Willem A. Velema

Photopharmacology: Beyond Proof of Principle

Pharmacotherapy is often severely hindered by issues related to poor drug selectivity, including side effects, environmental toxicity, and the emergence of resistance. Lack of selectivity is caused by the inability to control drug activity in time and space. Photopharmacology aims at solving this issue by incorporating photoswitchable groups into the molecular structure of bioactive compounds. These switching units allow for the use of light as an external control element for pharmacological activity, which can be delivered with very high spatiotemporal precision. This Perspective presents the reader with the current state and outlook on photopharmacology. In particular, the principles behind photoregulation of bioactivity, the challenges of molecular design, and the possible therapeutic scenarios are discussed.

Orthogonal photoswitching in a multifunctional molecular system.

The wavelength-selective, reversible photocontrol over various molecular processes in parallel remains an unsolved challenge. Overlapping ultraviolet-visible spectra of frequently employed photoswitches have prevented the development of orthogonally responsive systems, analogous to those that rely on wavelength-selective cleavage of photo-removable protecting groups. Here we report the orthogonal and reversible control of two distinct types of photoswitches in one solution, that is, a donor–acceptor Stenhouse adduct (DASA) and an azobenzene. The control is achieved by using three different wavelengths of irradiation and a thermal relaxation process. The reported combination tolerates a broad variety of differently substituted photoswitches. The presented system is also extended to an intramolecular combination of photoresponsive units. A model application for an intramolecular combination of switches is presented, in which the DASA component acts as a phase-transfer tag, while the azobenzene moiety independently controls the binding to α-cyclodextrin.

Light-Controlled Histone Deacetylase (HDAC) Inhibitors: Towards Photopharmacological Chemotherapy

Cancer treatment suffers from limitations that have a major impact on the patients quality of life and survival. In the case of chemotherapy, the systemic distribution of cytotoxic drugs reduces their efficacy and causes severe side effects due to nonselective toxicity. Photopharmacology allows a novel approach to address these problems because it employs external, local activation of chemotherapeutic agents by using light. The development of photoswitchable histone deacetylase (HDAC) inhibitors as potential antitumor agents is reported herein. Analogues of the clinically used chemotherapeutic agents vorinostat, panobinostat, and belinostat were designed with a photoswitchable azobenzene moiety incorporated into their structure. The most promising compound exhibits high inhibitory potency in the thermodynamically less stable cis form and a significantly lower activity for the trans form, both in terms of HDAC activity and proliferation of HeLa cells. This approach offers a clear prospect towards local photoactivation of HDAC inhibition to avoid severe side effects in chemotherapy.

Orthogonal Control of Antibacterial Activity with Light

Selection of a single bacterial strain out of a mixture of microorganisms is of crucial importance in healthcare and microbiology research. Novel approaches that can externally control bacterial selection are a valuable addition to the microbiology toolbox. In this proof-of-concept, two complementary antibiotics are protected with photocleavable groups that can be orthogonally addressed with different wavelengths of light. This allows for the light-triggered selection of a single bacterial strain out of a mixture of multiple strains, by choosing the right wavelength. Further improvement toward additional orthogonally addressable antibiotics might ultimately lead to a novel methodology for bacterial selection in complex populations.

Ciprofloxacin–Photoswitch Conjugates: A Facile Strategy for Photopharmacology

Photopharmacology aims to locally treat diseases and study biological processes with photoresponsive drugs. Herein, easy access to photoswitchable drugs is crucial, which is supported by simple and robust drug modifications. We investigated the possibility of creating drugs that can undergo remote activation and deactivation with light, by conjugating molecular photoswitches to the exterior of an existing drug in a single chemical step. This facile strategy allows the convenient introduction of various photochromic systems into a drug molecule, rendering it photoresponsive. To demonstrate the feasibility of this approach, two photoswitch-modified ciprofloxacin antibiotics were synthesized. Remarkably, for one of them a 50-fold increase in activity compared to the original ciprofloxacin was observed. Their antimicrobial activity could be spatiotemporally controlled with light, which was exemplified by bacterial patterning studies.

Design, Synthesis, and Inhibitory Activity of Potent, Photoswitchable Mast Cell Activation Inhibitors

Allergic reactions affect millions of people worldwide. The need for new and effective antiallergic agents is evident, and insight into the underlying mechanisms that lead to allergic events is necessary. Herein, we report the design, synthesis, and activity of photoswitchable mast cell activation inhibitors. In mast cell degranulation assays, these inhibitors possess significantly greater potency than an original, chromone-based antiallergic agent. Furthermore, one of the photoswitchable inhibitors shows a significant difference in inhibitory activity between its two photoisomeric forms. Further optimization could ultimately lead to a photoswitchable compound suitable for studying mechanisms involved in allergic reactions in a novel manner, with activity addressable by light and with precise spatiotemporal control over events at the molecular level.

Proteasome Inhibitors with Photocontrolled Activity

Proteasome inhibitors are widely used in cancer treatment as chemotherapeutic agents. However, their employment often results in severe side effects, due to their non‐specific cytotoxicity towards healthy tissue. This problem might be overcome by using a photopharmacological approach, that is, by attaining external, dynamic, spatiotemporal photocontrol over the activity of a cytotoxic agent, achieved by the introduction of a photoswitchable moiety into its molecular structure. Here we describe the design, synthesis, and activity of photoswitchable proteasome inhibitors. Substantial differences in proteasome inhibitory activity in cell extracts were observed before and after irradiation with light. The presented results show potential for the development of chemotherapeutic agents that can be switched on and off with light, constituting a new strategy for spatiotemporally modulating proteasomal activity.

Light-triggered self-assembly of a dichromonyl compound in water

External control over self-assembling structures is achieved by incorporating an azobenzene photoswitch into the structure of a dichromonyl compound. The self-assembly of dichromonyl compounds into fibers leads to the formation of a hydrogel and can be triggered with visible light.

Photocaging of Carboxylic Acids: A Modular Approach

Photocaged compounds are important tools for studying and regulating multiple processes, including biological functions. Reported herein is the use of the Passerini multicomponent reaction for modular preparation of photocaged carboxylic acids. The reaction is compatible with several functionalities and proceeds smoothly both in water and dichloromethane. The choice of aldehyde determines the wavelength used for deprotection and enables formation of orthogonally protected products. The isocyanide component can be used for introduction of reactive tags and photosensitizers, as well as for immobilization on a solid support.

Wavelength-selective cleavage of photoprotecting groups

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.