Novel photoswitches with features complementary to the well-established azobenzenes are increasingly driving high-precision research in photopharmacology in cells and in vivo. Styrylthiazolium (StyTz) and styrylbenzothiazolium (StyBtz) are cellularly untested E/Z-isomerisation photoswitches which are nearly isosteric to azobenzenes, but have distinct photophysical and physicochemical properties: including ca. 60 nm red-shifted π→π* absorption, self-reporting fluorescence, Z→E relaxation that matches typical biological timescales, and good solubility due to their permanent positive charge. We here tested StyTz and StyBtz for their potential as photopharmaceutical scaffolds, by applying them to photocontrol the dynamics of the microtubule cytoskeleton. We observed light-specific disruption of microtubule network architecture and antiproliferative activity, with a structure-activity relationship matching expectations for tubulin inhibitors. However, while testing the lead StyBtz2 for its molecular mechanism of action, we found that it did not inhibit microtubule dynamics. We tracked its localisation in live cells by relying on its self-reporting fluorescence, observing accumulation of E-StyBtz2 into mitochondria; after several minutes of illumination it was then released into the cytosol concomitant with blebbing and cell death. We interpret this as light-dependent catastrophic rupturing of mitochondria on acute timescales. We conclude that StyTz/StyBtz can be interesting photopharmaceutical scaffolds for addressing mitochondrial, rather than cytosolic, targets.

Novel photoswitches offering features complementary to the well-established azobenzenes, are increasingly driving high-precision research in cellular photopharmacology. Styrylthiazolium (StyTz) and styrylbenzothiazolium (StyBtz) are cellularly untested E/Z-isomerisation photoswitches which are nearly...