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.
MeSH terms
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ATP Binding Cassette Transporter 1 / genetics
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ATP Binding Cassette Transporter 1 / metabolism
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Cell Line, Tumor
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Ergosterol / analogs & derivatives*
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Ergosterol / chemical synthesis
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Ergosterol / pharmacology*
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Fatty Acid Synthase, Type I / genetics
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Fatty Acid Synthase, Type I / metabolism
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Gene Expression
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HEK293 Cells
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Humans
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Hydrocarbons, Fluorinated / pharmacology
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Liver X Receptors / agonists*
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Protein Isoforms / agonists
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RNA, Messenger / metabolism
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Stereoisomerism
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Sterol Regulatory Element Binding Protein 1 / genetics
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Sterol Regulatory Element Binding Protein 1 / metabolism
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Stigmasterol / analogs & derivatives*
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Stigmasterol / chemical synthesis
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Stigmasterol / pharmacology*
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Sulfonamides / pharmacology
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Syndecan-1 / genetics
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Syndecan-1 / metabolism
Substances
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ABCA1 protein, human
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ATP Binding Cassette Transporter 1
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Hydrocarbons, Fluorinated
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Liver X Receptors
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Protein Isoforms
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RNA, Messenger
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SDC1 protein, human
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Sterol Regulatory Element Binding Protein 1
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Sulfonamides
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Syndecan-1
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T0901317
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Stigmasterol
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FASN protein, human
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Fatty Acid Synthase, Type I
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Ergosterol