Abstract
Mitochondrial targeting represents an attractive strategy for treating metabolic, degenerative and hyperproliferative diseases, since this organelle plays key roles in essential cellular functions. Triphenylphosphonium (TPP(+)) moieties - the current "gold standard" - have been widely used as mitochondrial targeting vectors for a wide range of molecular cargo. Recently, further optimisation of the TPP(+) platform drew considerable interest as a way to enhance mitochondrial therapies. However, although the modification of this system appears promising, the core structure of the TPP(+) moiety remains largely unchanged. Thus, this study explored the use of aminophosphonium (PN(+)) and phosphazenylphosphonium (PPN(+)) main group frameworks as novel mitochondrial delivery vectors. The PPN(+) moiety was found to be a highly promising platform for this purpose, owing to its unique electronic properties and high lipophilicity. This has been demonstrated by the high mitochondrial accumulation of a PPN(+)-conjugated fluorophore relative to its TPP(+)-conjugated counterpart, and has been further supported by density functional theory and molecular dynamics calculations, highlighting the PPN(+) moiety's unusual electronic properties. These results demonstrate the potential of novel phosphorus-nitrogen based frameworks as highly effective mitochondrial delivery vectors over traditional TPP(+) vectors.