Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors
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Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors. / Xiong, Xiaofeng; Zhang, Hang; Underwood, Christina R.; Harpsøe, Kasper; Gardella, Thomas J.; Wöldike, Mie F.; Mannstadt, Michael; Gloriam, David E.; Bräuner-osborne, Hans; Strømgaard, Kristian.
I: Nature Chemistry, Bind 8, Nr. 11, 2016, s. 1035-1041.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
Y1 - 2016
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
VL - 8
SP - 1035
EP - 1041
JO - Nature Chemistry
JF - Nature Chemistry
SN - 1755-4330
IS - 11
ER -
ID: 164300071