Synthesis and biological evaluation of hAMCase inhibitors and anomeric equilibrium of gluco and xylopyranose derivatives in D2O

Asthma is considered a serious health and socioeconomic issue all over the world, affecting more than 300 million individuals. It is a chronic inflammatory disease characterized by airway inflammation, mucus hypersecretion and airway hyperresponsiveness. One of the causes of this disorder is the result of an abnormal Th2-dependent response to environmental antigens. In particular, Th2 cells produce cytokines, such as interleukin (IL)-4, IL-5, IL-9, and especially IL-13, in the airway wall, associated with the asthma symptoms. Acidic Mammalian Chitinase (AMCase) is a chitinolytic enzyme belonging to glycosyl hydrolases family. AMCase seems to be involved in Th2 inflammatory diseases, such as asthma. It has been demonstrated that during Th2-dependent inflammation IL-13 induces the AMCase expression in the airways epithelial cells and alveolar macrophages, which stimulates the release of chemokines, recruiters of proinflammatory agents. In conclusion, AMCase contributes to the pathogenesis of asthma and represents a potential therapeutic target for the treatment of this disease and other forms of Th2-mediated inflammation. Prof. Botta research group, after a careful study, designed and synthesized an innovative AMCase inhibitor, BM22 (Ki = 13.2 μM), characterized by a macrocyclic structure. The aim of this work was the study of BM22 chemical space in order to improve its activity with the exploration of the macrocyclic portion, the linker length and substitution the amidinourea terminal moiety with a diamino-triazole group. Some of these compounds have been tested against AMCase enzyme and showed a better activity compared to that of BM22. The last chapter of this thesis deals with the study of the anomeric equilibrium of xylo and glucopyranoses in D2O at room temperature. The anomeric effect is an effect that determines the increased preference of the axial position of the C1 substituent in a pyranose ring, rather than the sterically preferred equatorial position. Two models were proposed to explain this effect: Electrostatic model and Hyperconjugation model. The anomeric ratio was established by qNMR, which involved integration of resolved signals in 1H-NMR spectrum. Interesting results have been obtained, as all compounds showed a preference for α-anomer, including, surprisingly, the electron donating methoxy group as well.