Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA.
J Med Chem. 2009 Aug 27;52(16):5262-8. doi: 10.1021/jm9009263.
Nineteen new phenanthrene-based tylophorine analogues with various functional groups on the piperidine moiety were designed, synthesized, and evaluated for in vitro anticancer activity against four human tumor cell lines. Analogues 15 and 21 showed approximately 2-fold enhanced inhibitory activity as compared with our prior lead compound (PBT-1). Analogues 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.
设计、合成了 19 种新型基于菲的喜树碱类似物，哌啶部分带有各种功能基团，并评估了它们对四种人肿瘤细胞系的体外抗癌活性。与我们之前的先导化合物 (PBT-1) 相比，类似物 15 和 21 的抑制活性增强了约 2 倍。哌啶 3'-位具有 S-和 R-构型取代基的类似物 23 和 24 的细胞毒性与 PBT-1 相当。此外，研究这些新化合物对肺癌细胞中 Akt 蛋白和 NF-κB 信号通路影响的机制研究表明，这些化合物可能通过抑制 Akt 和 NF-κB 信号通路的激活来发挥其对肿瘤细胞的抑制活性。
