Recently, we reported the identification of a novel class of pregnane-X-receptor (PXR) agonists, solomonsterols A and B, isolated from the marine sponge Theonella swinhoei. Preliminary pharmacological studies demonstrated that these natural compounds are potential leads for the treatment of human disorders characterized by dysregulation of innate immunity. In this article, we describe the first total synthesis of solomonsterol A and its in vivo characterization in animal models of colitis. Using transgenic mice expressing the human PXR, we found that administration of synthetic solomonsterol A effectively protects against development of clinical signs and symptoms of colitis and reduced the generation of TNFR, a signature cytokine for this disorder. In addition, we have provided the first evidence that solomonsterol A might act by triggering the expression of TGFβ and IL-10, potent counterregulatory cytokines in inflammatory bowel diseases (IBD). Finally, we have shown that solomonsterol A inhibits NF-kB activation by a PXR dependent mechanism. In summary, solomonsterol A is a marine PXR agonist that holds promise in the treatment of inflammation-driven immune dysfunction in clinical settings.

Total Synthesis and Pharmacological Characterization of Solomonsterol A, a Potent Marine Pregnane-X-Receptor Agonist Endowed with Anti-Inflammatory Activity / Sepe, Valentina; Ummarino, Raffaella; D'Auria, MARIA VALERIA; Mencarelli, A.; D'Amore, C.; Renga, B.; Zampella, Angela; Fiorucci, S.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 54:13(2011), pp. 4590-4599. [10.1021/jm200241s]

Total Synthesis and Pharmacological Characterization of Solomonsterol A, a Potent Marine Pregnane-X-Receptor Agonist Endowed with Anti-Inflammatory Activity.

SEPE, VALENTINA;UMMARINO, RAFFAELLA;D'AURIA, MARIA VALERIA;ZAMPELLA, ANGELA;
2011

Abstract

Recently, we reported the identification of a novel class of pregnane-X-receptor (PXR) agonists, solomonsterols A and B, isolated from the marine sponge Theonella swinhoei. Preliminary pharmacological studies demonstrated that these natural compounds are potential leads for the treatment of human disorders characterized by dysregulation of innate immunity. In this article, we describe the first total synthesis of solomonsterol A and its in vivo characterization in animal models of colitis. Using transgenic mice expressing the human PXR, we found that administration of synthetic solomonsterol A effectively protects against development of clinical signs and symptoms of colitis and reduced the generation of TNFR, a signature cytokine for this disorder. In addition, we have provided the first evidence that solomonsterol A might act by triggering the expression of TGFβ and IL-10, potent counterregulatory cytokines in inflammatory bowel diseases (IBD). Finally, we have shown that solomonsterol A inhibits NF-kB activation by a PXR dependent mechanism. In summary, solomonsterol A is a marine PXR agonist that holds promise in the treatment of inflammation-driven immune dysfunction in clinical settings.
2011
Total Synthesis and Pharmacological Characterization of Solomonsterol A, a Potent Marine Pregnane-X-Receptor Agonist Endowed with Anti-Inflammatory Activity / Sepe, Valentina; Ummarino, Raffaella; D'Auria, MARIA VALERIA; Mencarelli, A.; D'Amore, C.; Renga, B.; Zampella, Angela; Fiorucci, S.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 54:13(2011), pp. 4590-4599. [10.1021/jm200241s]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/403330
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