Design, synthesis, and evaluation of sugar amino acid based inhibitors of protein prenyl transferases PFT and PGGT-1

Farid El Oualid; Brigitte E A Burm; Ingrid M Leroy; Louis H Cohen; Jacques H van Boom; Hans van den Elst; Herman S Overkleeft; Gijs A van der Marel; Mark Overhand

doi:10.1021/jm049927q

Design, synthesis, and evaluation of sugar amino acid based inhibitors of protein prenyl transferases PFT and PGGT-1

J Med Chem. 2004 Jul 29;47(16):3920-3. doi: 10.1021/jm049927q.

Authors

Farid El Oualid¹, Brigitte E A Burm, Ingrid M Leroy, Louis H Cohen, Jacques H van Boom, Hans van den Elst, Herman S Overkleeft, Gijs A van der Marel, Mark Overhand

Affiliation

¹ Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.

PMID: 15267228
DOI: 10.1021/jm049927q

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkyl and Aryl Transferases / antagonists & inhibitors*
Alkyl and Aryl Transferases / chemistry
Amino Acids / chemical synthesis*
Amino Acids / chemistry
Amino Acids / pharmacology
Animals
CHO Cells
Cell Line
Cricetinae
Drug Design
Farnesyltranstransferase
Structure-Activity Relationship
Sugar Acids / chemical synthesis*
Sugar Acids / chemistry
Sugar Acids / pharmacology

Substances

Amino Acids
Sugar Acids
Alkyl and Aryl Transferases
geranylgeranyltransferase type-I
Farnesyltranstransferase