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

Xiaodong Qin; Gang Xu; Feihong Chen; Lei Fang; Shaohua Gou

doi:10.1016/j.bmc.2017.03.007

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

Bioorg Med Chem. 2017 Apr 15;25(8):2507-2517. doi: 10.1016/j.bmc.2017.03.007. Epub 2017 Mar 7.

Authors

Xiaodong Qin¹, Gang Xu², Feihong Chen², Lei Fang³, Shaohua Gou⁴

Affiliations

¹ Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
² Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
³ Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China. Electronic address: lei.fang@seu.edu.cn.
⁴ Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China. Electronic address: sgou@seu.edu.cn.

PMID: 28314511
DOI: 10.1016/j.bmc.2017.03.007

Abstract

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 (ΔΨ_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.

Keywords: COX; Mitochondrial membrane potential; Pt(IV) prodrug; ROS; Wogonin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cyclooxygenase Inhibitors / pharmacology
DNA Damage
Flavanones / chemistry*
Flavanones / pharmacology
Humans
Platinum Compounds / chemistry*
Platinum Compounds / pharmacology
Reactive Oxygen Species / metabolism

Substances

Antineoplastic Agents
Cyclooxygenase Inhibitors
Flavanones
Platinum Compounds
Reactive Oxygen Species
wogonin