Synthesis and initial biological evaluation of new mimics of the LXR-modulator 22(S)-hydroxycholesterol

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• 作者：O. Alex ; er H. 脜str ; Marcel S ; berg ; Ingebrigt Sylte ; Carl Henrik G枚rbitz ; G. Hege Thoresen ; Eili T. Kase ; P氓l Rongved
• 关键词：Liver X receptor agonists ; Molecular modeling ; New chemical entities ; SAR ; Gene regulation
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：1 January, 2014
• 年：2014
• 卷：22
• 期：1
• 页码：643-650
• 全文大小：1310 K

文摘

The generic, synthetic oxysterol 22(S)-hydroxycholesterol (22SHC) has shown antagonistic effects towards liver X receptor (LXR) in vitro and promising effects on plasma triacylglycerol level and body weight-gain in animal studies. On the contrary, the endogenic LXR agonist 22(R)-hydroxycholesterol (22RHC) and synthetic LXR agonists convincingly have shown agonistic effects on genes involved in lipogenesis, and inhibitory effects on cell proliferation in vitro and in vivo. We hypothesized that the carbon side chain containing the hydroxyl group at the 22-position was a pharmacophore affecting these opposite effects on LXR. This prompted us to initiate a rational drug design incorporating the 22-hydroxylated 20-27 cholesterol moiety into cholesterol-mimicking building blocks. The two enantiomers of the 22-hydroxylated 20-27 cholesterol moiety were synthesized with an excellent enantiomeric excess and the stereochemistry are supported by X-ray crystallography. Molecular modelling of the new compounds showed promising LXR selectivity (LXR尾 over LXR伪) and initial in vitro biological evaluation in human myotubes showed that compound 16b had agonistic effects on the gene expression of SCD1 and increased lipogenesis.