对BTK相关癌细胞具有抑制作用的CNX-774类似物的设计与合成

Design and synthesis of CNX-774 analogues as BTK-related cancer inhibitors

目的为进一步研究CNX-774及引入新共价交联基团的类似物在布鲁顿氏酪氨酸蛋白激酶(Bruton's tyrosine kinase,BTK)相关细胞上的生物活性,设计合成并筛选具有较好活性的化合物。方法通过酰胺缩合、羟醛缩合等策略得到CNX-774的类似物,在几种淋巴瘤和HeLa细胞系上进行活性评价。结果通过简单的修饰得到了新的CNX-774的类似物1~17,其结构经氢谱、碳谱和质谱确认。在IgE多发性骨髓瘤(IgE MM)上化合物1和3的抑制率大于CNX-774;在Ramos、HBL^(-1)和HeLa细胞上化合物1和3对Ramos的抑制活性较好;在HeLa细胞上化合物1和3展现出与CNX-774类似或较低的生物活性。结论化合物1和3在IgE MM、Ramos上都表现出不错的分子活性,在HeLa细胞上也表现出低毒的结果,表明化合物1和3可以作为潜在的治疗BTK相关淋巴瘤的抑制剂。分子对接的结果也一定程度上解释了类似物与BTK的相互作用。

Bruton＇s tyrosine kinase（BTK） plays an important role in the lymphoma cell lines. In order to im- prove the activities and explore the effects of warheads in different BTK-related cell lines, a series of analogues were obtained via simple modifications of CNX-774, a BTK inhibitor. All analogues were evaluated on IgE multiple myeloma cell line at 200 nmol. L - 1. Compounds 1 and 3 showed better inhibition than CNX- 774, and were further tested on Ramos, HBL-1 and HeLa cell lines. It was showed that compounds 1 and 3 were the most potential molecules. Compared to CNX-774, they showed more excellent inhibition to IgE MM and Ramos cell lines, and possessed similar or even lower cytotoxicity in HeLa cell line. Compounds 1 and 3 would be valuable covalent molecules for treatment of BTK-related lymphomas. The docking results could explain their good activity.