TY - JOUR
T1 - Synthesis, pharmacological evaluation, and molecular modeling studies of novel peptidic CAAX analogues as farnesyl-protein-transferase inhibitors
AU - Santagada, Vincenzo
AU - Caliendo, Giuseppe
AU - Severino, Beatrice
AU - Lavecchia, Antonio
AU - Perissutti, Elisa
AU - Fiorino, Ferdinando
AU - Zampella, Angela
AU - Sepe, Valentina
AU - Califano, Daniela
AU - Santelli, Giovanni
AU - Novellino, Ettore
PY - 2006/3/23
Y1 - 2006/3/23
N2 - 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.
AB - 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.
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U2 - 10.1021/jm0506165
DO - 10.1021/jm0506165
M3 - Article
C2 - 16539374
AN - SCOPUS:33645393448
VL - 49
SP - 1882
EP - 1890
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 6
ER -