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

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.