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Alkyl vs Aryl Modifications: A Comparative Study on Modular Modifications of Triphenylphosphonium Mitochondrial Vectors

preprint
submitted on 19.04.2021, 07:28 and posted on 19.04.2021, 12:53 by How Chee Ong, João T.S. Coimbra, Maria João Ramos, Bengang Xing, Pedro Alexandrino Fernandes, Felipe Garcia
Triphenylphosphonium (TPP+) moieties are commonly conjugated to drug molecules to confer mitochondrial selectivity due to their positive charge and high lipophilicity. Although optimisation of lipophilicity can be achieved by modifying the length of the alkyl linkers between the TPP+ moiety and the drug molecule, it is not always possible. While methylation of the TPP+ moiety is a viable alternative to increase lipophilicity and mitochondrial accumulation, there are no studies comparing these two separate modular approaches. Thus, we have systematically designed, synthesised and tested a range of TPP+ molecules with varying alkyl chain lengths and degree of aryl methylation to compare the two modular methodologies for modulating lipophilicity. The ability of aryl/alkyl modified TPP+ to deliver cargo to the mitochondria was also evaluated by confocal imaging with a TPP+-conjugated fluorescein-based fluorophore. Furthermore, we have employed molecular dynamics simulations to understand the translocation of these molecules through biological membrane model systems. These results provides further insights into the thermodynamics of this process and the effect of alkyl and aryl modular modifications

Funding

Associate Laboratory for Green Chemistry Unit – LAQV

FCT/MCTES – Portuguese Foundation for Science and Technology within the scope of the project UIDB/50006/2020

A*STAR AME IRG

MOE Singapore Tier 1

History

Email Address of Submitting Author

Fgarcia@ntu.edu.sg

Institution

Nanyang Technological University

Country

Singapore

ORCID For Submitting Author

0000-0002-9605-3611

Declaration of Conflict of Interest

The authors declare no conflict of interest.

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