Synthesis and evaluation of homofarnesoyl-substituted CAAX-peptidomimetics as farnesyltransferase inhibitors and antiproliferative agents

Several CAAX-peptidomimetics were linked to homofarnesoic acid via a beta-alanyl spacer with the intention to obtain a novel type of bisubstrate analogue farnesyltransferase inhibitors. However, the compounds were found to be only weakly active in the farnesyltransferase inhibition assay. Neverthele...

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Published in:Bioorganic & medicinal chemistry 1999-09, Vol.7 (9), p.2037-2045
Main Authors: SCHLITZER, M, SATTLER, I, DAHSE, H.-M
Format: Article
Language:English
Subjects:
Alkyl and Aryl Transferases - antagonists & inhibitors
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Farnesyltranstransferase
General aspects
HL-60 Cells
Humans
K562 Cells
Medical sciences
Molecular Mimicry
Molecular Structure
Peptides - chemistry
Pharmacology. Drug treatments
Spectrum Analysis
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Summary:Several CAAX-peptidomimetics were linked to homofarnesoic acid via a beta-alanyl spacer with the intention to obtain a novel type of bisubstrate analogue farnesyltransferase inhibitors. However, the compounds were found to be only weakly active in the farnesyltransferase inhibition assay. Nevertheless, they displayed antiproliferative activity against different tumor cell lines in the low micromolar range. Replacement of the beta-alanine moiety by aspartic acid-1-methyl ester resulted in a compound which inhibited the farnesyltransferase with an IC50 of 860 nM. The corresponding free acid showed a eightfold loss in activity (IC50 = 6.9 microM).
ISSN:0968-0896
1464-3391
DOI:10.1016/S0968-0896(99)00165-0