Unravelling the Pivotal Role of Atropisomerism for Cellular Internalization
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Donohoe, Claire, Unravelling the Pivotal Role of Atropisomerism for Cellular Internalization, Trinity College Dublin, School of Chemistry, Chemistry, 2022Download Item:
Abstract:
Atropisomerism presents an intriguing, often neglected, source of varied biological activity in drug development. For a stable atropisomeric drug mixture, assessment of individual atropisomers may reveal an individual isomer with higher efficacy. Tetrapyrrole isomerism is rarely considered during photosensitizer (PS) development for photodynamic therapy (PDT). The atropisomers of a pre-clinical bacteriochlorin PS for PDT, redaporfin, are stable and separable. They displayed vastly different photodynamic efficacy profiles, which were discovered to be a consequence of differential cellular uptake. Redaporfin atropisomer uptake was determined as a predominantly passive process in vitro. The ¿4 atropisomer, which features sulfonamide substituents orientated on the same side of the tetrapyrrole macrocycle, appeared to enhance binding interaction with the cell membrane phospholipid bilayer and subsequent diffusion. Cells of the tumor microenvironment exhibited enhanced ¿4 uptake in vivo which was correlated to the PDT efficacy when tumor illumination was performed 24 h after ¿4 administration.
Orientation of polar groups to one side of the macrocycle plane appeared to benefit cell uptake in a manner which may be incorporated into drug design as an efficient cell-penetrating conformation. The validation of these findings was confirmed with the preparation of novel porphyrin photosensitizers with highly restrictive strap moieties to enforce the ¿4 configuration of polar groups. Direct condensation methods, between pyrrole and dialdehyde, yielded multiple double strapped porphyrin isomers which were characterized by single crystal X-ray crystallography and 1H NMR. Enhanced uptake of the cis-¿¿ isomer, analogous in structure to the redaporfin ¿4 configuration, illustrated the potential of this motif to promote internalization. The success of this strategy with high molecular weight photosensitizers (> 1000 Da) demonstrates its potential for incorporation in the design of macromolecules to aid membrane passage.
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Author: Donohoe, Claire
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Trinity College Dublin. School of Chemistry. Discipline of ChemistryType of material:
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