1,5‐Disubstituted‐1,2,3‐triazoles as inhibitors of the mitochondrial Ca²⁺‐activated F₁F_O‐ATP(hydrol)ase and the permeability transition pore

Abstract

The mitochondrial permeability transition pore (mPTP), a high‐conductance channel triggered by a sudden Ca2+ concentration increase, is composed of the F1FO‐ATPase. Since mPTP opening leads to mitochondrial dysfunction, which is a feature of many diseases, a great pharmacological challenge is to find mPTP modulators. In our study, the effects of two 1,5‐disubstituted 1,2,3‐triazole derivatives, five‐membered heterocycles with three nitrogen atoms in the ring and capable of forming secondary interactions with proteins, were investigated. Compounds 3a and 3b were selected among a wide range of structurally related compounds because of their chemical properties and effectiveness in preliminary studies. In swine heart mitochondria, both compounds inhibit Ca2+‐activated F1FO‐ATPase without affecting F‐ATPase activity sustained by the natural cofactor Mg2+. The inhibition is mutually exclusive, probably because of their shared enzyme site, and uncompetitive with respect to the ATP substrate, since they only bind to the enzyme–ATP complex. Both compounds show the same inhibition constant (Kʹi), but compound 3a has a doubled inactivation rate constant compared with compound 3b. Moreover, both compounds desensitize mPTP opening without altering mitochondrial respiration. The results strengthen the link between Ca2+‐activated F1FO‐ATPase and mPTP and suggest that these inhibitors can be pharmacologically exploited to counteract mPTP‐related diseases.

Molecular and Supramolecular Structure of the Mitochondrial Oxidative Phosphorylation System: Implications for Pathology

“…Interestingly, Ca 2+ rise in the mitochondrial matrix initiates a cascade of events which lead to cell death. So, in recent times Ca 2+ binding to the F 1 F O -ATPase in replacement of Mg 2+ , an event which can easily occur in the presence of relatively high Ca 2+ concentrations in mitochondria, since the enzyme affinity for Ca 2+ is lower than that for Mg 2+ [ 193 , 196 ], has been associated with the mPTP opening [ 192 , 195 , 197 , 198 , 199 ].…”

“…Accordingly, when Ca 2+ replaces Mg 2+ in the catalytic binding site, the cation insertion in the Ca 2+ -activated F 1 F O -ATPase, due to the higher steric hindrance, would promote conformational changes of F 1 domain, in turn transmitted by the peripheral stalk [198] to membrane subunits that form the mPTP [198]. Notably, when the Ca 2+ -activated F 1 F O -ATPase activity is decreased by various inhibitors, the mPTP formation is delayed or even prevented [196,197,200]. The c-ring contains two different phospholipids at the two opposite sides of its cavity.…”

Recent Progress in Catalytic Synthesis of 1,2,3-Triazoles

“…Notably, several sensitive functionalities such as chloro-, methyl-, methoxy-, and nitro-were unaffected under the present reaction conditions, and the reaction also tolerated ortho-substitution on the aromatic ring. Such substrates were further revealed to possess a very interesting biological activity as F 1 F O -ATP(hydrol)ase inhibitors and in preventing permeability transition pore (mPTP) opening [96].…”

Sulfide affects the mitochondrial respiration, the Ca2+-activated F1FO-ATPase activity and the permeability transition pore but does not change the Mg2+-activated F1FO-ATPase activity in swine heart mitochondria

“…Accordingly, the membrane depolarization (decrease in Δφ) ascribed to PTP formation was detected by the increase in the fluorescence intensity ratio which corresponds to an increased JC-10 aggregate/JC-10 monomers ratio. [20,39]. All measurements were processed by LabSolutions RF software.…”