Bioreduction activated prodrugs of camptothecin: molecular design, synthesis, activation mechanism and hypoxia selective cytotoxicity

Several water- soluble derivatives (CPT3, CPT3a-d) of camptothecin (CPT) were synthesized, among which CPT3 bearing an N, N '-dimethyl-1-aminoethylcarbamate side- chain was further conjugated with reductively eliminating structural units of indolequinone, 4-nitrobenzyl alcohol and 4- nitrofuryl alcohol to produce novel prodrugs of camptothecin (CPT4-6). All CPT derivatives were of lower cytotoxicity than their parent compound of CPT. In contrast, CPT4 and CPT6 showed higher hypoxia selectivity of cytotoxicity towards tumor cells than CPT. A mechanism by which a representative prodrug CPT4 is activated in the presence of DT- diaphorase to release CPT was also discussed. The bioreduction activated CPT prodrugs including CPT4 and CPT6 are identified to be promising for application to the hypoxia targeting tumor chemotherapy.