Structure-Activity Relationship Studies of the Cyclic Depsipeptide Natural Product YM-254890, Targeting the Gq Protein

TY - JOUR

T1 - Structure-Activity Relationship Studies of the Cyclic Depsipeptide Natural Product YM-254890, Targeting the Gq Protein

AU - Zhang, Hang

AU - Xiong, Xiao-feng

AU - Boesgaard, Michael W

AU - Underwood, Christina R

AU - Bräuner-Osborne, Hans

AU - Strømgaard, Kristian

N1 - © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

PY - 2017/6/7

Y1 - 2017/6/7

N2 - Extracellular signals perceived by G protein-coupled receptors are transmitted via G proteins, and subsequent intracellular signaling cascades result in a plethora of physiological responses. The natural product cyclic depsipeptides YM-254890 and FR900359 are the only known compounds that specifically inhibit signaling mediated by the Gq subfamily. In this study we exploit a newly developed synthetic strategy for this compound class in the design, synthesis, and pharmacological evaluation of eight new analogues of YM-254890. These structure-activity relationship studies led to the discovery of three new analogues, YM-13, YM-14, and YM-18, which displayed potent and selective Gq inhibitory activity. This provides pertinent information for the understanding of the Gq inhibitory mechanism by this class of compounds and importantly provides a pathway for the development of labeled YM-254890 analogues.

AB - Extracellular signals perceived by G protein-coupled receptors are transmitted via G proteins, and subsequent intracellular signaling cascades result in a plethora of physiological responses. The natural product cyclic depsipeptides YM-254890 and FR900359 are the only known compounds that specifically inhibit signaling mediated by the Gq subfamily. In this study we exploit a newly developed synthetic strategy for this compound class in the design, synthesis, and pharmacological evaluation of eight new analogues of YM-254890. These structure-activity relationship studies led to the discovery of three new analogues, YM-13, YM-14, and YM-18, which displayed potent and selective Gq inhibitory activity. This provides pertinent information for the understanding of the Gq inhibitory mechanism by this class of compounds and importantly provides a pathway for the development of labeled YM-254890 analogues.

KW - Journal Article

U2 - 10.1002/cmdc.201700155

DO - 10.1002/cmdc.201700155

M3 - Journal article

C2 - 28509439

SN - 1860-7179

VL - 12

SP - 830

EP - 834

JO - Farmaco, Edizione Pratica

JF - Farmaco, Edizione Pratica

IS - 11

ER -