Novel cobalt complex inhibitors of mitochondrial calcium uptake.
Reperfusion of the ischaemic myocardium leads to intracellular calcium overload followed by mitochondrial dysfunction, resulting in insufficient energy supply and ultimately myocardial necrosis. Ruthenium red (RR), a potent mitochondrial calcium uptake inhibitor, prevents this disruption to mitochondrial metabolism and improves post reperfusion recovery. This therefore suggested that mitochondrial calcium influx is an attractive target for the treatment of reperfusion injury. However, RR is unsuitable for therapeutic use, so we undertook a search for novel compounds which inhibit mitochondrial calcium uptake. The most potent compounds discovered were simple tris(ethylenediamine) transition metal complexes and dinuclear Co complexes. The structure-activity relationship (SAR) of these small molecules has helped to define the structural requirements for inhibition of calcium transport by outlining the size and charge dependency of the interactive site on the mitochondrial calcium uniporter.
Unitt
J F
JF
Biochemistry Department, Astra Charnwood, Leicestershire, UK. john.unitt@charnwood.gb.astra.com
Boden
K L
KL
Wallace
A V
AV
Ingall
A H
AH
Coombs
M E
ME
Ince
F
F
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003035:Cobalt / Q000737:chemistry*; D005029:Ethylenediamines / Q000737:chemistry / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D017136:Ion Transport; D008564:Membrane Potentials / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D005029:Ethylenediamines; D009942:Organometallic Compounds; C096699:tris(ethylenediamine)cobalt(III); D003035:Cobalt; D002118:Calcium