Antitumor Agents 268. Design Synthesis and Mechanistic Studies of New 9-Substituted Phenanthrene-based Tylophorine Analogs as Potent Cytotoxic Agents

摘要

Nineteen new phenanthrene-based tylophorine analogs with various functional groups on the piperidine moiety were designed, synthesized and evaluated for in vitro anticancer activity against four human tumor cell lines. Analogs >15 and >21 showed approximately two-fold enhanced inhibitory activity as compared with our prior lead compound (PBT-1). Analogs >23 and >24 with S- and R-configured substituents, respectively, at the piperidine 3’-position exhibited comparable cytotoxicity to that of PBT-1. Furthermore, mechanistic studies to investigate the effects of the new compounds on Akt protein in lung cancer cells and the NF-kB signaling pathway suggested that the compounds may exert their inhibitory activity on tumor cells through inhibition of activation of both Akt and NF-kB signaling pathway.