Design synthesis and potent cytotoxic activity of novel 7-(N-(substituted-sulfonyl)piperazinyl-methyl)-camptothecin derivatives

摘要

In an effort to discover potent camptothecin-derived antitumor agents, novel camptothecin analogues with sulfonylpiperazinyl motifs at position-7 were designed and synthesized. They were evaluated for in vitro cytotoxicity with the sulforhodamine-B (SRB) method in five types of human tumor cell lines, A-549, MDA-MB-231, KB, KB-VIN and MCF-7. With IC50 values in the low μM to nM level, most of the new analogues showed greater cytotoxicity activity than the reference compounds irinotecan and topotecan. Furthermore, compounds >12l (IC50, 1.2 nM) and >12k (IC50, 20.2 nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that integration of sulfonylpiperazinyl motifs into position-7 of camptothecin is an effective strategy for discovering new potent cytotoxic camptothecin derivatives.