title: Umbelliferone aminoalkyl derivatives as inhibitors of human oxidosqualene-lanosterol cyclase.
abstract: Human and murine lanosterol synthases (EC 5.4.99.7) were studied as targets of a series of umbelliferone aminoalkyl derivatives previously tested as inhibitors of oxidosqualene cyclases from other eukaryotes. Tests were carried out on cell cultures of human keratinocytes and mouse 3T3 fibroblasts incubated with radiolabeled acetate, and on homogenates prepared from yeast cells expressing human lanosterol synthase, incubated with radiolabeled oxidosqualene. In cell cultures of both human keratinocytes and mouse 3T3 fibroblasts, the observed inhibition of cholesterol biosynthesis was selective for oxidosqualene cyclase. The most active compounds bear an allylmethylamino chain in position-7 of the coumarin ring. The inhibition was critically dependent on the position and length of the inhibitor side chain, as well as on the type of aminoalkyl group inserted at the end of the same chain. Molecular docking analyses, carried out to clarify details of inhibitors/enzyme interactions, proved useful to explain the observed differences in inhibitory activities.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di Torino, Turin, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Oliaro-Bosso
authors.forename: Silvia
authors.initials: S
authors.lastname: Taramino
authors.forename: Franca
authors.initials: F
authors.lastname: Viola
authors.forename: Silvia
authors.initials: S
authors.lastname: Tagliapietra
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ermondi
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Cravotto
authors.forename: Gianni
authors.initials: G
authors.lastname: Balliano
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015603:Keratinocytes / Q000201:enzymology / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D013329:Structure-Activity Relationship; D014468:Umbelliferones / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014468:Umbelliferones; C031477:7-hydroxycoumarin; D019751:Intramolecular Transferases; C021924:lanosterol synthase