Cunha Micael R, Bhardwaj Rajesh, Lindinger Sonja, Butorac Carmen, Romanin Christoph, Hediger Matthias A, Reymond Jean-Louis
Department of Chemistry and Biochemistry, NCCR TransCure, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland.
Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bühlstrasse 28, 3012 Bern, Switzerland & Department of Nephrology and Hypertension, University Hospital Bern, Inselspital, 3010 Bern, Switzerland.
ACS Med Chem Lett. 2019 Aug 2;10(9):1341-1345. doi: 10.1021/acsmedchemlett.9b00298. eCollection 2019 Sep 12.
Herein we report the first photoswitchable inhibitor of Transient Receptor Potential Vanilloid 6 (TRPV6), a selective calcium channel involved in a number of diseases and in cancer progression. By surveying analogs of a previously reported TRPV6 inhibitor appended with a phenyl-diazo group, we identified a compound switching between a weak TRPV6 inhibitor in its dark, -diazo stereoisomer ( = 3:97, IC ≫ 10 μM) and a potent inhibitor as the -diazo stereoisomer accessible reversibly by UV irradiation at λ = 365 nm ( = 3:1, IC = 1.7 ± 0.4 μM), thereby allowing precise spatiotemporal control of inhibition. This new tool compound should be useful to deepen our understanding of TRPV6.
在此，我们报道了首个可光开关的瞬时受体电位香草酸亚型6（TRPV6）抑制剂，TRPV6是一种选择性钙通道，与多种疾病及癌症进展相关。通过研究先前报道的带有苯基重氮基团的TRPV6抑制剂的类似物，我们鉴定出一种化合物，其在黑暗状态下以 - 重氮立体异构体形式存在时是一种弱TRPV6抑制剂（比例 = 3:97，IC≫10 μM），而在λ = 365 nm的紫外光照射下可逆地转变为 - 重氮立体异构体时则成为一种强效抑制剂（比例 = 3:1，IC = 1.7±0.4 μM），从而实现对抑制作用的精确时空控制。这种新型工具化合物应有助于加深我们对TRPV6的理解。
