Synthesis and biological evaluation of lipophilic Ca(1)a(2)L analogues as potential bisubstrate inhibitors of protein:geranylgeranyl transferase-1.
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.
El Oualid
Farid
F
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
Baktawar
Jayand
J
Leroy
Ingrid M
IM
van den Elst
Hans
H
Cohen
Louis H
LH
van der Marel
Gijs A
GA
Overkleeft
Herman S
HS
Overhand
Mark
M
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013379:Substrate Specificity
D004151:Dipeptides; D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I