title: 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.affiliation: Institut für Pharmazie,  Martin-Luther-Universität Halle-Wittenberg , Wolfgang-Langenbeck-Strasse 4, 06120 Halle, Germany.
authors.forename: Aline
authors.initials: A
authors.lastname: Horling
authors.forename: Christoph
authors.initials: C
authors.lastname: Müller
authors.forename: Richard
authors.initials: R
authors.lastname: Barthel
authors.forename: Franz
authors.initials: F
authors.lastname: Bracher
authors.forename: Peter
authors.initials: P
authors.lastname: Imming
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D018922:HL-60 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D004791:Enzyme Inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase