Synthesis,Characterization And Antitumor Activity Of Platinum (Ⅳ) Complexes Containing Cannabidiol Active Group

Platinum-based chemotherapeutic agents are currently utilized extensively in the treatment of solid neoplasms.Despite their considerable success in terms of clinical efficacy,the administration of these agents is associated with severe adverse effects and the development of drug resistance.Platinum(Ⅳ)complexes offer a significant advantage in addressing these limitations.The introduction of functional or biologically active ligands at axial positions can confer novel physicochemical properties and biological characteristics to platinum-based drugs.In addition to its potent antiproliferative and pro-apoptotic effects across a range of tumor cell types,cannabidiol can also inhibit drug-resistant mediators through the activation of specific signaling pathways,thereby overcoming cancer cell resistance and ameliorating chemotherapyinduced side effects such as pain,nausea,vomiting and organ toxicity.Leveraging the favorable structure-activity relationship of Pt(IV)complexes and the potent pharmacological activity of CBD,this study reports the design and synthesis of two classes of Pt(IV)antitumor complexes containing CBD,designated C1-C6 and O1-O3.Initially,two types of Pt(IV)intermediates were synthesized using satraplatin and oxaliplatin as precursors.Subsequently,CBD was introduced at one axial position of the intermediates to confer optimal pharmacological activity to the target Pt(IV)complexes.At the other axial position,hydroxyl groups,chloride ions or acetate groups were introduced to facilitate cellular uptake of the Pt(IV)complexes.The structure of the target Pt(IV)complexes were characterized using techniques such as hydrogen nuclear magnetic resonance spectroscopy,high-resolution mass spectrometry and infrared spectroscopy.Based on the high lipophilicity of CBD and the kinetic inertness of platinum(IV)complexes,the platinum(IV)complexes containing cannabidiol active groups exhibit reasonable lipophilicity and high stability,with their decomposition rate of approximately 10% within 48 hours.HR-MS monitoring of the reduction process of the target Pt(Ⅳ)complexes under simulated in vitro conditions confirmed the effective release of CBD.In vitro antitumor activity studies demonstrated that satraplatin-derived complexes C1-C3 displayed significant cytotoxicity,with complex C3 exhibiting the most potent activity.Its cytotoxicity in HCT-116 cells was 9.5 times that of cisplatin,4.5 times that of satraplatin and 6.8 times that of oxaliplatin.Among the oxaliplatinderived complexes,O3 displayed the most pronounced activity,demonstrating 2.6times stronger cytotoxic activity than oxaliplatin in HCT-116 cells.The synthesized novel Pt(IV)complexes exhibited significantly higher cytotoxic activity against cancer cells than normal cells,indicating their selectivity for cancer cells.This demonstrates that CBD can synergistically enhance the antitumor activity of platinum drugs while reducing their toxic side effects to some extent.Furthermore,the apoptosis rate of HCT-116 cells induced by C3 and O3 complexes was approximately twice that of oxaliplatin,and mitochondrial dysfunction caused by large amount of intracellular ROS production and decreased mitochondrial membrane potential was one of the mechanisms inducing cell apoptosis.In summary,the strategy of combining cannabidiol with platinum drugs not only effectively enhances the cytotoxic activity of chemotherapy drugs,but also improves their toxic and side effects to a certain extent through improved selectivity for cancer cells.This approach provides a novel direction for the development of clinical chemotherapy drugs.