Structure–Activity Relationship Studies of the Natural Product G                         
                        q/11
                                                  Protein Inhibitor YM-254890

Xiao Feng Xiong; Hang Zhang; Michael W. Boesgaard; Christina R. Underwood; Hans Bräuner-Osborne; Kristian Strømgaard

doi:10.1002/cmdc.201900018

Structure–Activity Relationship Studies of the Natural Product G _q/11 Protein Inhibitor YM-254890

Xiao Feng Xiong, Hang Zhang, Michael W. Boesgaard, Christina R. Underwood, Hans Bräuner-Osborne, Kristian Strømgaard^*

^*Corresponding author for this work

10 Citations (Scopus)

Abstract

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 _q/11 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 _q/11 -, G _i/o - and G _s -mediated signaling showed that the simplified analogue YM-19 is the most potent G _q/11 inhibitor among the new analogues. This study provides information for the future design of potent and simplified YM-254890 analogues.

Original language	English
Journal	ChemMedChem
Volume	14
Issue number	8
Pages (from-to)	865-870
ISSN	1860-7179
DOIs	https://doi.org/10.1002/cmdc.201900018
Publication status	Published - 17 Apr 2019

Keywords

G protein inhibitors
G protein-coupled receptors
G proteins
structure–activity relationships
YM-254890

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10.1002/cmdc.201900018

Cite this

Xiong, X. F., Zhang, H., Boesgaard, M. W., Underwood, C. R., Bräuner-Osborne, H., & Strømgaard, K. (2019). Structure–Activity Relationship Studies of the Natural Product G _q/11 Protein Inhibitor YM-254890. ChemMedChem, 14(8), 865-870. https://doi.org/10.1002/cmdc.201900018

Structure–Activity Relationship Studies of the Natural Product G _q/11 Protein Inhibitor YM-254890. / Xiong, Xiao Feng; Zhang, Hang; Boesgaard, Michael W. et al.
In: ChemMedChem, Vol. 14, No. 8, 17.04.2019, p. 865-870.

Research output: Contribution to journal › Journal article › Research › peer-review

Xiong, XF, Zhang, H, Boesgaard, MW, Underwood, CR, Bräuner-Osborne, H & Strømgaard, K 2019, 'Structure–Activity Relationship Studies of the Natural Product G _q/11 Protein Inhibitor YM-254890', ChemMedChem, vol. 14, no. 8, pp. 865-870. https://doi.org/10.1002/cmdc.201900018

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title = "Structure–Activity Relationship Studies of the Natural Product G q/11 Protein Inhibitor YM-254890",

abstract = " 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 q/11 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 q/11 -, G i/o - and G s -mediated signaling showed that the simplified analogue YM-19 is the most potent G q/11 inhibitor among the new analogues. This study provides information for the future design of potent and simplified YM-254890 analogues. ",

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AU - Bräuner-Osborne, Hans

AU - Strømgaard, Kristian

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N2 - 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 q/11 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 q/11 -, G i/o - and G s -mediated signaling showed that the simplified analogue YM-19 is the most potent G q/11 inhibitor among the new analogues. This study provides information for the future design of potent and simplified YM-254890 analogues.

AB - 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 q/11 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 q/11 -, G i/o - and G s -mediated signaling showed that the simplified analogue YM-19 is the most potent G q/11 inhibitor among the new analogues. This study provides information for the future design of potent and simplified YM-254890 analogues.

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ER -

Structure–Activity Relationship Studies of the Natural Product G q/11 Protein Inhibitor YM-254890

Abstract

Keywords

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Structure–Activity Relationship Studies of the Natural Product G _q/11 Protein Inhibitor YM-254890