Strapped Porphyrins as Model Systems for Atropisomeric Photosensitizer Drugs

Abstract

The time dependence of atropisomer interconversion has limited the pursuit of single atropisomer drug candidates, even in circumstances where one atropisomer presents favorable biological activity over another. Moderate interconversion energy barriers risk compromising drug stability. As a result, examples of atropisomerically pure drugs in current clinical use are rare. However, in recent years, there has been a shift towards the development of single, stable atropisomer drug candidates with enhanced activity. Consequently, development of methods which effectively restrict rotation in a configuration which favors activity is highly beneficial. The picket fence porphyrin α4 atropisomer configuration has been previously demonstrated to improve the cell internalization of the pre-clinical drug, redaporfin, applied in photodynamic therapy. In this work, the α4 configuration was modelled with novel porphyrin photosensitizers through strapped moieties which effectively fixed the atropisomeric configuration. The stable cis-αα configuration demonstrated enhanced cell membrane permeation, effectively predicting the behavior of the α4 configuration and indicates that strapped porphyrins can serve as stable model systems for the investigation of photoactive drugs.