Diarylethene‐Containing Photoswitchable Analogues of Tubulysins—Design, Synthesis, Biological, and Structural Evaluation

The discovery of tubulysins sparked considerable interest due to their high cytotoxic activity against multidrug resistant tumors. Total synthesis of these complex natural products—peptidic metabolites from myxobacteria Archangium gephyra and Angiococcus disciformis —demonstrated the power of organic chemistry and paved the way for the development of simpler, more stable, and selective derivatives. Despite these significant achievements, tubulysins are not used as stand‐alone drugs due to their toxic side effects. In this study, we outline the design, synthesis, and evaluation of photoswitchable tubulysin analogues, which could be starting points for development of photopharmacological therapies aimed at addressing the toxicity challenges associated with tubulysins. The cytotoxic activity of one of the key analogues was shown to be light‐controllable. For the first time, we provide a comparative analysis of the crystal structures of both photoisomers of a diarylethene‐containing compound complexed with target proteins. This comparison enables a mechanistic explanation for the experimentally observed differences in the target binding efficiency and respective activity between the two photoisomers of the photoswitchable tubulysin analogue.