title: Novel indolizine derivatives with unprecedented inhibitory activity on human farnesyltransferase.
abstract: The rational structural modification of new substituted indolizin-3-yl(phenyl)methanones 1a-i, 2a-i and 3a-i has greatly improved human farnesyltransferase inhibition. The para-bromophenyl analog 2f bearing an ester unit on the indolizine ring demonstrates the highest inhibition potential, with IC50 value of 1.3±0.2 μM. The amidic series 1a-i proves to be the most promising for future modulations, particularly at the triple bond level.
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, 'Al. I. Cuza' University of Iasi, B-dul Carol I, Nr. 11, Corp A, 700506 Iasi, Romania.
authors.forename: Carmen
authors.initials: C
authors.lastname: Dumea
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, 'Al. I. Cuza' University of Iasi, B-dul Carol I, Nr. 11, Corp A, 700506 Iasi, Romania.
authors.forename: Dalila
authors.initials: D
authors.lastname: Belei
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, 'Al. I. Cuza' University of Iasi, B-dul Carol I, Nr. 11, Corp A, 700506 Iasi, Romania; Univ Lille Nord de France, F-59000 Lille, France; UCLille, EA GRIIOT (4481), Laboratoire de pharmacochimie, Ecole des Hautes Etudes d'Ingénieur (HEI), 13 rue de Toul, F-59046 Lille, France.
authors.forename: Alina
authors.initials: A
authors.lastname: Ghinet
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR2301 CNRS, Centre de Recherche de Gif, Avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dubois
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France; Faculté des Sciences Pharmaceutiques et Biologiques, EA GRIIOT (4481), IFR114, 3 Rue du Pr Laguesse, B.P. 83, F-59006 Lille, France.
authors.forename: Amaury
authors.initials: A
authors.lastname: Farce
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, 'Al. I. Cuza' University of Iasi, B-dul Carol I, Nr. 11, Corp A, 700506 Iasi, Romania. Electronic address: elena@uaic.ro.
authors.forename: Elena
authors.initials: E
authors.lastname: Bîcu
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007212:Indolizines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007212:Indolizines; C035094:indolizine; D051231:Farnesyltranstransferase
keywords: Activated ester; Butynyl ester; Farnesyltransferase inhibitor; Indolizine; Propargyl amide; Propargyl ester