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

O Alexander H Strand; Marcel Sandberg; Ingebrigt Sylte; Carl Henrik Görbitz; G Hege Thoresen; Eili T Kase; Pål Rongved

doi:10.1016/j.bmc.2013.10.024

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

Bioorg Med Chem. 2014 Jan 1;22(1):643-50. doi: 10.1016/j.bmc.2013.10.024. Epub 2013 Nov 5.

Authors

O Alexander H Strand¹, Marcel Sandberg², Ingebrigt Sylte³, Carl Henrik Görbitz⁴, G Hege Thoresen⁵, Eili T Kase⁴, Pål Rongved⁶

Affiliations

¹ Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068, Blindern, N-0315 Oslo, Norway.
² Synthetica AS, Oslo Innovation Center, Gaustadalleen 21, 0349 Oslo, Norway.
³ Medicinal Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, The Arctic University of Norway, , Tromsø, Norway.
⁴ Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
⁵ Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway; Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
⁶ Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068, Blindern, N-0315 Oslo, Norway. Electronic address: pal.rongved@farmasi.uio.no.

PMID: 24268541
DOI: 10.1016/j.bmc.2013.10.024

Abstract

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 (LXRβ over LXRα) 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.

Keywords: Gene regulation; Liver X receptor agonists; Molecular modeling; New chemical entities; SAR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Gene Expression
Humans
Hydroxycholesterols / chemical synthesis*
Hydroxycholesterols / chemistry
Hydroxycholesterols / metabolism
Models, Molecular
Structure-Activity Relationship

Substances

Hydroxycholesterols