Synthesis, Pharmacological Evaluation, and Molecular Modeling Studies of Novel Peptidic CAAX Analogues as Farnesyl-Protein-Transferase Inhibitors

Fifteen analogues of the C-terminal CA1A2X motif were synthesized and evaluated for their inhibition potency against farnesyltransferase (FTase). Replacement of the A2 residue by phenylalanine or tyrosine-derived analogues, in which a different number of methyl groups were introduced on the aromatic...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-03, Vol.49 (6), p.1882-1890
Main Authors: Santagada, Vincenzo, Caliendo, Giuseppe, Severino, Beatrice, Lavecchia, Antonio, Perissutti, Elisa, Fiorino, Ferdinando, Zampella, Angela, Sepe, Valentina, Califano, Daniela, Santelli, Giovanni, Novellino, Ettore
Format: Article
Language:English
Subjects:
Alanine - analogs & derivatives
Alanine - chemical synthesis
Alanine - pharmacology
Alkyl and Aryl Transferases - antagonists & inhibitors
Alkyl and Aryl Transferases - chemistry
Animals
Binding Sites
Biological and medical sciences
Cell Line
Cell Line, Tumor
Humans
Indoles - chemical synthesis
Indoles - pharmacology
Medical sciences
Mice
Miscellaneous
Models, Molecular
Oligopeptides - chemical synthesis
Oligopeptides - pharmacology
Pharmacology. Drug treatments
Rats
Stereoisomerism
Structure-Activity Relationship
Tyrosine - analogs & derivatives
Tyrosine - chemical synthesis
Tyrosine - pharmacology
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Summary:Fifteen analogues of the C-terminal CA1A2X motif were synthesized and evaluated for their inhibition potency against farnesyltransferase (FTase). Replacement of the A2 residue by phenylalanine or tyrosine-derived analogues, in which a different number of methyl groups were introduced on the aromatic ring, resulted in compounds less active than the reference compound CVFM against FTase except for compounds I and VI (IC50 = 1 μM and 2.5 μM, respectively) that were comparable to CVFM and compound IV (IC50 = 0.1 μM), which was 6-fold more active than the reference compound. Because pseudopeptidic derivatives I−IX were inactive in the cellular assays, the N-formyl- and methyl-ester derivatives (compounds X−XV) were synthesized and tested on different cell lines, showing, in some cases, activity and appreciable selectivity against transformed cells. To rationalize the obtained results, molecular modeling experiments were carried out suggesting the molecular basis of FTase inhibition by these products.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0506165