Integration of a Diselenide Unit Generates Fluorogenic Camptothecin Prodrugs with Improved Cytotoxicity to Cancer Cells

A diselenide/disulfide unit was introduced into camptothecin (CPT), and two selenoprodrugs (e.g., CPT & minus;Se3 and CPT & minus;Se4) were identifiedto show improved potency in killing cancer cells and inhibiting tumor growthinvivo. Interestingly, the intrinsicfluorescence of CPT was severely quenched by thediselenide bond. Both the selenoprodrugs were activated by glutathione with anearly complete recovery of CPT & rsquo;sfluorescence. The activation of prodrugs wasaccompanied by the production of selenol intermediates, which catalyzed theconstant conversion of glutathione and oxygen to oxidized glutathione andsuperoxides. The diselenide unit is widely employed in constructing thiol-responsive materials. However, the selenol intermediates were largely ignored inthe activation process prior to this study. Our work verified that integration of thediselenide unit may further enhance the parent drug & rsquo;sefficacy. Also, the discoveryof thefluorescence quenching property of the diselenide/disulfide bond furthershed light on constructing novel theranostic agents