Development of CO-releasing molecular for the treatment of inflammatory diseases

Dissertation presented to obtain a Ph.D. degree (Doutoramento) in Chemistry at the Instituto de Tecnologia Quimica e Biol6gica da Universidade Nova de Lisboa

Carbon Monoxide, CO, has been recognized as an endogenously produced, potent biological mediator involved in many defense mechanisms both in physiologic and pathologic situations. As a result of these signaling processes, CO possesses a strong therapeutic potential on a wide range of disease indications. However, the hardly avoidable safety and practical problems associated with therapeutic inhalation of toxic CO gas, led to the search for molecules capable of delivering CO to tissues in a living organism in a controlled and therapeutically useful manner. From all the areas of the chemical space where such CO-Releasing Molecules (CO-RMs) can be found, Metal Carbonyls Complexes (MCCs) seems to be the most versatile. It is the purpose of this Thesis to provide an extensive characterization of the behavior of MCCs in the presence of biological molecules and media, in order to identify the chemical and structural parameters that are more relevant to define the profile of a therapeutically effective metal-based CO-RM drug.(...)

This Thesis was financially supported by Fundacao para a Ciencia e Tecnologia, European Social Fund grant number SFRH/BDE/15501/2004 and ALFAMAResearch and Development of Pharmaceutical Drugs Ltd