利用由两个重氮苯衍生物组成的新型光致变色化合物高效光控有丝分裂驱动蛋白 Eg5 ATP 酶活性。

Highly efficient photocontrol of mitotic kinesin Eg5 ATPase activity using a novel photochromic compound composed of two azobenzene derivatives.

机构信息

Department of Bioinformatics, Graduate School of Engineering Soka University, 1-236 Tangi-cho, Hachioji, Tokyo, Japan.

出版信息

J Biochem. 2018 Oct 1;164(4):295-301. doi: 10.1093/jb/mvy051.

Abstract

Mitotic kinesin Eg5 plays an important physiological role in cell division. Several small-molecule inhibitors of Eg5 are the focus of cancer therapies. Azobenzene is a photochromic compound exhibiting cis-trans isomerization upon ultraviolet (UV) and visible (VIS) light irradiation. Photochromic compounds of azobenzene derivatives, mimicking Eg5-specific inhibitors of STLC, indicated photoreversible inhibitory effects on Eg5 ATPase activity; however, the photoreversible switching efficiency was not significant. This study presents a novel synthesized photochromic Eg5 inhibitor 2, 3-bis[(2,5-dioxo-1-{4-[(E)-2-phenyldiazen-1-yl]phenyl}pyrrolidin-3-yl)sulfanyl] butanedioic acid (BDPSB), which is composed of two azobenzenes. BDPSB exhibited cis-trans isomerization with UV and VIS light irradiation. The trans form of BDPSB significantly inhibited microtubule-dependent ATPase activity of Eg5, with an IC50 of 74 μM. Cis BDPSB showed weak effects on the microtubule-dependent ATPase activity. The results suggest that the novel photochromic Eg5 inhibitor BDPSB, which exhibits highly efficient photoswitching, shows a switch 'ON' and 'OFF' behaviour with VIS and UV light irradiation.

摘要

有丝分裂驱动蛋白 Eg5 在细胞分裂中发挥着重要的生理作用。几种 Eg5 的小分子抑制剂是癌症治疗的重点。偶氮苯是一种光致变色化合物，在紫外（UV）和可见光（VIS）照射下会发生顺反异构化。偶氮苯衍生物的光致变色化合物模拟 STLC 对 Eg5 的特异性抑制剂，表明对 Eg5 ATP 酶活性具有光可逆抑制作用；然而，光可逆开关效率并不显著。本研究提出了一种新型合成的光致变色 Eg5 抑制剂 2,3-双[（2,5-二氧代-1-｛4-[(E)-2-苯重氮-1-基]苯基｝吡咯烷-3-基）硫基]丁二酸（BDPSB），它由两个偶氮苯组成。BDPSB 在 UV 和 VIS 光照射下发生顺反异构化。BDPSB 的反式构象显著抑制 Eg5 微管依赖性 ATP 酶活性，IC50 为 74 μM。顺式 BDPSB 对微管依赖性 ATP 酶活性的影响较弱。结果表明，新型光致变色 Eg5 抑制剂 BDPSB 具有高效的光开关，在 VIS 和 UV 光照射下表现出开关“ON”和“OFF”行为。