A new class of selective and potent 7-dehydrocholesterol reductase inhibitors.

Abstract

We prepared a number of N-phenethyltetrahydroisoquinolines structurally related to protoberberines. They were tested for activity against bacteria, fungi, and human leukemia HL-60 cells and also for inhibition of biosynthesis: ergosterol in yeasts and cholesterol in human cells. In the latter assay panel, several of the compounds were distinguished by a strong and selective inhibition of 7-dehydrocholesterol reductase (7-DHCR, EC 1.3.1.21), an enzyme responsible for the conversion of 7-dehydrocholesterol to cholesterol in the last step of cholesterol biosynthesis. In a whole-cell assay, the most active compound 5f showed a much stronger inhibition of overall cholesterol biosynthesis (IC(50) 2.3 nM) than BM 15.766 (IC(50) 500 nM), presently the most selective known inhibitor of 7-DHCR. Since a defect of 7-dehydrocholesterol reductase is associated with Smith-Lemli-Opitz syndrome (SLOS), the potent and selective inhibitors reported here will enable more detailed investigation of the pathogenesis of SLOS.

• Authors: Aline Horling, Christoph Müller, Richard Barthel, Franz Bracher, Peter Imming
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 17 Pg. 7614-22 (Sep 13 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22882119 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Oxidoreductases Acting on CH-CH Group Donors
• 7-dehydrocholesterol reductase

Topics

• Enzyme Inhibitors (chemistry, pharmacology)
• Gas Chromatography-Mass Spectrometry
• HL-60 Cells
• Humans
• Magnetic Resonance Spectroscopy
• Oxidoreductases Acting on CH-CH Group Donors (antagonists & inhibitors)
• Spectrometry, Mass, Electrospray Ionization