Hayallah Alaa M
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut-71526, Egypt.
Indian J Pharm Sci. 2014 Sep;76(5):387-400.
Cytohesins are small guanine nucleotide exchange factors that stimulate ADP ribosylation factors, Ras-like GTPases, which control various cellular regulatory networks ranging from vesicle trafficking to integrin activation. A small molecule SecinH3 (1,2,4-triazole derivative) in an aptamer displacement assay as a pan-cytohesin Sec7-domain inhibitor was previously identified. Here a series of different SecinH3-analogues was designed and synthesised as potential cytohesin Sec7-domain inhibitors. All final synthesized compounds 6-8, 43-58 and their intermediates were confirmed by (1)H NMR, (13)C NMR and high resolution Mass. Preliminary biological screening of target compounds indictaed that some of the new synthesized secinH3 derivatives showed higher potency and promising activity more than secinH3 itself (unpublished results). Compund 9 and 10 were approximate equal to secinH3 activity as cytohesin antagonist activity. Furthermore compound 52 showed twice inhibition potency if compared to secinH3.
细胞衔接蛋白是小分子鸟嘌呤核苷酸交换因子，可刺激ADP核糖基化因子（一种类Ras GTP酶），后者控制从囊泡运输到整合素激活等各种细胞调节网络。先前在适体置换试验中鉴定出一种小分子SecinH3（1,2,4-三唑衍生物）作为泛细胞衔接蛋白Sec7结构域抑制剂。在此，设计并合成了一系列不同的SecinH3类似物作为潜在的细胞衔接蛋白Sec7结构域抑制剂。所有最终合成的化合物6-8、43-58及其中间体均通过¹H NMR、¹³C NMR和高分辨率质谱进行了确认。对目标化合物的初步生物学筛选表明，一些新合成的SecinH3衍生物表现出比SecinH3本身更高的效力和有前景的活性（未发表结果）。化合物9和10作为细胞衔接蛋白拮抗剂的活性与SecinH3大致相当。此外，与SecinH3相比，化合物52的抑制效力提高了两倍。
