title: Synthesis and evaluation of homofarnesoyl-substituted CAAX-peptidomimetics as farnesyltransferase inhibitors and antiproliferative agents.
abstract: Several CAAX-peptidomimetics were linked to homofarnesoic acid via a beta-alanyl spacer with the intention to obtain a novel type of bisubstrate analogue farnesyltransferase inhibitors. However, the compounds were found to be only weakly active in the farnesyltransferase inhibition assay. Nevertheless, they displayed antiproliferative activity against different tumor cell lines in the low micromolar range. Replacement of the beta-alanine moiety by aspartic acid-1-methyl ester resulted in a compound which inhibited the farnesyltransferase with an IC50 of 860 nM. The corresponding free acid showed a eightfold loss in activity (IC50 = 6.9 microM).
authors.affiliation: Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schlitzer
authors.forename: I
authors.initials: I
authors.lastname: Sattler
authors.forename: H M
authors.initials: HM
authors.lastname: Dahse
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D018716:Molecular Mimicry; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D013057:Spectrum Analysis
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010455:Peptides; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase