Department of Drug Design and Pharmacology, University of Copenhagen, 2100, Copenhagen, Denmark.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
ChemMedChem. 2019 Apr 17;14(8):865-870. doi: 10.1002/cmdc.201900018. Epub 2019 Mar 21.
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 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 -, G - and G -mediated signaling showed that the simplified analogue YM-19 is the most potent G inhibitor among the new analogues. This study provides information for the future design of potent and simplified YM-254890 analogues.
G 蛋白作为 G 蛋白偶联受体信号通路中的分子开关，是许多重要生理过程的关键介质。天然产物环二肽 YM-254890 与结构相似的 FR900359 是唯一已知的 G 蛋白亚家族的选择性抑制剂。我们最近报道了 YM-254890 和 FR900359 的首次全合成，并在此基础上合成了类似物进行构效关系研究。然而，由于对其构效关系的不完全了解，阻碍了进一步开发强效且结构简化的类似物。在此，我们通过设计和合成七个新的类似物，首次对 YM-254890 中的 N-甲酰基脱氢丙氨酸部分进行了系统的构效关系研究。对这七个化合物进行 G -、G -和 G -介导的信号转导的药理学表征表明，简化类似物 YM-19 是新类似物中最有效的 G 抑制剂。这项研究为设计强效且简化的 YM-254890 类似物提供了信息。
