We propose to design, synthesize and evaluate novel CPTs for the treatment of cancer. Extensive investigations on CPTs, specific topoisomerase I inhibitors, have led to the FDA approval of two water-soluble derivatives of CPT. However, under physiological conditions, the intrinsic instability of their active lactone structures remains to be resolved. ENDs represent another promising type of topoisomerase I inhibitors. While these two series of compounds appear to share similar inhibitory mechanism and common structural features, INDs intercalate DNA with high affinity and CPTs are weak DNA binders. Aided by modeling analysis, we hypothesize that CPT binds with the DNA-topoisomerase I complex in a very similar mode as IND, and that the weak DNA binding affinity of CPTs could be improved by introducing potential DNA groove binding moieties at the C and D rings, by mimicking INDS Accordingly, we have designed and propose to synthesize novel CPTs and evaluate the compounds for inhibition of human topoisomerase I, lactone stability, DNA binding and in vitro anticancer activities. In Phase II, we will optimize the leads identified in Phase I and conduct in vivo anticancer studies in animal models. The overall goal is to develop novel highly efficacious CPT-related compounds. PROPOSED COMMERCIAL APPLICATION: Two inhibitors of topoisomerase I (topotacen anc CPT-11) have been approved as anticancer agents. Several other compounds are under Phase I/II clinical investigation. With acceptable pharmacokinetic and toxicological profiles, new anticancer agents could find enormous commercial applications, and provide alternative therapeutical management for patients resistant to existing anticancer drugs.
