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.肌动蛋白细胞骨架（actin cytoskeleton）在调控细胞形状、收缩、分裂或迁移等核心细胞特性方面发挥着核心作用。由精细调控机制控制的丝状体生长，也可被阻止肌动蛋白聚合的小分子所抑制，例如拉春库林B（latrunculin B）。该化合物已被广泛应用于细胞生物学领域，以抑制胞质分裂或细胞迁移。为进一步拓展此类应用，并为细胞迁移的时空调控提供手段，我们通过全合成制备了光响应性拉春库林B，使其可引入光响应性偶氮苯基团。其中一款修饰后的拉春库林B展现出优异的光物理性质：具备良好的光稳态（两种可逆状态下比例约为90/10）、较长的半衰期，以及在370纳米和440纳米下进行光开关转换时出色的抗疲劳性能。与E型光异构体相比，Z型光异构体可在体外显著抑制单根肌动蛋白丝的生长——这一可逆行为通过分子对接（molecular docking）得到了合理解释。最为关键的是，该抑制作用可在迁移细胞中被光诱导，以可逆方式阻断肌动蛋白依赖的膜动态过程，且可在单个细胞内局部触发。