This project aims to synthesise deliverable organometallic compounds which release the therapeutic small molecule carbon monoxide (CO) when subjected to a suitable ‘trigger'. CO, like nitric oxide (NO), is a vasodilatating substance and has been implicated in the regulation of large number of physiological and pathological processes, including inhibition of platelet aggregation and hormone release. Recognition of these roles has begun to drive research into CO-releasing therapeutics, including initial exploration of metallosystems, but the area is in its infancy. We have identified a new family of iron-containing molecules with benign co-ligands and which offer a starting point for research on the dynamics of triggered release. These possess ferracyclic structures analogous to those found at the active site of certain enzymes: an iron atom is held within an organometallic five-membered ring formed and importantly these systems bind up to three CO molecules. The first stage of the project will focus on synthesising water- and lipo-soluble systems by modification of the ferracyclic ring which are relevant to deliverability and targeting. For example attachment of ionic groups such phosphate will give enhanced water-solubility, while introducing alkyl groups will contribute to lipo-solubility.

The second phase of the project will focus on understanding detailed mechanistic aspects of triggered CO release and how this can be tailored by modification of the iron co-ordination sphere. Thus the kinetics will be investigated using a range of advanced techniques, such as stopped-flow spectroscopy and coupled spectroscopy-electrochemistry, with release triggered by photolytic, redox or chemical activation pathways.

The generation of superoxide takes place in biological systems when subjected to stress and this can lead to extensive tissue damage. Carbon monoxide is known to act as an anti-inflammatory and targeted release at the site of damage is attractive. We will seek to design complexes which release CO in a chemically triggered response to superoxide in the final phase of the project.

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