Book of Abstracts - Ruhr-Universität Bochum

OP-28
ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum
Mechanistic and Synthetic Studies of Bio-compatible
Carbon Monoxide-Releasing Molecules
Anthony J. Atkin, a Ian J. S. Fairlamb, a Jason M. Lynam, *a and Wei-Qiang Zhang a
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
E-mail: jml12@york.ac.uk
Carbon monoxide – releasing molecules (CO-RMs) have become an exciting target for therapeutic
intervention. 1 CO generated in mammals is responsible for a variety of important physiological
functions and is a fundamental signalling mediator. CO gas also elicits a range of beneficial
therapeutic effects, although the associated toxicity and inherent poor selectivity of CO in its naked
form is clearly not ideal. The method of choice for taking advantage of the beneficial role of CO is to
utilise a CO-RM, such as a metal carbonyl complex, which act as a source of CO in biological
systems.
Although the biological effects of CO (and CO-RMs) are now well established, there is little
understanding of the precise requirements needed for transition metal carbonyl compounds to act as
effective therapeutic agents. We have therefore undertaken a systematic study in order to elucidate the
factors that may control CO-release. 2 This has allowed us to determine which metal-carbonyl scaffolds
have the greatest potential to act as CO-RMs which has in turn informed a synthetic programme
designed to prepare a library of novel complexes with bio-compatible ligands. For example, we have
prepared a range of Group 6 compounds which contain both natural and non-natural amino acids
incorporated into the coordination sphere of the metal through a range of binding modes (Figure 1).
This presentation will detail the key results from the findings of our synthetic and mechanistic studies
into the CO-release process, as well as the behaviour of the new bio-compatible CO-RMs. For
example, we have demonstrated how the CO-release behaviour of the amino ester derivatives 1 may
be simply modulated by the choice of the substituent on the organic ligand. A mechanistic study has
demonstrated that this process is controlled by loss of the amino ester and therefore supply of the
“M(CO)5” (M = Cr, Mo, W) fragment is crucial to CO-release in aqueous systems. For the CO-RMs
with structure 2 the rate of CO-release correlates with the electrophilicity of the carbene carbon,
consistent with a mechanism in which nucleophilic attack of water initiates the CO-release process.
The scope of biologically-relevant ligands which can be introduced into the coordination sphere of the
metal will also be detailed.
References
1. (a) T. T. Johnson, B. E. Mann, J. E. Clark, R. Foresti, C. J. Green, R. Motterlini, R. Angew. Chem.
Int. Ed. 2003, 42, 3722-3729. (b) I. J. S. Fairlamb, A.-K. Duhme-Klair, J. M. Lynam, B. E. Moulton,
C. T. O’Brien, P. Sawle, J. Hammad, R. Motterlini, Bioorg. & Med. Chem. Lett. 2006, 16, 995-998.
(c) P. Sawle, J. Hammad, I. J. S. Fairlamb, B. E. Moulton, C. T. O'Brien, J. M. Lynam, A.-K. Duhme-
Klair, R. Foresti, R. Motterlini, J. Pharmacol. Exp. Ther. 2006, 318, 403-410. (d) I. J. S. Fairlamb, J.
M. Lynam, B. E. Moulton, I. E. Taylor, A. K. Duhme-Klair, P. Sawle, R. Motterlini, Dalton Trans.
2007, 3603-3605.
2. W.-Q. Zhang, A. J. Atkin, R. J. Thatcher, A. C. Whitwood, I. J. S. Fairlamb, J. M. Lynam, Dalton
Trans. 2009, 4351-4358.
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