School of Pharmaceutical Sciences, Guizhou University, Guiyang, China.
Guizhou Engineering Laboratory for Synthetic Drugs, Guiyang, China.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):2170-2182. doi: 10.1080/14756366.2021.1986491.
A novel series of triazoloquinazolinone derivatives were designed, synthesised, and evaluated for their biological activities against the SHP2 protein. Moreover, some compounds were evaluated against A375 cells. The results revealed that target compounds possessed moderate to excellent inhibitory activity against SHP2 protein, whereas compounds , , , , and have strong antiproliferative activity on A375 cells. The compound showed remarkable cytotoxicity against A375 cells and a strong inhibitory effect against SHP2 protein when compared with . The structure-activity relationships (SARs) indicated that electron-donating groups (EDGs) on phenyl rings are beneficial for improving the antitumor activity; compounds with a hydroxyl substituent at the 2-position of phenyl ring exhibited superior activities than compounds with a substituent at the 4-position. In addition, compound displayed improved physicochemical properties as well as metabolic stability compared to . Our efforts identified as a promising SHP2 protein inhibitor, warranting its further investigation.
我们设计、合成了一系列新型的三唑并喹唑啉酮衍生物，并对它们的生物活性进行了评估，以研究它们对 SHP2 蛋白的抑制作用。此外，我们还评估了一些化合物对 A375 细胞的抑制作用。结果表明，目标化合物对 SHP2 蛋白具有中等至优异的抑制活性，而化合物 、 、 、 、 对 A375 细胞具有较强的增殖抑制活性。与 相比，化合物 对 A375 细胞表现出显著的细胞毒性和对 SHP2 蛋白的强烈抑制作用。构效关系（SARs）表明，苯环上的供电子基团（EDGs）有利于提高抗肿瘤活性；苯环 2-位取代的化合物比 4-位取代的化合物具有更高的活性。此外，与 相比，化合物 表现出更好的理化性质和代谢稳定性。我们的努力确定 是一种很有前途的 SHP2 蛋白抑制剂，值得进一步研究。
