Metal Carbonyls. A New Class of Pharmaceuticals?
by Brian Mann
In recent years, it has become apparent that CO is an important signalling molecule in mammals, and is probably as important as NO. Perhaps one of the clearest applications of CO gas in medicine is the recent paper in Nature Medicine describing that it suppresses organ graft rejection and arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. (L.E. Otterbein, B.S. Zuckerbraun, M. Haga, F. Liu, R. Song, A. Usheva, C. Stachulak, N. Bodyak, R.N. Smith, E. Csizmadia, S. Tyagi, Y. Akamatsu, R.J. Flavell, T.R. Billiar, E. Tzeng, F.H. Bach, A.M.K. Choi and M.G. Soares, Nature Medicine, 2003, 9, 183-190.) Carbon monoxide acts on the cardiovascular system and produces a wide range of responses including:-
- It regulates blood pressure under stress conditions,
- It modulates vascular smooth muscle tone,
- It protects against ischemia, septic shock, and hyperoxia
More information can be found at
R. Wang, (ed.), "Carbon Monoxide and Cardiovascular Functions", CRC Press, Boca Raton, 2002, 320 pp.
L.E. Otterbein, Antioxid. Redox Signal., 2002, 4, 309.
We have shown that metal carbonyls can perform many of these functions, presumably acting as CO releasing molecules. Working with Dr. Roberto Motterlini and Professor Colin Green at Northwick Park Hospital, London, we have shown that [Ru(CO)3Cl(glycinate)]
- Causes vasodilation in pre-contracted rat aortic rings.
- Attenuates coronary vasoconstriction in hearts ex vivo.
- Significantly reduces acute hypertension in vivo.
- Prevents damage due to ischemia in an isolated rat
- Reduces rejection of transplanted hearts in mice.
- Blood platelet aggregation is partially inhibited.
- NO production by macrophages is partially inhibited.
R. Motterlini, J.E. Clark, R. Foresti, P. Sarathchandra, B.E. Mann and C.J. Green, Circ. Res., 2002, 90, e17.
J.E. Clark, P. Naughton, S. Shurey, C.J. Green, T.R. Johnson, B.E. Mann, R. Foresti and R. Motterlini, Circ. Res., 2003, 93, e2-e8.
R.A. Motterlini and B.E. Mann, PCT Int. Appl., 2002, 86 pp. WO 0292075 A2 20021121. Chem. Abs., 2002, 137, 375272.
B.E. Mann, T.R. Johnson, J.E. Clark, R. Foresti, C. Green and R. Motterlini, Angew. Chem., Int. Ed., 2003, 42, 3722-3729.
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[Brian Mann's home page]
[Department of Chemistry]
[University of Sheffield]
Date:- September 4, 2003.