CN-122011041-A - Tetravalent platinum rhein conjugate and application thereof in preparation of anticancer drugs

Abstract

The invention belongs to the technical field of biological medicines, and particularly discloses a tetravalent platinum rhein conjugate and application thereof in preparation of anticancer drugs, wherein the tetravalent platinum rhein conjugate has a structure shown in the following formula I or formula II: . As shown by pharmacodynamic experiments, compared with the existing platinum drugs, rhein, the combination of the two drugs and the structural analogues, the tetravalent platinum rhein conjugate of the invention has unexpectedly strong inhibitory activity on various solid tumor cells, especially human pancreatic cancer cells MIAPaca-2. Animal in vivo experiments further prove that the composition has excellent tumor inhibition effect and good safety. The invention provides a candidate compound with great potential for developing a new generation of high-efficiency low-toxicity anticancer drugs, in particular to an anti-pancreatic cancer drug.

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 (8)

1. 1. Application of tetravalent platinum rhein conjugate in preparing anticancer medicine is provided.
2. 2. The use of a tetravalent platinum rhein conjugate according to claim 1 for the preparation of an anticancer drug, wherein the tetravalent platinum rhein conjugate has the structure represented by the following formula I or formula II: 。
3. 3. the use of a tetravalent platinum rhein conjugate according to claim 1 for the preparation of an anticancer drug, wherein the anticancer drug is an anti-solid tumor drug.
4. 4. Use of a tetravalent platinic rhein conjugate according to claim 3 for the preparation of an anticancer drug, wherein the solid tumor is pancreatic cancer, lung cancer, breast cancer or colon cancer.
5. 5. The use of a tetravalent platinum rhein conjugate according to claim 4 for the preparation of an anticancer drug, wherein said solid tumor is pancreatic cancer.
6. 6. Use of a tetravalent platinum rhein conjugate according to claim 3 for the preparation of an anticancer drug, wherein said anticancer drug further comprises pharmaceutically acceptable excipients.
7. 7. The use of tetravalent platinum rhein conjugate according to claim 6 for the preparation of anticancer drugs, wherein the adjuvant is carrier, solvent or/and excipient.
8. 8. The use of tetravalent platinum rhein conjugate according to claim 3 for preparing anticancer drugs, wherein the dosage form of the anticancer drugs is injection, tablet, capsule or powder injection.

Description

Tetravalent platinum rhein conjugate and application thereof in preparation of anticancer drugs Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to a tetravalent platinum rhein conjugate and application thereof in preparation of anticancer drugs. Background Pancreatic cancer is a digestive system tumor with extremely high malignancy, has hidden onset, rapid progress, extremely poor prognosis and survival rate of less than 10% in 5 years, and is one of the most challenging cancer species in the current clinical treatment. Platinum-based chemotherapeutic drugs represented by cisplatin are first-line drugs for treating various solid tumors, but single drugs in pancreatic cancer treatment have limited curative effects and are often accompanied with serious toxic and side effects and drug resistance problems. Rhein is a key active ingredient derived from traditional Chinese medicinal materials such as rheum palmatum and polygonum cuspidatum, and belongs to anthraquinone compounds. Research shows that the compound has various biological activities such as anti-inflammatory, antioxidant and anticancer, and has certain potential in the aspect of pancreatic cancer resistance. In order to improve the efficacy and reduce toxicity of platinum-based chemotherapeutic agents, researchers have tried a variety of strategies. One such combination is, for example, the combination of a platinum-based drug with other natural products having anti-cancer activity (e.g., rhein). However, simple physical mixing often makes it difficult to produce a synergistic effect of "1+1>2", and the pharmacokinetic behavior of the two drugs in vivo is different, making it difficult to ensure simultaneous arrival at the tumor site for action. The other is to construct a prodrug conjugate, where two active molecules are linked by chemical bonds into a single entity. In recent years, there have been some reports on conjugates of tetravalent platinum with rhein. For example, literature (Dalton trans 2020, 49:1613-1619) reports a symmetrical compound of cisplatin coupled to two molecules of rhein (denoted cp_2r). Literature (Dalton trans.,2022, 51:6014-6026) reports an asymmetric compound (denoted cpr_ac) of cisplatin coupled with one molecule of rhein and one molecule of acetic acid. However, these known conjugates have limited data on anti-pancreatic cancer activity and their activity does not show breakthrough advantages. In view of the above, although there have been attempts to couple platinum to rhein, the prior art has failed to provide a novel compound that exhibits significantly better therapeutic effects on solid tumors such as pancreatic cancer than existing drugs and known analogues. Thus, there is a strong need in the art for a novel platinum-rhein conjugate that truly has potent anti-cancer activity, particularly potent anti-pancreatic cancer activity. Based on the above statement, the invention provides a tetravalent platinum rhein conjugate and application thereof in preparation of anticancer drugs. Disclosure of Invention In order to solve the problems that in the prior art, although platinum and rhein are coupled, a novel compound which shows a treatment effect which is remarkably superior to that of the existing medicines and known analogues on solid tumors such as pancreatic cancer and the like cannot be provided, the invention provides a tetravalent platinum rhein conjugate and application thereof in preparation of anticancer medicines. 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: 。 preferably, the tetravalent platinic rhein conjugate is prepared by the following method: 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 in the step S2 is triethylamine. 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 interm