摘要
Glutathione depletion provides a promising strategy for the design of non-platinum anticancer drugs.Here we report a series of electrophilic (salen)osmium(Ⅵ) nitrides that react with glutathione to generate (salen)osmium(Ⅲ) ammine compounds.In vitro studies indicate that these osmium(VI) nitrides show comparable cytotoxicity to cisplatin against various carcinoma.Mechanistic studies with the representative compound[OsⅥ(N)(LH)(OH_(2))](PF6)(1,LH=N,N’-bis(salicylidene)-o-cyclohexyldiamine dianion) suggest that 1 induces glutathione depletion,reactive oxygen species generation,endoplasmic reticulum stress,and in turn triggers death receptor-mediated apoptosis and autophagy in lung cancer cells.In vivo evaluations show that 1 can inhibit tumor xenograft growth effectively with no body weight drop.
基金
financially supported by the Guangdong Major Project of Basic and Applied Basic Research(No.2019B030302009)
the National Natural Science Foundation of China(No.21401125)
the Li Ka Shing Foundation Cross-Disciplinary Research Grant(No.2020LKSFG01F)
Research Grants Council of Hong Kong(No.HKBU 12300121)
Hong Kong Baptist University for the start-up fund(No.RC-OFSGT2/20-21/SCI/008)
supported by"Laboratory for Synthetic Chemistry and Chemical Biology"under the Health@Inno HK Program launched by Innovation and Technology Commission,The Government of Hong Kong Special Administrative Region of the People’s Republic of China。
