Ester prodrugs of malonate with enhanced intracellular delivery protect against cardiac ischemia-reperfusion injury in vivo

Prag, H. A. et al. (2022) Ester prodrugs of malonate with enhanced intracellular delivery protect against cardiac ischemia-reperfusion injury in vivo. Cardiovascular Drugs and Therapy, 36(1), pp. 1-13. (doi: 10.1007/s10557-020-07033-6) (PMID:32648168) (PMCID:PMC8770414)

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

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Caldwell, Dr Stuart and Pala, Ms Laura and Hartley, Professor Richard
• Authors: Prag, H. A., Pala, L., Kula-Alwar, D., Mulvey, J. F., Luping, D., Beach, T. E., Booty, L. M., Hall, A. R., Logan, A., Sauchanka, V., Caldwell, S. T., Robb, E. L., James, A. M., Xu, Z., Saeb-Parsy, K., Hartley, R. C., Murphy, M. P., and Krieg, T.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Cardiovascular Drugs and Therapy
• Publisher: Springer
• ISSN: 0920-3206
• ISSN (Online): 1573-7241
• Published Online: 09 July 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Cardiovascular Drugs and Therapy 36(1): 1-13
• Publisher Policy: Reproduced under a Creative Commons License
• Data DOI: 10.5525/gla.researchdata.1007

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
172617		Exploring mitochondrial metabolism in health and disease using targeted biological chemistry	Richard Hartley	Wellcome Trust (WELLCOTR)	110158/Z/15/Z	Chemistry