Novel platinum(IV) complexes conjugated with a wogonin derivative as multi-targeted anticancer agents

摘要

Platinum-based complexes like cisplatin and oxaliplatin are well known the mainstay of chemotherapy regimens on clinic. Wogonin, a natural product that possesses wide biological activities, is now in phase I clinical test as an anticancer agent in China. Herein reported are a series of novel Pt(IV) complexes that conjugated a wogonin derivative (compound 3) to the axial position via a linker group. After being tethered to the platinum(IV) complexes, the wogonin derivative provided multiple anticancer effects, especially in compound 10, a fusion containing wogonin and cisplatin units. Compound 10 not only inherited the genotoxicity from cisplatin, but also obtained the COX inhibitory property from the wogonin derivative. Further mechanistic investigation revealed that compound 10 caused the accumulation of ROS, decreased the mitochondrial membrane potential (Delta Psi m,) and then activated the p53 pathway. Overall, the research demonstrates that the "integrative" prodrug can be an effective strategy to promote the anticancer potency of Pt-based drugs for cancer treatment. (C) 2017 Elsevier Ltd. All rights reserved.