Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 44-50 |
| Number of pages | 7 |
| Journal | Chemistry and Physics of Lipids |
| Volume | 212 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 2018 |
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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 journal › Article
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TY - JOUR
T1 - C24-hydroxylated stigmastane derivatives as Liver X Receptor agonists
AU - Castro Navas, FF
AU - Giorgi, G
AU - Maggioni, D
AU - Pacciarini, M
AU - Russo, V
AU - Marinozzi, M
PY - 2018
Y1 - 2018
N2 - 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.
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.
U2 - 10.1016/j.chemphyslip.2018.01.005
DO - 10.1016/j.chemphyslip.2018.01.005
M3 - Article
VL - 212
SP - 44
EP - 50
JO - Chemistry and Physics of Lipids
JF - Chemistry and Physics of Lipids
SN - 0009-3084
IS - 2
ER -