title: Aminopropylindenes derived from Grundmann's ketone as a novel chemotype of oxidosqualene cyclase inhibitors.
abstract: A series of aminopropylindenes, designed as mimics of a cationic high energy intermediate in the oxidosqualene cyclase(1) (OSC)-mediated cyclization of 2,3-oxidosqualen to lanosterol was prepared from Grundmann's ketone. Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds. A N,N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi OSC in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line.
authors.affiliation: Department für Pharmazie, Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, D-81377 Munich, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Lange
authors.forename: Marco
authors.initials: M
authors.lastname: Keller
authors.forename: Christoph
authors.initials: C
authors.lastname: Müller
authors.forename: Simonetta
authors.initials: S
authors.lastname: Oliaro-Bosso
authors.forename: Gianni
authors.initials: G
authors.lastname: Balliano
authors.forename: Franz
authors.initials: F
authors.lastname: Bracher
mesh_terms: D017360:Arabidopsis / Q000187:drug effects / Q000201:enzymology; D055162:Biocatalysis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007659:Ketones / Q000737:chemistry* / Q000378:metabolism; D007810:Lanosterol / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D010940:Plant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013185:Squalene / Q000737:chemistry / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D007659:Ketones; D010940:Plant Proteins; D015800:Protozoan Proteins; D007810:Lanosterol; D013185:Squalene; D002784:Cholesterol; D019751:Intramolecular Transferases; C021924:lanosterol synthase