Development of Photoswitchable Cholesterol Derivatives through Side Chain Replacement

Cholesterol is ubiquitous in biology, shaping membrane properties and serving as a biosynthetic precursor for essential signaling molecules and hormonesand, in some contexts, acting as a signaling molecule itself. Here, we describe the development of photoswitchable versions of cholesterol that retain the lipophilic profile of the parent compound. These analogs were designed through computationally guided replacement of the native iso-octyl side chain with azobenzene-based photoswitches. Our compounds, termed photocholesterols (PChols), were assembled through a modular and readily diversifiable semisynthetic route involving transition metal-catalyzed cross-couplings followed by stereo- and chemoselective hydrogenations. They can be used to optically control binding to the sterol transport proteins ORP1/2 and OSBP, which play key roles in distributing cholesterol within intracellular compartments. Our work establishes a template for photoresponsive sterols that closely mimic cholesterol and may be applied broadly to investigate cholesterol’s roles in membrane behavior, signaling, and transport.胆固醇（cholesterol）在生物学中广泛存在，可塑造细胞膜的特性，同时作为关键信号分子与激素的生物合成前体；在部分场景下，其自身亦能充当信号分子。本研究报道了可光开关修饰的胆固醇衍生物的开发工作，这类衍生物保留了母本化合物的亲脂性特征。此类类似物通过计算辅助设计，将天然胆固醇的异辛基侧链替换为基于偶氮苯（azobenzene）的光开关基团。本研究将此类化合物命名为光控胆固醇（photocholesterols, PChols），其通过模块化且易于衍生化的半合成路线合成：先经过渡金属催化的交叉偶联反应，再进行立体选择性与化学选择性氢化反应。此类化合物可通过光学手段调控与固醇转运蛋白ORP1/2及OSBP的结合，而这两类蛋白在胆固醇向细胞内区室的分布过程中发挥关键作用。本研究为高度模拟天然胆固醇的光响应性固醇类化合物提供了通用合成模板，有望广泛应用于探究胆固醇在细胞膜行为、信号转导及物质转运过程中的功能。