Carbon monoxide is a endogenous signaling molecule with therapeutic potentials. Among CO’s therapeutic indications, cancer, bacterial infection and inflammation are the most widely investigated, and CO has been firmly established as a promising therapeutic agent against these diseases. Notably, these diseases are all associated with elevated levels of reactive oxygen species (ROS). Thus, ROS-sensitive CO prodrugs are highly desired. In this work, we have designed and synthesized two ROS-sensitive prodrugs containing a phenylselenyl group, which is prone to ROS oxidation and the formed selenoxide analogue readily undergoes syn-elimination leading to an intermediate for the subsequent cheletropic reaction to release CO. The sensitivity study of such prodrugs to different ROS species shows that they are sensitive toward hypochlorite (ClO-), singlet oxygen (1O2) and O2−. We have demonstrated that such CO prodrugs can selectively delivery CO to cells with elevated ROS levels (e.g. cancer cells and cells with activated inflammatory responses). Additionally, such CO prodrugs also sensitized cancer cells to Dox treatment, which could potentially reduce the dosage of Dox used, and thereby alleviate Dox-related side effects. In summary, CO prodrugs as such could serve as powerful tools for targeted delivery to disease sites with elevated ROS levels and for exploring the therapeutic applications of CO.

Organic CO prodrugs activated by endogenous ROS

255th National Meeting (2018)

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