2. Academic Validation
  3. Side-Chain Modified Ergosterol and Stigmasterol Derivatives as Liver X Receptor Agonists

Side-Chain Modified Ergosterol and Stigmasterol Derivatives as Liver X Receptor Agonists

  • J Med Chem. 2017 Aug 10;60(15):6548-6562. doi: 10.1021/acs.jmedchem.7b00091.
Maura Marinozzi 1,  Francisco Fermin Castro Navas 1,  Daniela Maggioni 2,  Emanuele Carosati 3,  Giovanni Bocci 3,  Maria Carloncelli 1,  Gianluca Giorgi 4,  Gabriele Cruciani 3,  Raffaella Fontana 2,  Vincenzo Russo 2
Affiliations

Affiliations

  • 1 Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia , Via del Liceo, 1-06123 Perugia, Italy.
  • 2 Istituto Scientifico Ospedale San Raffaele (IRCCS) , Via Olgettina, 58-20132 Milano, Italy.
  • 3 Dipartimento di Chimica, Biologia e Biotecnologie, Università degli Studi di Perugia , Via Elce di Sotto, 8-06123 Perugia, Italy.
  • 4 Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena , Via A. Moro, 53100 Siena, Italy.
PMID: 28741954 DOI: 10.1021/acs.jmedchem.7b00091
Abstract

A series of stigmasterol and ergosterol derivatives, characterized by the presence of oxygenated functions at C-22 and/or C-23 positions, were designed as potential liver X receptor (LXR) agonists. The absolute configuration of the newly created chiral centers was definitively assigned for all the corresponding compounds. Among the 16 synthesized compounds, 21, 27, and 28 were found to be selective LXRα agonists, whereas 20, 22, and 25 showed good selectivity for the LXRβ isoform. In particular, 25 showed the same degree of potency as 22R-HC (3) at LXRβ, while it was virtually inactive at LXRα (EC50 = 14.51 μM). Interestingly, 13, 19, 20, and 25 showed to be LXR target gene-selective modulators, by strongly inducing the expression of ABCA1, while poorly or not activating the lipogenic genes SREBP1 and SCD1 or FASN, respectively.

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