Synthesis and preliminary bioevaluation of novel E-ring modified acetal analog of camptothecin as cytotoxic agents

In an effort to improve the metabolic stability of the E-ring and decrease the toxicity of camptothecin (CPT), a novel cytotoxic acetal analog with 21-alkoxy groups was designed and synthesized. The preliminary results revealed that this class of compounds showed superior antiproliferative activity in vitro and moderate in vivo activity, while their Topoisomerase I (Topo I) inhibitory activity was weakened significantly. The implications of these results within the current understanding of the structure-activity relationship of camptothecin are analyzed in detail. The obtained information provides insight into the role of the 21-carbonyl group in the binding of CPT to Topo I-DNA complex.