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2.B.74.  The Triphenylphosphonium Ylide (TPPY) [Ilide-type Protonophore] Family 

Triphenylphosphonium ylides are commonly used as key intermediates in the Wittig reaction. Based on the known acidities of stabilized ylide precursors, Kirsanov et al. 2023 proposed that a methylene group adjacent to phosphorus in these compounds could ensure proton shuttling across lipid membranes. Kirsanov et al. 2023 synthesized (decyloxycarbonylmethyl)triphenylphosphonium bromide (CMTPP-C(10)) by reaction of triphenylphosphine with decyl bromoacetate. This phosphonium salt precursor of the ester-stabilized phosphorus ylide along with its octyl (CMTPP-C(8)) and dodecyl (CMTPP-C(12)) analogues was found to be a carrier of protons in mitochondrial, chloroplast and artificial lipid membranes, suggesting that it can reversibly release hydrogen ions and diffuse through the membranes in both zwitterionic (ylide) and cationic forms. The CMTPP-C(10)-mediated electrical current across planar bilayer lipid membranes exhibited pronounced proton selectivity. Similar to conventional protonophores, known to uncouple electron transport and ATP synthesis, CMTPP-C(n) (n = 8, 10, 12) stimulated mitochondrial respiration, while decreasing membrane potential, at micromolar concentrations, thereby showing the classical uncoupling activity in mitochondria. CMTPP-C(12) also caused dissipation of the transmembrane pH gradient on chloroplast membranes. CMTPP-C(10) exhibited substantially lower toxicity in cell culture than C(12)TPP. Thus, a new class of ylide-type protonophores is described, which is of substantial interest due to promising therapeutic properties of uncouplers (Kirsanov et al. 2023).

References associated with 2.B.74 family:

Kirsanov, R.S., L.S. Khailova, T.I. Rokitskaya, I.R. Iaubasarova, P.A. Nazarov, A.A. Panteleeva, K.G. Lyamzaev, L.B. Popova, G.A. Korshunova, E.A. Kotova, and Y.N. Antonenko. (2023). Ester-stabilized phosphorus ylides as protonophores on bilayer lipid membranes, mitochondria and chloroplasts. Bioelectrochemistry 150: 108369. 36638678