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

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 TNFα, 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 counter-regulatory cytokines in inflammatory bowel diseases (IBD). Finally, we have shown that solomonsterol A inhibits NF-κB 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.

Marine and Semi-Synthetic Hydroxysteroids as New Scaffolds for Pregnane X Receptor Modulation

“…PXR agonists have been shown to attenuate inflammatory bowel disease by reducing nuclear factor-κB target gene expression that mediates colon inflammation [6,7,8,9,10]. …”

“…Among these, solomonsterols [14], truncated chain sulfated steroids, malaitasterol A [15], an unusual bis-secosterol, and gracilioethers [16] were endowed with selective activation action on the PXR, whereas theonellasterols and conicasterols showed a dual modulatory profile on the PXR and FXR [17,18,19,20,21]. The in vivo evaluation of a synthetic sample of solomonsterol A in a colitis model using transgenic mice expressing hPXR demonstrated the effectiveness of this PXR agonist in protecting the mouse against the development of the disease [7,8]. …”

Phallusiasterols A and B: Two New Sulfated Sterols from the Mediterranean Tunicate Phallusia fumigata and Their Effects as Modulators of the PXR Receptor

“…The role of marine steroids as nuclear receptor ligands has been recently highlighted [13] and several sulfated marine steroids have been identified as a new class of the pregnane X receptor (PXR) agonists [21,22]. Based on this background, we have investigated a possible role of phallusiasterols A ( 1) and B ( 2 ) in regulating the PXR activity.…”

Small-molecule modulators of PXR and CAR

“…Solomonsterol A, isolated from the marine sponge Theonella swinhoei , is a potent PXR agonist and effectively protects humanized PXR mice from developing the clinical signs and symptoms of colitis through PXR-dependent inhibition of NF-κB activation [30]. Artemisinin, a natural compound used to treat malaria, was identified as a potential PXR agonist [31], and a recent report indicated that this drug can prevent and reduce IBD development in a mouse model of DSS-induced IBD by a mechanism associated with the transcriptional activation of PXR [32].…”