Novel platinum(IV) complexes conjugated with a wogonin derivative as multi-targeted anticancer agents.
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 (ΔΨm) 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.
Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
Xiaodong
X
Qin
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.
Gang
G
Xu
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.
Feihong
F
Chen
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.
Lei
L
Fang
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.
Shaohua
S
Gou
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004249:DNA Damage; D044950:Flavanones / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D017671:Platinum Compounds / Q000737:chemistry* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D016861:Cyclooxygenase Inhibitors; D044950:Flavanones; D017671:Platinum Compounds; D017382:Reactive Oxygen Species; C085514:wogonin
COX; Mitochondrial membrane potential; Pt(IV) prodrug; ROS; Wogonin