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.

In: Nature Chemistry, Vol. 8, No. 11, 2016, p. 1035-1041.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Xiong, X, Zhang, H, Underwood, CR, Harpsøe, K, Gardella, TJ, Wöldike, MF, Mannstadt, M, Gloriam, DE, Bräuner-osborne, H & Strømgaard, K 2016, 'Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors' Nature Chemistry, vol. 8, no. 11, pp. 1035-1041. https://doi.org/10.1038/nchem.2577

APA

Xiong, X., Zhang, H., Underwood, C. R., Harpsøe, K., Gardella, T. J., Wöldike, M. F., ... Strømgaard, K. (2016). Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors. Nature Chemistry, 8(11), 1035-1041. https://doi.org/10.1038/nchem.2577

Vancouver

Xiong X, Zhang H, Underwood CR, Harpsøe K, Gardella TJ, Wöldike MF et al. Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors. Nature Chemistry. 2016;8(11):1035-1041. https://doi.org/10.1038/nchem.2577

Author

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. / Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors. In: Nature Chemistry. 2016 ; Vol. 8, No. 11. pp. 1035-1041.

Bibtex

@article{8006ba34cf364980aaa908daa628b22d,
title = "Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors",
abstract = "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.",
author = "Xiaofeng Xiong and Hang Zhang and Underwood, {Christina R.} and Kasper Harps{\o}e and Gardella, {Thomas J.} and W{\"o}ldike, {Mie F.} and Michael Mannstadt and Gloriam, {David E.} and Hans Br{\"a}uner-osborne and Kristian Str{\o}mgaard",
year = "2016",
doi = "10.1038/nchem.2577",
language = "English",
volume = "8",
pages = "1035--1041",
journal = "Nature Chemistry",
issn = "1755-4330",
publisher = "nature publishing group",
number = "11",

}

RIS

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

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

VL - 8

SP - 1035

EP - 1041

JO - Nature Chemistry

JF - Nature Chemistry

SN - 1755-4330

IS - 11

ER -

ID: 164300071