关键词: 真菌环氧二烯(MED); 热休克蛋白90(Hsp90); 客户蛋白质; Akt; 抗肿瘤活性

Abstract:

Antitumor lead compound mycoepoxydiene(MED) was isolated from marine fungus in the year of 2002, but till now the mechanism of MED against cancer is still unclearly. Heat shock protein 90(Hsp90) has emerged in recent years as a promising new target for anticancer therapies, owing to a lot of tumorigenesis relative client proteins need the help of Hsp90 for folding and keeping stable. The experiment of denatural luciferase renature showed that MED is a potential inhibitor of Hsp90, which stimuli us to perform the research for MED both as a novel inhibitor of Hsp90 and the antitumor leading compound. The nicotinoid derivatives of MED(NDM) was designed based on the structure of MED and the prediction of molecular docking program. MTT assay showed that nicotinoid derivate 4-NDM exhibited antitumor activity against HeLa cells in vitro with IC₅₀ 4.7 μmol/L. The derivate 4-NDM also can induce deregulation of the client protein Akt, Raf-1 and P-Akt, when treated HeLa cell with the compound, just as MED done. Compare with MED, 4-NDM not only showed stronger antitumor activity, but also exhibited higher affinity for Hsp90. The results illustrate that MED and its nicotinoid derivatives may be target for Hsp90 as the inhibitor has antitumor activity.

Key words: Mycoepoxydiene; Heat shock protein 90; Client protein; Akt; Antitumor activity