Optical control of physiological processes with high precision using photoswitches is an emerging strategy for non-invasive diagnosis and therapies, providing innovative solutions to complex biomedical challenges. Light-responsive cyclic conjugated-dienes (cCDs) have long been recognized for their 4π-photocyclization, however the photoswitching behaviour in medium-sized cCDs has been recently unravelled and marks a pioneering discovery in the field. Reinforced by previous experimental evidences corroborating the Woodward-Hoffmann (WH) rules, we analysed that cCDs illustrate ring-size dependence and direct 4π-electrocyclization based thermo-reversible photoswitching is impeded in large cCD analogues. Considering cyclodeca-1,3-diene as a prototype, this report delves insight into the origin of the exotic dual photoexcitation mechanism devised to achieve thermo-reversible photoswitching in large cCD. The operation of this mechanism enables access to four distinct photoisomers during a single photoswitching cycle, introducing new dimensions in the functionality of cCDs. The interaction behaviour of these isomers with β-barrel protein has also been analysed to rationalize their potential for photopharmacology. Results decipher that photoisomers engage in different interactions inside the cavity that prompts variable conformational changes in the protein. Photoisomers of cCD-based photoswitches could serve as mediators for precise reversible optical regulation of biological events including allosteric functions that can trigger a cascade of cell signaling processes. Thus, the versatile architecture of cCDs can expand the toolbox of photoswitch designs to evolve photoresponsive pharmaceuticals and contribute to the development of highly selective and advanced medical treatments.

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