Researchers unravel the fundamentals of light-switchable molecules for photopharmacology

An international team of researchers, including chemists from the Universities of Amsterdam and Groningen, has recently made significant strides in understanding the behavior of a unique category of molecules known as azonium compounds. These molecules possess the remarkable ability to change shape when exposed to light, a characteristic that makes them promising candidates for various biomedical applications, particularly in the development of light-controlled drugs.

Their findings, detailed in the Journal of the American Chemical Society, stem from a comprehensive analysis employing advanced laser spectroscopy, quantum chemical modeling, and theoretical calculations. This research marks a crucial step toward harnessing these compounds for practical use in biomedical applications.

Chemists worldwide have been drawn to molecules capable of undergoing light-induced shape transformations because they offer precise control over molecular processes. For instance, Professor Ben Feringa was awarded the Nobel Prize in Chemistry in 2016 for his work on light-controlled molecular motors.

One particularly pertinent domain for these molecules is photopharmacology, where light-responsive compounds play a vital role in regulating physiological processes. Light-induced shape changes can be employed to, for instance, block ion channels or inhibit enzymes. The ability to use light to precisely govern therapeutic processes at specific times and locations holds the promise of reducing unwanted side effects.

Professor Wiktor Szymanski, a colleague of Feringa at the University of Groningen, is actively pursuing applications in this field. As a specialist in photopharmacology, he is particularly interested in azonium compounds, a class of molecules originally developed by Professor Andrew Woolley at the University of Toronto (Canada).

These azonium compounds stand out as one of the very few molecular systems that meet all the prerequisites for effective use in photopharmacology. They can be activated by red or infrared light, which is safe for humans and can penetrate deep into living tissue. Additionally, they exhibit stability under the typical conditions found in the human body, which includes an aqueous environment at pH 7. Furthermore, these molecules maintain their functionality even after undergoing multiple light-triggered transformations.

Graphical abstract of the JACS paper. The image depicts the transitions between the shapes of the azonium compound depending on light and pH. Credit: Journal of the American Chemical Society (2023). DOI: 10.1021/jacs.3c06157

First detailed mechanistic insight

A collaborative effort by a diverse and international team of scientists, including synthetic chemists Szymanski and Feringa, spectroscopists Prof. Wybren Jan Buma (University of Amsterdam) and Mariangela di Donato (LENS research center, Florence), and computational chemists Miroslav Medved’ (Matej Bel University, Slovak Republic) and Adèle Laurent (Nantes University), has delved deep into understanding the behavior of azonium ions – molecules crucial for photopharmaceutical applications. This groundbreaking research builds upon their prior successful collaboration in developing innovative photoswitches and now includes the pioneer of azonium switches, Andrew Woolley, who coordinated the study.

Their findings, published in the Journal of the American Chemical Society (JACS), offer the first comprehensive mechanistic insights into the photochemistry of azonium ions. This understanding was achieved through a combination of time-resolved spectroscopies, spanning time scales from picoseconds to seconds, quantum chemical calculations, and theoretical analysis. The results shed light on how the absorption of photons triggers changes in molecular shape, how proton exchange with the solvent stabilizes this transformation, and how the solution’s pH level governs the switch’s relaxation rate following exposure to light.

This analysis presents a complete mechanistic framework that elucidates the intricate photoswitching behavior of azonium ions across various pH values. Moreover, it paves the way for potential modifications of azonium ions to enhance their suitability for precisely controlling biomolecules using light. The initial strides have already been taken towards integrating these photoswitches into molecular systems that interact with living cells. While still in its nascent stages, this development holds promise for the future generation of intelligent pharmaceuticals.

Source: University of Amsterdam

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