Abstract
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 provide further insights into the thermodynamics of this process and the effect of alkyl and aryl modular modifications.