Synthesis and biological evaluation of lipophilic Ca(1)a(2)L analogues as potential bisubstrate inhibitors of protein:geranylgeranyl transferase-1

Farid El Oualid; Jayand Baktawar; Ingrid M Leroy; Hans van den Elst; Louis H Cohen; Gijs A van der Marel; Herman S Overkleeft; Mark Overhand

doi:10.1016/j.bmc.2004.12.035

Synthesis and biological evaluation of lipophilic Ca(1)a(2)L analogues as potential bisubstrate inhibitors of protein:geranylgeranyl transferase-1

Bioorg Med Chem. 2005 Mar 1;13(5):1463-75. doi: 10.1016/j.bmc.2004.12.035.

Authors

Farid El Oualid¹, Jayand Baktawar, Ingrid M Leroy, Hans van den Elst, Louis H Cohen, Gijs A van der Marel, Herman S Overkleeft, Mark Overhand

Affiliation

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

PMID: 15698762
DOI: 10.1016/j.bmc.2004.12.035

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.

Publication types

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

MeSH terms

Alkyl and Aryl Transferases / antagonists & inhibitors*
Dipeptides / chemical synthesis*
Dipeptides / chemistry
Dipeptides / pharmacology*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Magnetic Resonance Spectroscopy
Mass Spectrometry
Substrate Specificity

Substances

Dipeptides
Enzyme Inhibitors
Alkyl and Aryl Transferases
geranylgeranyltransferase type-I