Triphenylphosphonium salts of 1,2,4-benzothiadiazine 1,1-dioxides related to diazoxide targeting mitochondrial ATP-sensitive potassium channels

Bioorg Med Chem Lett. 2013 Nov 1;23(21):5878-81. doi: 10.1016/j.bmcl.2013.08.091. Epub 2013 Sep 6.

Abstract

The present work aims at identifying new ion channel modulators able to 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 chain at the 3-position of 4H-1,2,4-benzothiadiazine 1,1-dioxides KATP channel openers increased, in most cases, the selectivity towards the pancreatic-type (SUR1/Kir6.2) KATP channel. In order to target cardiac mitoKATP channels, we decided to introduce a triphenylphosphonium group through an ester link on the SUR1-selective (R)-7-chloro-3-(1-hydroxy-2-propyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide. The new compounds were found to preserve an inhibitory activity on insulin secretion (SUR1-type KATP channel openers) while no clear demonstration of an impact on mitochondria from cardiomyocytes (measurement of oxygen consumption, respiratory parameters and ATP production on H9C2 cells) was observed. However, the most active (inhibition of insulin release) compound 17 was found to penetrate the cardiac cells and to reach mitochondria.

Keywords: ATP; ATP-sensitive potassium channels; Benzothiadiazine dioxides; DCC; DCVC; DMSO; Diazoxide; HOBt; Kir; Mitochondria; N,N′-dicyclohexylcarbodiimide; N-hydroxysuccinimide; NHS; SUR; TMS; Triphenylphosphonium salts; adenosine triphosphate; dimethylsulfoxide; dry column vacuum chromatography; hydroxybenzotriazole; inwardly rectifying potassium channel; mitoK(ATP) channel; mitochondrial ATP-sensitive potassium channel; sulfonylurea receptor; tetramethylsilane.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzothiadiazines / chemistry*
  • Benzothiadiazines / pharmacology*
  • Cell Line
  • Diazoxide / chemistry*
  • Diazoxide / pharmacology*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Organophosphorus Compounds / chemistry
  • Organophosphorus Compounds / pharmacology
  • Potassium Channels / metabolism*
  • Rats

Substances

  • Benzothiadiazines
  • Organophosphorus Compounds
  • Potassium Channels
  • mitochondrial K(ATP) channel
  • Diazoxide