Novel cobalt complex inhibitors of mitochondrial calcium uptake

Reperfusion of the ischaemic myocardium leads to intracellular calcium over load followed by mitochondrial dysfunction, resulting in insufficient energ y supply and ultimately myocardial necrosis, Ruthenium red (RR), a potent m itochondrial calcium uptake inhibitor, prevents this disruption to mitochon drial metabolism and improves post reperfusion recovery. This therefore sug gested that mitochondrial calcium influx is an attractive target for the tr eatment of reperfusion injury. However, RR is unsuitable for therapeutic us e, so we undertook a search for novel compounds which inhibit mitochondrial calcium uptake. The most potent compounds discovered were simple tris(ethy lenediamine) transition metal complexes and dinuclear Co complexes. The str ucture-activity relationship (SAR) of these small molecules has helped to d efine the structural requirements for inhibition of calcium transport by ou tlining the size and charge dependency of the interactive site on the mitoc hondrial calcium uniporter. (C) 1999 Elsevier Science Ltd. All rights reser ved.