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A few ruthenium based metal carbonyl complexes, e.g. CORM-2 and CORM-3, have therapeutic activity attributed to their ability to deliver CO to biological targets. In this work, a series of related complexes with the formula [Ru(CO)3Cl2L] (L = DMSO (3), L-H3CSO(CH2)2CH(NH2)CO2H) (6a); D,L-H3CSO(CH2)2CH(NH2)CO2H (6b); 3-NC5H4(CH2)2SO3Na (7); 4-NC5H4(CH2)2SO3Na (8); PTA (9); DAPTA (10); H3CS(CH2)2CH(OH)CO2H (11); CNCMe2CO2Me (12); CNCMeEtCO2Me (13); CN(c-C3H4)CO2Et) (14)) were designed, synthesized and studied. The effects of L on their stability, CO release profile, cytotoxicity and anti-inflammatory properties are described. The stability in aqueous solution depends on the nature of L as shown using HPLC and LC-MS studies. The isocyanide derivatives are the least stable complexes, and the S-bound methionine oxide derivative is the more stable one. The complexes do not release CO gas to the headspace, but release CO2 instead. X-ray diffraction of crystals of the model protein Hen Egg White Lysozyme soaked with 6b (4UWN) and 8 (4UWN) shows the addition of Ru(II)(CO)(H2O)4 at the His15 binding site. Soakings with 7(4UWN) produced the metallacarboxylate [Ru(COOH)(CO)(H2O)3](+) bound to the His15 site. The aqueous chemistry of these complexes is governed by the water-gas shift reaction initiated with the nucleophilic attack of HO(-) on coordinated CO. DFT calculations show this addition to be essentially barrierless. The complexes have low cytotoxicity and low hemolytic indices. Following i.v. administration of CORM-3, the in vivo bio-distribution of CO differs from that obtained with CO inhalation or with heme oxygenase stimulation. A mechanism for CO transport and delivery from these complexes is proposed.

The discovery of the biological effects of carbon monoxide (CO) in recent years strongly suggests that CO could find applications as a therapeutic agent. CO is a highly toxic gas when used at industrial doses, due in part to its binding affinity to hemoglobin. Since hemoglobin binds CO with the highest affinity in vivo, it also constitutes a major barrier to the delivery of CO to tissues in need of therapy. A method of delivering CO that can bypass hemoglobin is the use of pro-drugs or CO carriers, called CO-releasing molecules (CO-RMs) that become activated and release CO in tissues in need of treatment. Organometallic carbonyl complexes are best suited to play the role of CO carriers, and indeed the natural CO carrier molecules hemoglobin and myoglobin belong to this class of chemical compounds. Here we describe the preparation of novel molybdenum CO-RMs of general formula Mo(CO)3(CNCR′R″CO2R‴)3 (R′, R″ = H, Me, iPr, CH2Ph, CO2Li, −CH2CH2–, −CH2(CH2)3CH2–; R‴ = H, Li), which present favorable druglike c...

Decarbonylation of the tertiary aldehydes 4-ethyl-4-formyl-hexanenitrile (2) and 2-methyl-2-phenylpropanal (4) promoted by dioxygen occurs at room temperature only if suspended in water probably via the sequential acyl radical–CO liberation–tertiary radical that is promoted by an ‘on water’ process originating preferentially from the corresponding tertiary hydroperoxide.

The complex fac-[Mo(CO)(3)(histidinate)]Na has been reported to be an effective CO-Releasing Molecule in vivo, eliciting therapeutic effects in several animal models of disease. The CO releasing profile of this complex in different settings both in vitro and in vivo reveals that the compound can readily liberate all of its three CO equivalents under biological conditions. The compound has low toxicity and cytotoxicity and is not hemolytic. CO release is accompanied by a decrease in arterial blood pressure following administration in vivo. We studied its behavior in solution and upon the interaction with proteins. Reactive oxygen species (ROS) generation upon exposure to air and polyoxomolybdate formation in soaks with lysozyme crystals were observed as processes ensuing from the decomposition of the complex and the release of CO.

Objective— Carbon monoxide (CO) is a weak soluble guanylyl cyclase stimulator, leading to transient increases in cGMP and vasodilation. The aim of the present work was to measure the effect of CO-releasing molecules (CORMs) on the cGMP/nitric oxide (NO) pathway and to evaluate how selected CORMs affect NO-induced vasorelaxation. Methods and Results— Incubation of smooth muscle cells with some but not all of the CORMs caused a minor increase in cGMP levels. Concentration-response curves were bell-shaped, with higher CORMs concentrations producing lower increases in cGMP levels. Although exposure of cells to CORM-2 enhanced cGMP formation, we observed that the compound inhibited NO-stimulated cGMP accumulation in cells and NO-stimulated soluble guanylyl cyclase activity that could be reversed by superoxide anion scavengers. Reactive oxygen species generation from CORMs was confirmed using luminol-induced chemiluminescence and electron spin resonance. Furthermore, we observed that NO is scavenged by CORM-2. When used alone CORM-2 relaxed vessels through a cGMP-mediated pathway but attenuated NO donor-stimulated vasorelaxation. Conclusion— We conclude that the CORMs examined have context-dependent effects on vessel tone, as they can directly dilate blood vessels, but also block NO-induced vasorelaxation.