Insights on pregnane-X-receptor modulation. Natural and semisynthetic steroids from Theonella marine sponges

Valentina Sepe, Claudio D'Amore, Raffella Ummarino, Barbara Renga, Maria Valeria D'Auria, Ettore Novellino, Annamaria Sinisi, Orazio Taglialatela-Scafati, Youichi Nakao, Vittorio Limongelli, Angela Zampella, Stefano Fiorucci

    Research output: Contribution to journalArticle

    10 Citations (Scopus)

    Abstract

    Pregnane-X-receptor (PXR) is a member of nuclear receptors superfamily that activates gene transcription by binding to responsive elements in the promoter of target genes. PXR is a master gene orchestrating the expression/activity of genes involved in the metabolism of endobiotics including bilirubin, bile acids, glucose and lipid. In addition PXR oversights the metabolism of the large majority of xenobiotics including a large amount of prescribing drugs. Thus, developing PXR ligands represents a great opportunity for a therapeutic intervention on human diseases including diabetes, obesity, dyslipidemias and liver disorders. To this end, natural compounds represent an arsenal of new chemical scaffolds useful for the identification of novel PXR ligands. Here, we report a series of 4-methylenesteroid derivatives isolated from Theonella marine sponges as novel PXR modulators. In addition, combining medicinal chemistry, pharmacological experiments and computational studies, we have investigated the effects of different modifications on ring A and on the side chain of 4-methylenesteroid derivatives toward PXR modulation. This study provides the molecular bases of ligand/PXR interaction useful for designing novel PXR modulators.

    Original languageEnglish
    Pages (from-to)126-134
    Number of pages9
    JournalEuropean Journal of Medicinal Chemistry
    Volume73
    DOIs
    Publication statusPublished - 2014 Feb 12

    Fingerprint

    Theonella
    Porifera
    Steroids
    Modulation
    Genes
    Ligands
    Metabolism
    Modulators
    Arsenals
    Derivatives
    pregnane X receptor
    Drug Prescriptions
    Pharmaceutical Chemistry
    Xenobiotics
    Transcription
    Cytoplasmic and Nuclear Receptors
    Medical problems
    Dyslipidemias
    Bile Acids and Salts
    Bilirubin

    Keywords

    • 4-Methylenesteroids
    • Conicasterol
    • Molecular docking
    • Pregnane-X-receptor
    • Structure-activity relationship
    • Theonella marine sponges

    ASJC Scopus subject areas

    • Drug Discovery
    • Organic Chemistry
    • Pharmacology

    Cite this

    Insights on pregnane-X-receptor modulation. Natural and semisynthetic steroids from Theonella marine sponges. / Sepe, Valentina; D'Amore, Claudio; Ummarino, Raffella; Renga, Barbara; D'Auria, Maria Valeria; Novellino, Ettore; Sinisi, Annamaria; Taglialatela-Scafati, Orazio; Nakao, Youichi; Limongelli, Vittorio; Zampella, Angela; Fiorucci, Stefano.

    In: European Journal of Medicinal Chemistry, Vol. 73, 12.02.2014, p. 126-134.

    Research output: Contribution to journalArticle

    Sepe, V, D'Amore, C, Ummarino, R, Renga, B, D'Auria, MV, Novellino, E, Sinisi, A, Taglialatela-Scafati, O, Nakao, Y, Limongelli, V, Zampella, A & Fiorucci, S 2014, 'Insights on pregnane-X-receptor modulation. Natural and semisynthetic steroids from Theonella marine sponges', European Journal of Medicinal Chemistry, vol. 73, pp. 126-134. https://doi.org/10.1016/j.ejmech.2013.12.005
    Sepe, Valentina ; D'Amore, Claudio ; Ummarino, Raffella ; Renga, Barbara ; D'Auria, Maria Valeria ; Novellino, Ettore ; Sinisi, Annamaria ; Taglialatela-Scafati, Orazio ; Nakao, Youichi ; Limongelli, Vittorio ; Zampella, Angela ; Fiorucci, Stefano. / Insights on pregnane-X-receptor modulation. Natural and semisynthetic steroids from Theonella marine sponges. In: European Journal of Medicinal Chemistry. 2014 ; Vol. 73. pp. 126-134.
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