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.