Design, synthesis, and evaluation of sugar amino acid based inhibitors of protein prenyl transferases PFT and PGGT-1.
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.
El Oualid
Farid
F
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
Burm
Brigitte E A
BE
Leroy
Ingrid M
IM
Cohen
Louis H
LH
van Boom
Jacques H
JH
van den Elst
Hans
H
Overkleeft
Herman S
HS
van der Marel
Gijs A
GA
Overhand
Mark
M
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
D000596:Amino Acids; D013400:Sugar Acids; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase