title: Synthesis and biological evaluation of lipophilic Ca(1)a(2)L analogues as potential bisubstrate inhibitors of protein:geranylgeranyl transferase-1.
abstract: Ca(1)a(2)L analogues, having the central dipeptide a(1)a(2) replaced by a sugar amino acid, were provided at the N-terminal end directly or via a spacer with a lipid. The inhibitory potency toward PGGT-1 of the set of lipophilic Ca(1)a(2)L analogues was improved in comparison with the original analogues, 1 and 2. The most potent inhibitors, 39 and 40, were found to inhibit PGGT-1 with an IC(50)-value of 12.7 and 12.3 microM, respectively, which is a 6-fold improvement over the corresponding analogue 1.
authors.affiliation: Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Farid
authors.initials: F
authors.lastname: El Oualid
authors.forename: Jayand
authors.initials: J
authors.lastname: Baktawar
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Leroy
authors.forename: Hans
authors.initials: H
authors.lastname: van den Elst
authors.forename: Louis H
authors.initials: LH
authors.lastname: Cohen
authors.forename: Gijs A
authors.initials: GA
authors.lastname: van der Marel
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.forename: Mark
authors.initials: M
authors.lastname: Overhand
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013379:Substrate Specificity
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I