SINTESI DI NUOVE MOLECOLE PER IL TRATTAMENTO DI PATOLOGIE INFIAMMATORIE

Recently, the role of hydrogen sulphide (H2S) a well known toxic gas with reducing properties has received a great interest. It has been found that H2S is produced in consistent quantity in the mammalian tissues and it exerts several physiological effects that suggest its role as a regulating mediator. H2S is involved in the regulation of the muscular tone, of the myocardial contractility, in the inflammatory processes, in the neurotransmission and in insulin secretion. Reduced levels of H2S were observed in several animal models of artery and pulmonary hypertension, damages of gastric mucosa and hepatic cirrhosis. Exogenous H2S inhibits inflammation, improves cardiac dysfunctions associated to ischemia/reperfusion and reduces the gastric damage induced by anti-inflammatory drugs. On the other hand, if not properly controlled and in excessive doses, endogenous H2S may contribute to tissue inflammation through stimulation of related converting enzymes (CBA and CBS). H2S has also an active role in the redox imbalance processes. In particular this gas mediator influences the activation of cellular inflammatory processes interacting with signalling mechanisms, transcription factors and neutralizing ROS. Moreover it has been reported that it has cytoprotective properties due to GSH production in several tissues. On this basis, it is clear the utility of molecules capable to modulate the plasma and tissue concentration of H2S especially in pathologies characterised by disorders of GSH homeostasis and increase of oxidative stress as it happens in neurodegenerative diseases, cystic fibrosis and other severe lung pathologies, but also in cardiovascular diseases (such as metabolic syndrome) etc. An interesting and innovative approach is the synthesis of hybrid molecules that combine the structure of a known drug with a sulfurated moiety able to in vivo slowly release H2S. Therefore, the purpose of this thesis was the synthesis of hybrid compounds active in neurodegenerative diseases (PD), such as sulfurated derivatives of L-DOPA and H2S-releasing drugs active on the peripheral circulatory system, such as sulfurated derivatives of phosphodiesterase 5 (PDE-5) inhibitors, in order to improve the efficacy and tolerability of the parent compound. Cysteine hybrid compounds coupled to dithiolethiones, addressed to treatment of specific metabolic conditions such as hyperhomocysteinemia, were also synthesized. The pharmacological studies conducted until now show that the H2S-releasing drugs, described in this thesis, by in vivo H2S releasing and modulating, have important antioxidant, anti-inflammatory and cytoprotective properties, while maintaining the pharmacological profile of the original drug. These data confirm the potential usefulness of new compounds in the treatment of many different diseases in which there is an inflammatory and / or a redox imbalance component.