Total Synthesis of Photoswitchable Latrunculin B Enables Reversible Control of Actin Polymerization and Cell Migration

The actin cytoskeleton plays a central role in regulating
essential
cellular properties such as cell shape, contraction, division, or
migration. The filament growth, controlled by subtle regulation mechanisms,
can also be inhibited by small molecules preventing actin polymerization,
such as latrunculin B. This compound has been widely used in cell
biology to inhibit cytokinesis or cell migration. To further these
applications and provide a means for the spatiotemporal control of
cell migration, we prepared photoswitchable latrunculin B through
total synthesis, allowing for the incorporation of a light-responsive
azobenzene moiety. One of these modified latrunculins displayed excellent
photophysical properties, with good photostationary states (ca. 90/10
in the two reversible states), long half-lives, and excellent fatigue
resistance during photoswitching, performed at 370 and 440 nm. The Z-photoisomer induced a significant inhibition of the growth
of single actin filaments in vitro, compared to the E-isomera reversible behavior that was rationalized
through molecular docking. Most importantly, this inhibition was photoinduced
in migrating cells, stopping actin-dependent membrane dynamics in
a reversible manner, and was induced locally in a single cell.