纺锤体驱动蛋白抑制剂的设计、合成与生物活性研究

纺锤体驱动蛋白(kinesin spindle protein, KSP/Eg5)作为潜在的肿瘤治疗靶点, 使发现KSP抑制剂成为热点. 设计并合成了4-氧基-β-四氢咔啉衍生物作为新型的KSP抑制剂, 并测定了其对KSP的抑制活性, 均优于阳性对照物. 其中化合物9c抑制KSP的IC50＝0.065 μmol•L－1, 优于阳性对照物Monastro l100多倍. 生物活性研究表明为抗肿瘤药物提供了新结构类型的候选化合物.

Design, Synthesis and Biological Evaluation of Novel KSP Inhibitors

The kinesin spindle protein (KSP/Eg5) is a potential target in cancer therapy.It, which has attracted great interest in discovery of compounds that inhibit KSP. Here, a series of 4-oxo-tetrahydro-β-carline derivatives 9a～94f have been designed and synthesized as a novel class of KSP inhibitor. The synthesized compounds were, and evaluated for their inhibition of aganist KSP. All compounds inhibited ATPase activity with IC50 below that of the analog Monastrol. 9c has an IC50＝0.065 μmol•L－1 for inhibition of KSP, ＞100-fold more active than Monastrol. The research results provide new candidate molecules for study of anticancer drugs.