Biochemical properties and bioactivities of carbon monoxide-releasing molecules (CO-RMs)
Carbon monoxide (CO), synonymous of the "silent killer", is rapidly emerging as an important and versatile mediator of physiological processes. The study of CO has been hampered by the lack of a means to simulate its release biologically. Current means to replicate the effects of CO include, most notably, the use of CO gas and upregulation of haem oxygenase-1 (HO-1) to generate endogenous CO. Both are limited in their approach and offer only a partial solution. The recent discovery that certain transition metal carbonyls function as CO-releasing molecules (CO-RMs) in biological systems highlighted the potential of exploiting this and similar classes of compounds as a stratagem to deliver CO for research and therapeutic purposes. Initially a large portfolio of CO-RMs was investigated to determine their CO releasing capability. This thesis examines a number of aspects related to the characterisation of a core group of CO-RMs including: a) CORM-3, the prototypic water soluble transition metal carbonyl b) CORM-A1, a water soluble CO-RM without a metal centre c) CORM-319, an iron based water soluble CO-RM and d) CORM-311, an ethanol soluble iron centred CO-RM. Specifically, the study will examine CO-RMs for their ability to: i) release CO ii) suppress LPS-induced nitrite production iii) promote toxicity iv) induce haem oxygenase (HO) activity and HO-1 expression and v) modulate inducible nitric oxide synthase (iNOS) expression. These different aspects of CO-RM characterisation were addressed using biochemical, molecular biology and cell culture techniques. Further work was also carried out determining certain chemical aspects of each CO-RM including the decomposition rate and pH/temperature stability. The study into the CO release of the new CO-RMs emphasizes the versatile potential of the metal carbonyl complexes and related compounds. This research on CO-RMs will help lay the foundations for a novel therapeutic agent based on the delivery of safe and controlled quantities of CO.