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Zwitterionic Protonophore Derived from 2-(2-Hydroxyaryl)alkenylphosphonium as an Uncoupler of Oxidative Phosphorylation.
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2019-08-16 , DOI: 10.1021/acs.bioconjchem.9b00516 Tatyana I Rokitskaya 1 , Natalia V Terekhova 2 , Lyudmila S Khailova 1 , Elena A Kotova 1 , Egor Y Plotnikov 1 , Dmitry B Zorov 1 , Dmitry A Tatarinov 2, 3 , Yuri N Antonenko 1
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2019-08-16 , DOI: 10.1021/acs.bioconjchem.9b00516 Tatyana I Rokitskaya 1 , Natalia V Terekhova 2 , Lyudmila S Khailova 1 , Elena A Kotova 1 , Egor Y Plotnikov 1 , Dmitry B Zorov 1 , Dmitry A Tatarinov 2, 3 , Yuri N Antonenko 1
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2-(2-Hydroxyaryl)alkenylphosphonium salts (here coined as PPR) representing derivatives of quaternary phosphonium with two phenyl (P) and one alkyl (R) substituents linked through alkenyl bridge to substituted phenol were applied here to planar bilayer lipid membranes (BLM), isolated mitochondria, and cell culture. PPR with six carbon atoms in R (PP6) induced proton-selective currents across BLM and caused mitochondrial uncoupling. In particular, PP6 at submicromolar concentrations accelerated respiration, decreased membrane potential, and reduced ATP synthesis in isolated rat liver mitochondria (RLM). Methylation of a hydroxyl group substantially suppressed the protonophoric activity of PP6 on BLM and its uncoupling potency in RLM. Of note, the methylated derivative PP6-OMe was synthesized here via a new synthetic route including cyclization of PP6 with subsequent ring opening. PPR were considered as protonophoric uncouplers of a zwitterionic type, capable of penetrating membranes both as a zwitterion composed of a deprotonated phenol and a cationic quaternary phosphonium, and as a protonated cation. The protonophoric and uncoupling properties of PPR found here were speculated to account for their strong antibacterial activity described previously.
中文翻译：
衍生自2-（2-羟基芳基）烯基phosph的两性离子质子体作为氧化磷酸化的解偶联剂。
代表季phospho衍生物的2-（2-羟基芳基）烯基phosph盐（在此以PPR命名）具有两个苯基（P）和一个通过烯基桥与取代酚连接的烷基（R）取代基的衍生物被应用于平面双层脂质膜（BLM ），分离的线粒体和细胞培养。R中具有六个碳原子的PPR（PP6）诱导了BLM上的质子选择性电流，并导致线粒体解偶联。特别是，在分离的大鼠肝线粒体（RLM）中，亚微摩尔浓度的PP6加快了呼吸作用，降低了膜电位，并降低了ATP合成。羟基的甲基化基本上抑制了PP6对BLM的质子活性及其在RLM中的解偶联力。值得注意的是 甲基化的衍生物PP6-OMe在这里通过新的合成途径合成，包括将PP6环化并随后开环。PPR被认为是两性离子型的质子解偶联剂，能够以由去质子化的酚和阳离子季phospho组成的两性离子和质子化阳离子的形式穿透膜。据推测，此处发现的PPR的质子和解偶联性质是由于其先前所述的强抗菌活性。
更新日期：2019-08-02
中文翻译：
衍生自2-（2-羟基芳基）烯基phosph的两性离子质子体作为氧化磷酸化的解偶联剂。
代表季phospho衍生物的2-（2-羟基芳基）烯基phosph盐（在此以PPR命名）具有两个苯基（P）和一个通过烯基桥与取代酚连接的烷基（R）取代基的衍生物被应用于平面双层脂质膜（BLM ），分离的线粒体和细胞培养。R中具有六个碳原子的PPR（PP6）诱导了BLM上的质子选择性电流，并导致线粒体解偶联。特别是，在分离的大鼠肝线粒体（RLM）中，亚微摩尔浓度的PP6加快了呼吸作用，降低了膜电位，并降低了ATP合成。羟基的甲基化基本上抑制了PP6对BLM的质子活性及其在RLM中的解偶联力。值得注意的是 甲基化的衍生物PP6-OMe在这里通过新的合成途径合成，包括将PP6环化并随后开环。PPR被认为是两性离子型的质子解偶联剂，能够以由去质子化的酚和阳离子季phospho组成的两性离子和质子化阳离子的形式穿透膜。据推测，此处发现的PPR的质子和解偶联性质是由于其先前所述的强抗菌活性。
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