Synthesis, pharmacological evaluation, and molecular modeling studies of novel peptidic CAAX analogues as farnesyl-protein-transferase inhibitors

Vincenzo Santagada, Giuseppe Caliendo, Beatrice Severino, Antonio Lavecchia, Elisa Perissutti, Ferdinando Fiorino, Angela Zampella, Valentina Sepe, Daniela Califano, Giovanni Santelli, Ettore Novellino

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Abstract

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.

Original languageEnglish
Pages (from-to)1882-1890
Number of pages9
JournalJournal of Medicinal Chemistry
Volume49
Issue number6
DOIs
Publication statusPublished - Mar 23 2006

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ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Santagada, V., Caliendo, G., Severino, B., Lavecchia, A., Perissutti, E., Fiorino, F., Zampella, A., Sepe, V., Califano, D., Santelli, G., & Novellino, E. (2006). Synthesis, pharmacological evaluation, and molecular modeling studies of novel peptidic CAAX analogues as farnesyl-protein-transferase inhibitors. Journal of Medicinal Chemistry, 49(6), 1882-1890. https://doi.org/10.1021/jm0506165