Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors

TY - JOUR

T1 - Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors

AU - Xiong, Xiaofeng

AU - Zhang, Hang

AU - Underwood, Christina R.

AU - Harpsøe, Kasper

AU - Gardella, Thomas J.

AU - Wöldike, Mie F.

AU - Mannstadt, Michael

AU - Gloriam, David E.

AU - Bräuner-osborne, Hans

AU - Strømgaard, Kristian

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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.

U2 - 10.1038/nchem.2577

DO - 10.1038/nchem.2577

M3 - Journal article

C2 - 27768111

SN - 1755-4330

VL - 8

SP - 1035

EP - 1041

JO - Nature Chemistry

JF - Nature Chemistry

IS - 11

ER -