In this study, unique methyl-functionalized derivatives (T*PP) of the drug carrier triphenylphosphonium (TPP) that exhibit significant enhancement of the accumulation of both the cation and its conjugated cargo in cell mitochondria are designed. We show that the presence of methyl group(s) at key positions within the phenyl ring results in an increase in the hydrophobicity and solvent accessible surface area of T*PP. In particular, when the para position of the phenyl ring in T*PP is functionalized with a methyl group, the cation is most exposed to the surrounding environment, leading to a large decrease in water entropy and an increase in the level of van der Waals interaction with and partition into a nonpolar solvent. Therefore, stronger binding between the hydrophobic T*PP and mitochondrial membrane occurs. This is exemplified in a (hexachloro-fluorescein)-TPP conjugate system, where an ∼12 times increase in the rate of mitochondrial uptake and a 2 times increase in photodynamic therapy (PDT) efficacy against HeLa and FU97 cancer cells are achieved when TPP is replaced with T*PP. Importantly, nearly all the FU97 cells treated with the (hexachloro-fluorescein)-T*PP conjugate are killed as compared to only half the population of cells in the case of the (hexachloro-fluorescein)-TPP conjugate at a similar PDT light dosage. This study thus forms a platform for the healthcare community to explore alternative TPP derivatives that can act as optimal drug transporters for enhanced mitochondrially targeted therapies.

Mechanochemistry is emerging as a powerful solvent-free approach to chemical synthesis, having been applied to metal oxides, pharmaceutical materials, organic compounds and to a lesser extent, coordination complex synthesis. Notably, examples of applications of mechanochemical methodologies in the synthesis of main-group compounds are few and far between. Herein, we demonstrate that ball milling enabled the solvent-free synthesis of a range of phosphazane frameworks with a broad substrate scope, yielding seven new acyclic and macrocyclic species. The strength of this methodology is highlighted by a fast, selective and high-conversion product generation from poorly soluble starting materials, thereby demonstrating mechanochemistry as a real alternative to solution-based methods in synthetic main-group chemistry.

Bench-top stable cis-cyclodiphosph(v/v)azanes are demonstrated to form robust R21(8) bifurcated hydrogen-bonds and PSe⋯Br halogen bonds. This work highlights the potential of cyclodiphosph(v/v)azane building blocks in creating new supramolecular assemblies.

Mechanochemistry has been established to be an environmentally-friendly way of conducting reactions in a solvent-free manner. The development of mechanochemical orthogonal reactions, in which multiple reagents are milled together, can be a powerful strategy to selectively yield the desired product. Such orthogonal syntheses are rare, especially those involving main group frameworks - based on bonds other than carbon - which are yet to be reported. Herein, we demonstrate the direct formation of air- and moisture-stable cyclophosph(v)azanes enabled by an orthogonal "one-step one-pot" mechanochemical reaction. In addition, detailed hydrolytic- and air-stability studies, conducted over one and 12 months, respectively, revealed high robustness of these compounds.