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In the last decade, the use of carbon monoxide (CO) as a therapeutic agent molecule has received increasing attention in medicine due to its documented beneficial effects. There are three main areas where CO is evaluated as a clinically valuable medical agent: 1) inflammation, 2) cardiovascular diseases and 3) organ preservation and transplantation. The anti-inflammatory properties of CO have been corroborated in a large number of animal models including rheumatoid arthritis, diabetes and acute hepatitis. The protective effects of CO as vasodilator have been successfully evaluated on several cardiovascular diseases including pulmonary arterial hypertension, for which there is no cure. Carbon monoxide proved effectiveness in prolonging organ graft survival, particularly in heart and kidney transplants for which CO inhalation has entered Phase II clinical trials. Despite its current evaluation in novel therapies, the use of gaseous CO poses several problems related to safe handling and delivery to specific target sites in a controlled and measurable fashion. The challenges associated with clinical application of the gas by inhalation have sparked the design of CO-releasing molecules (CORMs) as an alternative approach to the administration of CO (e.g. orally or by injection). However, none of the characterized CO-releasing molecules displays drug-like acceptable properties such as: a) water solubility and biocompatibility, b) stability in aqueous aerobic media, c) slow decay of the M(CO)x fragment in the blood, d) low toxicity and rapid excretion of the metal scaffold after CO release. In order to meet the above mentioned requirements for a pharmaceutically acceptable CORM, this research project intends to synthesize, investigate, develop and apply new Re-based CO-releasing molecules coupled to with biomolecules. In particular cyanocobalamin (vitamin B12) and other natural hemes will be investigated as the scaffolds for the targeted delivery of the new CORMs.
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