Ester Prodrugs of Malonate with Enhanced Intracellular Delivery Protect Against Cardiac Ischemia-Reperfusion Injury In Vivo

• DOI: 10.1007/s10557-020-07033-6
• Publication Date: 2020-07-09T07:37:50Z
• Authors: Hiran A. Prag; Laura Pala; Duvaraka Kula-Alwar; John F. Mulvey; Du Luping; Timothy E. Beach; Lee M. Booty; Andrew R. Hall; Angela Logan; Volha Sauchanka; Stuart T. Caldwell; Ellen L. Robb; Andrew M. James; Zhelong Xu; Kourosh Saeb-Parsy; Richard C. Hartley; Michael P. Murphy; Thomas Krieg
• Keywords: Malonate

Abstract Purpose Mitochondrial reactive oxygen species (ROS) production upon reperfusion of ischemic tissue initiates the ischemia/reperfusion (I/R) injury associated with heart attack. During ischemia, succinate accumulates and its oxidation by dehydrogenase (SDH) drives ROS production. Inhibition accumulation and/or dimethyl malonate (DMM), a cell permeable prodrug SDH inhibitor malonate, can decrease I/R injury. However, DMM is hydrolysed slowly, requiring administration to prior precluding patients at point reperfusion, for example same time as unblocking coronary artery following To accelerate delivery, here we developed more rapidly hydrolysable esters. Methods We synthesised series esters assessed their uptake hydrolysis isolated mitochondria, C2C12 cells in mice vivo. In addition, protection against cardiac using an vivo mouse model acute myocardial infarction. Results found that diacetoxymethyl diester (MAM) most delivered large amounts Furthermore, MAM could inhibit mitochondrial from was protective when added reperfusion. Conclusions The protect clinically relevant model.