Structure-Activity Relationship Studies of the Natural Product Gq/11 Protein Inhibitor YM-254890

G proteins act as molecular switches in G protein-coupled receptor signaling pathways and are key mediators for numerous important physiological processes. The natural product, cyclic depsipeptide YM-254890, together with the structurally similar FR900359, is the only known selective inhibitor of the G(q/11) subfamily of G proteins. We recently reported the first total synthesis of YM-254890 and FR900359, followed by synthesizing analogues to perform structure-activity relationship studies. However, incomplete information about their structure-activity relationship prevents the further development of potent and structurally simplified analogues. Herein we report the first systematic structure-activity relationship study toward the N-methyldehydroalanine moiety in YM-254890, by designing and synthesizing seven new analogues. Pharmacological characterization of the seven compounds for G(q/11)-, G(i/o)- and G(s)-mediated signaling showed that the simplified analogue YM-19 is the most potent G(q/11)inhibitor among the new analogues. This study provides information for the future design of potent and simplified YM-254890 analogues.

G蛋白在G蛋白偶联受体信号通路中充当分子开关，是众多重要生理过程的关键介质。天然产物环缩肽YM - 254890以及结构相似的FR900359是已知唯一对G蛋白的G(q/11)亚家族具有选择性的抑制剂。我们最近报道了YM - 254890和FR900359的首次全合成，随后合成了类似物以进行构效关系研究。然而，关于它们构效关系的信息不完整，阻碍了强效且结构简化的类似物的进一步开发。在此，我们通过设计和合成七种新的类似物，报道了对YM - 254890中N - 甲基脱氢丙氨酸部分的首次系统性构效关系研究。对这七种化合物针对G(q/11) -、G(i/o) - 和G(s)介导的信号传导进行的药理学特性研究表明，简化类似物YM - 19是新类似物中最有效的G(q/11)抑制剂。这项研究为未来设计强效且简化的YM - 254890类似物提供了信息。