CN-122011040-A - Tetravalent platinum rhein conjugate and preparation method thereof

Abstract

The invention relates to the technical field of biological medicines, and particularly discloses a tetravalent platinic rhein conjugate and a preparation method thereof, wherein the tetravalent platinic rhein conjugate has a structure shown in the following formula I or formula II: The preparation method comprises the steps of oxidizing a bivalent platinum drug by H 2 O 2 to obtain an oxidation intermediate, reacting the oxidation intermediate with rhein in a solvent in the presence of a condensing agent and an organic base under the protection of inert atmosphere and under mild reaction conditions, and separating and purifying to obtain the tetravalent platinum rhein conjugate. The tetravalent platinic rhein conjugate is a novel asymmetric monosubstituted conjugate with a definite structure, and the preparation method is mild in condition, high in selectivity, simple and convenient to operate and suitable for industrial production.

Inventors

• LI YULIANG
• ZHAI XIAOFANG
• LIU BIN
• LU GANG
• YE FENG
• XU MINGZE

Assignees

• 山东大学齐鲁第二医院

Dates

Publication Date

20260512

Application Date

20260127

Claims (10)

1. 1. A tetravalent platinic rhein conjugate, characterized in that the tetravalent platinic rhein conjugate has a structure represented by the following formula I or formula II: 、 。
2. 2. a method for preparing a tetravalent platinic rhein conjugate according to claim 1, comprising the steps of: S1, oxidizing a bivalent platinum drug by H 2 O 2 to obtain an oxidation intermediate; s2, under the protection of inert atmosphere, the oxidation intermediate reacts with rhein in the presence of a condensing agent and organic base in a solvent, and then the tetravalent platinum rhein conjugate is obtained through separation and purification.
3. 3. The method for preparing tetravalent platinum rhein conjugate according to claim 2, wherein the bivalent platinum drug in step S1 is oxaliplatin or cisplatin.
4. 4. The method for preparing tetravalent platinum rhein conjugate according to claim 3, wherein the mass ratio of divalent platinum drug to H 2 O 2 in step S1 is 1:15-25.
5. 5. The method for preparing tetravalent platinum rhein conjugate according to claim 2, wherein the oxidation temperature in step S1 is 60-75 ℃ and the oxidation time is 5-12h.
6. 6. The method for preparing tetravalent platinum rhein conjugate according to claim 2, wherein the condensing agent in the step S2 is TBTU, the organic base is triethylamine, and the solvent is N, N-dimethylformamide or dimethyl sulfoxide.
7. 7. The method for preparing tetravalent platinum rhein conjugate according to claim 2, wherein the reaction temperature in step S2 is 10-40 ℃ and the reaction time is 12-48h.
8. 8. The method for preparing tetravalent platinum rhein conjugate according to claim 6, wherein in step S2, the molar ratio of oxidation intermediate to rhein is 1:1.2-1.8, the molar ratio of oxidation intermediate to triethylamine is 1:1.5-2, and the molar ratio of oxidation intermediate to TBTU is 1:1.5-2.
9. 9. The method for preparing tetravalent platinum rhein conjugate according to claim 3, wherein the separation and purification step in step S2 comprises the steps of precipitating the reaction solution with diethyl ether, filtering to collect precipitate I, dissolving precipitate I in saturated sodium bicarbonate solution for washing, filtering to collect precipitate II, and subjecting precipitate II to silica gel column chromatography to obtain the target product.
10. 10. The preparation method of the tetravalent platinum rhein conjugate according to claim 9, wherein in the step S2, the volume ratio of dichloromethane to methanol in the eluent of the compound of formula I as the target product is 20:1, and the volume ratio of dichloromethane to methanol in the eluent of the compound of formula II as the target product is 30:1.

Description

Tetravalent platinum rhein conjugate and preparation method thereof Technical Field The invention relates to the technical field of biological medicine, in particular to a tetravalent platinum rhein conjugate and a preparation method thereof. Background The platinum medicine is one of the most widely used anticancer medicines in clinic, and the platinum medicine commonly used in clinic at present mainly comprises five kinds of cisplatin, carboplatin, nedaplatin, oxaliplatin and lobaplatin. However, the platinum drugs are bivalent platinum Pt (II) compounds, have relatively active chemical properties in organisms, are easy to be combined with biomolecules such as plasma proteins in a non-specific way, cause relatively strong toxic and side effects (such as nephrotoxicity, neurotoxicity and the like), and are easy to generate drug resistance after long-term use. In order to overcome the defects of strong toxic and side effects and easy drug resistance of the traditional bivalent platinum drugs, development of tetravalent platinum Pt (IV) prodrugs with octahedral configuration and stable kinetic properties has become a research hotspot. By introducing bioactive ligands at two axial positions of Pt (IV) center, a synergistic anticancer drug with multiple pharmacological activities can be constructed. Rhein has been used as a natural product with antitumor activity to construct Pt (IV) prodrugs. For example, chinese patent No. CN110950915B discloses a novel rhein-platinum (IV) precursor anticancer complex, and its synthesis method and application. The technical proposal of the patent is that cisplatin hydroxide and twice molar amount of rhein are heated and reacted in an acetic acid system at high temperature (120 ℃ for example) for a long time to prepare a double-substituted conjugate with symmetrical structure, wherein the two axial positions of the double-substituted conjugate are substituted by rhein. The double substituent has been proved to have good inhibitory activity on cisplatin-resistant lung adenocarcinoma cells. However, the preparation method adopted by the technical scheme disclosed in the patent is a high-temperature heat condensation method, the reaction conditions are relatively severe, and the method is mainly suitable for preparing symmetrical disubstituted products. No technical suggestion is provided as to how to obtain other possible substitution patterns selectively under mild conditions. Based on the above statement, the invention provides a tetravalent platinic rhein conjugate and a preparation method thereof. Disclosure of Invention The invention provides a tetravalent platinum rhein conjugate and a preparation method thereof, aiming at solving the problems that the preparation of the tetravalent platinum rhein conjugate in the prior art adopts a high-temperature heat condensation method, has severe reaction conditions, is mainly suitable for preparing symmetrical double-substituted products, cannot obtain other possible substituted forms and the like. In a first aspect, the invention provides a tetravalent platinum rhein conjugate, which adopts the following technical scheme: A tetravalent platinic rhein conjugate having the structure of formula I or formula II: 、。 In a second aspect, the invention provides a preparation method of tetravalent platinum rhein conjugate, which adopts the following technical scheme: A method for preparing tetravalent platinic rhein conjugate, comprising the following steps: S1, oxidizing a bivalent platinum drug by H 2O2 to obtain an oxidation intermediate; s2, under the protection of inert atmosphere, the oxidation intermediate reacts with rhein in the presence of a condensing agent and organic base in a solvent, and then the tetravalent platinum rhein conjugate is obtained through separation and purification. Preferably, the bivalent platinum drug in the step S1 is oxaliplatin or cisplatin. Preferably, the mass ratio of the bivalent platinum drug to the H 2O2 in the step S1 is 1:15-25. Preferably, the temperature of the oxidation in the step S1 is 60-75 ℃ and the oxidation time is 5-12h. Preferably, the condensing agent in step S2 is O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU). Preferably, the organic base triethylamine in the step S2. Preferably, the solvent in the step S2 is N, N-dimethylformamide or dimethyl sulfoxide. Preferably, the reaction temperature in the step S2 is 10-40 ℃ and the reaction time is 12-48h. Preferably, the molar ratio of the oxidation intermediate to rhein in the step S2 is 1:1.2-1.8. Preferably, the molar ratio of the oxidation intermediate to the triethylamine in the step S2 is 1:1.5-2. Preferably, the molar ratio of the oxidation intermediate to TBTU in step S2 is from 1:1.5 to 2. Preferably, the separation and purification step in the step S2 comprises the steps of precipitating the reaction solution with diethyl ether, filtering and collecting the precipitate I, dissolving the precipi