Merocytochalasans, Photocytochalasans, and the Optical Control of the Actin Cytoskeleton Project Summary/Abstract The goal of this project is to synthesize and study cytochalasans with new structural and functional features. Cytochalasans generally target the actin cytoskeleton and account for some of the most potent natural products known. New members of this family that combine fascinating molecular structures with interesting bioactivities, such as the merocytochalasans, continue to emerge. We propose to synthesize these compounds and evaluate them in depth for their effect on the actin cytoskeleton. To this end, we will develop biomimetic cascade reactions that are based on the largely unexplored oxidative coupling chemistry of pyrogallols. In parallel, we will design and synthesize cytochalasans that bear photoswitches and can be reversibly activated with light. These ?photocytochalasans? change their affinity, efficacy, or bioavailability upon irradiation and allow for the precision control of actin dynamics. We will extend our program on the optical control of the actin cytoskeleton to photoswitchable derivatives of the jasplakinolides. To support our claims, we provide preliminary results that demonstrate that the photopharmacology of the actin cytoskeleton is indeed viable.
