Ummarino, Raffaella (2013) Natural ligands of nuclear receptors. Isolation, design, synthesis, biochemical decodification and potential therapeutic applications. [Tesi di dottorato]

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Natural products have historically been a rich source of lead compounds in drug discovery. The biochemical investigation of marine organisms, through the deep collaboration between chemists and pharmacologists, focused on searching of new biologically active compounds, is a central issue of this kind of studies. My research work, described in this PhD thesis, has been developed in this research area and was addressed to the identification of new ligands of nuclear receptors, discovering potent and selective modulators of farnesoid-X-receptor (FXR) and pregnane-X-receptor (PXR), regulators of various processes including reproduction, development, and metabolism of xeno- and endobiotics. First, analysis of the polar extract of the sponge Theonella swinhoei afforded two new sulfated sterols, solomonsterols (SA and SB), the first example of marine PXR agonists. Both have been synthesized and characterized in animal models of inflammation. Administration of synthetic solomonsterol A effectively protects against development of clinical signs and symptoms of colitis; therefore SA holds promise in the treatment of inflammatory bowel deseases (IBDs). To overcome a limitation of SA in clinical settings, a small library of SA derivatives has been designed and prepared. Indeed, SA could be absorbed from the GIT causing severe systemic side effects resulting from the activation of PXR in the liver. This study disclosed cholestan disulfate (Coldisolf) as a new, simplified agonist of PXR, currently in pharmacological evaluation on animal models of liver fibrosis induced by HIV infection. Simultaneously, a wide family of 4-methylene steroids were isolated from the apolar extracts of Theonella swinhoei. These marine steroids are endowed with a potent agonistic activity on PXR while antagonize the effects of natural ligands for FXR. Among this rich family, we have identified theonellasterol as the first example of a sponge derived highly selective FXR antagonist demonstrating its pharmacological potential in the treatment of cholestasis. Using this compound as a novel FXR antagonist hit, we have prepared a series of semi-synthetic derivatives in order to gain insights into the structural requirements for exhibiting antagonistic activity. These molecules could be used for the pharmacological treatment of cholestasis but also in chemotherapy of carcinoma characterized by over-expression of FXR. In summary, Nature continues to be one of the best sources not only of potential chemotherapeutic agents but also of lead compounds that could represent an inspiration for the discovery of new therapeutic strategies.

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