title: Design, synthesis, and evaluation of sugar amino acid based inhibitors of protein prenyl transferases PFT and PGGT-1.
abstract: Eleven analogues of the C-terminal Ca(1)a(2)X motif found in natural substrates of the prenyl transferases PFT and PGGT-1 were synthesized and evaluated for their inhibition potency and selectivity against PFT and PGGT-1. Replacement of the central dipeptide part a(1)a(2) by a benzylated sugar amino acid resulted in a good and highly selective PFT inhibitor (8, IC(50) = 250 +/- 20 nM). The methyl ester of 8 (13) selectively inhibited protein farnesylation in cultured cells.
authors.affiliation: Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Farid
authors.initials: F
authors.lastname: El Oualid
authors.forename: Brigitte E A
authors.initials: BE
authors.lastname: Burm
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Leroy
authors.forename: Louis H
authors.initials: LH
authors.lastname: Cohen
authors.forename: Jacques H
authors.initials: JH
authors.lastname: van Boom
authors.forename: Hans
authors.initials: H
authors.lastname: van den Elst
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.forename: Gijs A
authors.initials: GA
authors.lastname: van der Marel
authors.forename: Mark
authors.initials: M
authors.lastname: Overhand
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D015195:Drug Design; D051231:Farnesyltranstransferase; D013329:Structure-Activity Relationship; D013400:Sugar Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D013400:Sugar Acids; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase