C24-hydroxylated stigmastane derivatives as Liver X Receptor agonists

FF Castro Navas, G Giorgi, D Maggioni, M Pacciarini, V Russo, M Marinozzi

Research output: Contribution to journalArticle

Abstract

Phytosterols are stucturally correlated to the endogenous ligands of Liver X Receptor (LXR), a ligand-activated nuclear receptor that has emerged as an attractive drug target due to its ability to integrate metabolic and inflammatory signaling. Natural and semi-synthetic phytosterol derivatives characterized by the presence of side-chain oxygenated functions have shown to be able to modulate LXR activity. Here, we describe the efficient synthesis of four stigmastane derivatives, endowed with a hydroxyl group at C24 position, namely (24R)- and (24S)-stigmasta-5,28-diene-3β,24-ols (also referred to as saringosterols, 10a and 10b) and (24R)- and (24S)-stigmasta-5-ene-3β,24-ols (11a and 11b), starting from the readily available stigmasterol. Thanks to X-ray crystallography the absolute configuration of the newly created chiral centers was definitively assigned for all the four compounds. The subsequent luciferase assays with GAL-4 chimeric receptors evidenced the ability of the two 24(S)-epimers, 10b and 11b, to interact with LXRs, showing the same degree of affinity as (22R)-hydroxycholesterol (1). With regard to the isoform selectivity both the derivatives 10b and 11b showed a preference for LXRβ up to 4-fold in terms of efficacy for 11b. The gene expression profiling of (24S)-stigmasta-5,28-diene-3β,24-ol (10a) and (24S)-stigmasta-5-ene-3β,24-ol (11a) demonstrated the capability of both the compounds to induce the expression of four well-known LXR target genes, such as ABCA1, SREBP1c, FASN, and SCD1 in U937 monocytic cell line, thus supporting the hypothesis they were LXR positive modulators. © 2018 Elsevier B.V.
Original languageEnglish
Pages (from-to)44-50
Number of pages7
JournalChemistry and Physics of Lipids
Volume212
Issue number2
DOIs
Publication statusPublished - 2018

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Liver
Derivatives
Phytosterols
Stigmasterol
Ligands
U937 Cells
X ray crystallography
X Ray Crystallography
Gene Expression Profiling
Cytoplasmic and Nuclear Receptors
Luciferases
Gene expression
Hydroxyl Radical
Modulators
Assays
Protein Isoforms
Genes
Cells
Liver X Receptors
Cell Line

Cite this

C24-hydroxylated stigmastane derivatives as Liver X Receptor agonists. / Castro Navas, FF; Giorgi, G; Maggioni, D; Pacciarini, M; Russo, V; Marinozzi, M.

In: Chemistry and Physics of Lipids, Vol. 212, No. 2, 2018, p. 44-50.

Research output: Contribution to journalArticle

Castro Navas, FF ; Giorgi, G ; Maggioni, D ; Pacciarini, M ; Russo, V ; Marinozzi, M. / C24-hydroxylated stigmastane derivatives as Liver X Receptor agonists. In: Chemistry and Physics of Lipids. 2018 ; Vol. 212, No. 2. pp. 44-50.
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AU - Russo, V

AU - Marinozzi, M

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AB - Phytosterols are stucturally correlated to the endogenous ligands of Liver X Receptor (LXR), a ligand-activated nuclear receptor that has emerged as an attractive drug target due to its ability to integrate metabolic and inflammatory signaling. Natural and semi-synthetic phytosterol derivatives characterized by the presence of side-chain oxygenated functions have shown to be able to modulate LXR activity. Here, we describe the efficient synthesis of four stigmastane derivatives, endowed with a hydroxyl group at C24 position, namely (24R)- and (24S)-stigmasta-5,28-diene-3β,24-ols (also referred to as saringosterols, 10a and 10b) and (24R)- and (24S)-stigmasta-5-ene-3β,24-ols (11a and 11b), starting from the readily available stigmasterol. Thanks to X-ray crystallography the absolute configuration of the newly created chiral centers was definitively assigned for all the four compounds. The subsequent luciferase assays with GAL-4 chimeric receptors evidenced the ability of the two 24(S)-epimers, 10b and 11b, to interact with LXRs, showing the same degree of affinity as (22R)-hydroxycholesterol (1). With regard to the isoform selectivity both the derivatives 10b and 11b showed a preference for LXRβ up to 4-fold in terms of efficacy for 11b. The gene expression profiling of (24S)-stigmasta-5,28-diene-3β,24-ol (10a) and (24S)-stigmasta-5-ene-3β,24-ol (11a) demonstrated the capability of both the compounds to induce the expression of four well-known LXR target genes, such as ABCA1, SREBP1c, FASN, and SCD1 in U937 monocytic cell line, thus supporting the hypothesis they were LXR positive modulators. © 2018 Elsevier B.V.

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