The field of photopharmacology uses molecular photoswitches to establish control over the action of bioactive molecules. It aims to reduce systemic drug toxicity and the emergence of resistance, while achieving unprecedented precision in treatment. By using small molecules, photopharmacology provides a viable alternative to optogenetics. We present here a critical overview of the different pharmacological targets in various organs and a survey of organ systems in the human body that can be addressed in a non-invasive manner. We discuss the prospects for the selective delivery of light to these organs and the specific requirements for light-activatable drugs. We also aim to illustrate the druggability of medicinal targets with recent findings and emphasize where conceptually new approaches have to be explored to provide photopharmacology with future opportunities to bring "smart" molecular design ultimately to the realm of clinical use.

Photocleavable protecting groups (PPGs) are extensively used in chemical and biological sciences. In their application, advantage is taken of using light as an external, non-invasive stimulus, which can be delivered with very high spatiotemporal precision. More recently, orthogonally addressing multiple PPGs, in a single system and with different wavelengths of light, has been explored. This approach allows one to independently control multiple functionalities in an external, non-invasive fashion. In this tutorial review, we discuss the design principles for dynamic systems involving wavelength-selective deprotection, focusing on the choice and optimization of PPGs, synthetic methods for their introduction and strategies for combining multiple PPGs into one system. Finally, we illustrate the design principles with representative examples, aiming at providing the reader with an instructive overview on how the wavelength-selective cleavage of photoprotecting groups can be applied in materials science, organic synthesis and biological systems.

Molecular photoswitches comprise chromophores that can be interconverted reversibly with light between two states with different photochemical and physicochemical properties. This feature renders them useful for diverse applications, ranging from materials science, biology (specifically photopharmacology) to supramolecular chemistry. With new and more challenging systems to control, especially extending towards biomedical applications, using visible or near-infrared light for photoswitch activation becomes vital. Donor-acceptor Stenhouse adducts are a novel class of visible light-responsive negative photochromes that provide a possible answer to current limitations of other photoswitch classes in the visible and NIR window. Their rapid development since their discovery in 2014, together with first successful examples of applications, demonstrate both their potential and areas where improvements are needed. A better understanding of DASA characteristics and its photoswitching mechanism has revealed that they are in fact a subset of a more general structural class of photochromes, namely Stenhouse photoswitches. This tutorial review aims at providing an introduction and practical guide on DASAs: it focuses on their structure and synthesis, provides fundamental insights for understanding their photoswitching behavior and demonstrates guiding principles for tailoring these switches for given applications.

Molecular photoswitches have opened up a myriad of opportunities in applications ranging from responsive materials and control of biological function to molecular logics. Here, we show that the photoswitching mechanism of donor-acceptor Stenhouse adducts (DASA), a recently reported class of photoswitches, proceeds by photoinduced Z-E isomerization, followed by a thermal, conrotatory 4π-electrocyclization. The photogenerated intermediate is manifested by a bathochromically shifted band in the visible absorption spectrum of the DASA. The identification of the role of this intermediate reveals a key step in the photoswitching mechanism that is essential to the rational design of switching properties via structural modification.