Triphenylphosphonium salts of 1,2,4-benzothiadiazine 1,1-dioxides related to diazoxide targeting mitochondrial ATP-sensitive potassium channels
作者:Céline Constant-Urban、Mounia Charif、Eric Goffin、Jean-Claude Van Heugen、Benaïssa Elmoualij、Patrice Chiap、Ange Mouithys-Mickalad、Didier Serteyn、Philippe Lebrun、Bernard Pirotte、Pascal De Tullio
DOI:10.1016/j.bmcl.2013.08.091
日期:2013.11
target mitochondrial ATP-sensitive potassium channels (mitoKATP channels). An innovative approach should consist in fixing a cationic and hydrophobic triphenylphosphonium fragment on the structure of known KATP channel openers. Such phosphonium salts are expected to cross the biological membranes and to accumulate into mitochondria. Previous works revealed that the presence of an (R)-1-hydroxy-2-propylamino
本工作旨在确定能够靶向线粒体ATP敏感性钾通道(mitoK ATP通道)的新型离子通道调节剂。一种创新方法应包括将阳离子和疏水性三苯基phosph片段固定在已知的K ATP通道开放剂的结构上。预期此类phospho盐穿过生物膜并积聚到线粒体中。 先前的工作表明,在大多数情况下,在4 H -1,2,4-苯并噻二嗪1,1-二氧化物K ATP通道开放剂的3位上存在(R)-1-羟基-2-丙基氨基链,对胰腺型(SUR1 / Kir6.2)K ATP通道的选择性。为了靶向心脏mitoK ATP通道,我们决定通过SUR1选择性(R)-7-氯-3-(1-羟基-2-丙基)氨基-4 H -1上的酯键引入三苯基phosph基团,2,4-苯并噻二嗪1,1-二氧化物。发现新化合物保留了对胰岛素分泌的抑制活性(SUR1型K ATP通道开放剂),但没有观察到明显的证据表明心肌细胞对线粒体有影响(氧气消耗量,呼吸参数和H