Total synthesis and structure-activity relationship studies of a series of selective G protein inhibitors.
Total synthesis and structure-activity relationship studies of a series of selective G protein inhibitors.
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DOI：
10.1038/nchem.2577
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发表时间：
2016-11
期刊：
影响因子：
21.8
通讯作者：
Strømgaard K
中科院分区：
文献类型：
--
作者：
Xiong XF;Zhang H;Underwood CR;Harpsøe K;Gardella TJ;Wöldike MF;Mannstadt M;Gloriam DE;Bräuner-Osborne H;Strømgaard K
G蛋白是G蛋白偶联受体信号传导的关键介质，其促进了大量重要的生理过程。环状缩酚肽YM-254890和FR 900359是G蛋白Gq亚家族的唯一已知特异性抑制剂;然而，以前没有报道过这些复杂天然产物的合成路线，并且它们不容易从天然来源中分离。本文报道了YM-254890和FR 900359以及两个已知类似物YM-385780和YM-385781的首次全合成。该合成方法的多功能性也使得能够设计和合成十个类似物，这为这类化合物提供了第一个结构-活性关系研究。所有化合物在Gq-、Gi-和Gs-介导的信号传导中的药理学表征提供了关于抑制的结构要求的简洁信息，并证明YM-254890和FR 900359都是Gq信号传导的高效抑制剂，其中FR 900359是最有效的。这些天然产物及其类似物代表了G蛋白抑制的探索性研究的独特工具。
G proteins are key mediators of G protein-coupled receptor signalling, which facilitates a plethora of important physiological processes. The cyclic depsipeptides YM-254890 and FR900359 are the only known specific inhibitors of the Gq subfamily of G proteins; however, no synthetic route has been reported previously for these complex natural products and they are not easily isolated from natural sources. Here we report the first total synthesis of YM-254890 and FR900359, as well as of two known analogues, YM-385780 and YM-385781. The versatility of the synthetic approach also enabled the design and synthesis of ten analogues, which provided the first structure–activity relationship study for this class of compounds. Pharmacological characterization of all the compounds at Gq-, Gi- and Gs-mediated signalling provided succinct information on the structural requirements for inhibition, and demonstrated that both YM-254890 and FR900359 are highly potent inhibitors of Gq signalling, with FR900359 being the most potent. These natural products and their analogues represent unique tools for explorative studies of G protein inhibition.
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影响因子：
3.6
作者：
Kamato D;Thach L;Bernard R;Chan V;Zheng W;Kaur H;Brimble M;Osman N;Little PJ
通讯作者：
Little PJ
DOI：
10.1073/pnas.75.7.3050
发表时间：
1978-01-01
影响因子：
11.1
作者：
GILL, DM;MEREN, R
通讯作者：
MEREN, R
影响因子：
3.6
作者：
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通讯作者：
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影响因子：
2.9
作者：
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通讯作者：
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影响因子：
46.9
作者：
Schroeder, Ralf;Janssen, Nicole;Kostenis, Evi
通讯作者：
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