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

被引：27

作者：

Marinozzi, Maura ^{[1
]}

Navas, Francisco Fermin Castro ^{[1
]}

Maggioni, Daniela ^{[2
]}

Carosati, Emanuele ^{[3
]}

Bocci, Giovanni ^{[3
]}

Carloncelli, Maria ^{[1
]}

Giorgi, Gianluca ^{[4
]}

Cruciani, Gabriele ^{[3
]}

Fontana, Raffaella ^{[2
]}

Russo, Vincenzo ^{[2
]}

机构：

[1] Univ Perugia, Dipartimento Sci Farm, Via Liceo, I-06123 Perugia, Italy

[2] IRCCS, Ist Sci Osped San Raffaele, Via Olgettina 58, I-20132 Milan, Italy

[3] Univ Perugia, Dipartimento Chim Biol & Biotecnol, Via Elce Sotto 8, I-06123 Perugia, Italy

[4] Univ Siena, Dipartimento Biotecnol Chim & Farm, Via A Moro, I-53100 Siena, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 15期

关键词：

NUCLEAR RECEPTOR; LXR-ALPHA; CHOLESTEROL HOMEOSTASIS; SIGNALING PATHWAY; OXYSTEROLS; METABOLISM; ABSORPTION; EXPRESSION; MODULATORS; DISCOVERY;

D O I：

10.1021/acs.jmedchem.7b00091

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 LXR alpha agonists, whereas 20, 22, and 25 showed good selectivity for the LXR beta isoform. In particular, 25 showed the same degree of potency as 22R-HC (3) at LXR beta, while it was virtually inactive at LXR alpha (EC50 = 14.51 mu M). 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.

引用

页码：6548 / 6562

页数：15

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