Triphenylphosphonium moieties are traditionally used to deliver a wide range of molecular cargo to mitochondria organelle. However, benefits associated with the modification of this simple and widely used moiety used as a mitochondrial transporter remains largely unexplored. Here we demonstrate the drastic change in properties displayed by a new series of TPP mono and dications derivatives (Figure 1). Our studies illustrate that presence of methyl group(s) on key positions within the ring result in a significant increase in the accumulation properties of these new carriers. Our theoretical work also, reveals strong correlations between mitochondria uptake and molecular volume, surface area, and chemical hardness. Most notably, the molecular volume has been shown to be a strong predictor of accumulation for both mono- and bis-TPP<sup>+</sup> salts. Furthermore, we have illustrated the differential ability of the monocationic carriers by delivering FITC-CL conjugates and undertaking PDT studies on HeLa cells and FU97 gastric cancer cells (Figure 1b and 1c)We anticipate our results to be the starting point of a broader multidisciplinary effort to rationally design tailored suit-to-purpose mitochondrial delivery agents.

New T*PP lipophilic cations for enhanced mitochondrial delivery

ACS Fall 2020 Virtual Meeting

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