reaction is finished, centrifuging, washing centrifuged solids twice with distilled water, ethanol and diethyl ether respectively, and drying to obtain light yellow solid hydroxyl platinum;
(2) synthesis of veratric acid tetravalent platinum: weighing the hydroxyl platinum, adding DMF (dimethyl formamide) for dissolving, sequentially adding veratric acid, triethylamine and TBTU, keeping out of the sun, protecting with nitrogen, stirring at normal temperature until a reaction solution is clear, adding ice water into the reaction solution, and separating out a yellow precipitate;
(3) purification of veratric acid tetravalent platinum: dissolving the yellow precipitate with methanol, purifying with silica gel column, and gradient eluting with mixed solution of dichloromethane and methanol to obtain yellow solid tetravalent platinum veratric acid.
3. The method for preparing tetravalent platinum veratric acid according to claim 2, wherein in the step (1), the molar ratio of the cisplatin to the hydrogen peroxide is 1: 5-200.
4. The method for preparing tetravalent platinum veratric acid according to claim 2, wherein the concentration of hydrogen peroxide in step (1) is 30% by mass.
5. The method of claim 2, wherein the heating and refluxing are carried out at 70 ℃ for 5 hours in step (1).
6. The method for preparing tetravalent platinum veratric acid according to claim 2, wherein the temperature of the crystallization in step (1) is 4 ℃.
7. The method for preparing tetravalent platinum veratric acid according to claim 2, wherein in the step (2), the ratio of the hydroxyl platinum: veratric acid: triethylamine: the TBTU molar ratio was 1:3:3: 3.
8. The method of claim 2, wherein in the step (2), the stirring time at room temperature is 12-96 hours.
9. The method for preparing tetravalent platinum veratric acid according to claim 2, wherein in the step (3), the volume ratio of the dichloromethane to the methanol is 20: 1.
10. An application of veratric acid tetravalent platinum in preparing anticancer and antitumor drugs is provided.
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