基于抗肿瘤活性化合物MED烟酸类衍生物的设计及作用靶点

Probing Target and Designing Nicotinoid Derivatives for Antitumor Leading Compound MED

通过变性荧光素酶的再复性实验发现真菌环氧二烯(Mycoepoxydiene,MED)对热休克蛋白(Heat shock protein 90,Hsp90)具有抑制作用.Western Blot实验结果表明,MED影响人宫颈癌细胞株HeLa中Hsp70及Hsp90的客户蛋白质(Akt,Raf-1)的表达,表明MED是Hsp90的抑制剂.通过靶向对接技术预测了MED与人Hsp90 N端ATP结合位点的结合情况,并在此基础上发现,MED的烟酸类衍生物4-NDM与Hsp90的结合具有比MED与Hsp90更强的亲和作用.体外实验结果证明,MED的烟酸类衍生物4-NDM及3-NDM对HeLa细胞表现出比MED更强的细胞毒活性;可通过上调Hsp70,并下调Akt和Raf-1而影响HeLa细胞中Hsp90相关蛋白质的表达.由此推测,MED及其烟酸类衍生物可以通过抑制Hsp90,而使其客户蛋白Akt或Raf-1发生降解,发挥其抗肿瘤作用.

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 lucife-rase 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.