Synthesis and biological activity of pseudopeptides inhibitors of Ras farnesyl transferase containing unconventional amino acids

Giuseppe Caliendo, Ferdinando Fiorino, Paolo Grieco, Elisa Perissutti, Stefania De Luca, Ada Giuliano, Giovanni Santelli, Daniela Califano, Beatrice Severino, Vincenzo Santagada

Research output: Contribution to journalArticlepeer-review

Abstract

A study was performed on the structure-activity relationships of a series of phenol derivatives, CVFM analogs, derived from the two most active compounds of a first series (1(A) and 1(B)) of inhibitors of Ras farnesyl transferase (FTase) that we have recently described. We report the synthesis and the activity of a second series of compounds in which the phenylalanine residue was replaced by unconventional aromatic and non-aromatic amino acids, with varying electronic, lipophilic, steric and conformational properties. The compounds showed to be significantly less active than reference compounds against FT, with the only exception of derivative 3(A) (IC50 = 3 μM), which is slightly more active than 1(A) but not 1(B). Subsequently we tested the effects of compounds 1(A), 1(B) and 3(A), 3(B) on the anchorage-dependent growth of two epithelial cell lines of rats, FRTL-5 and the same line v-Ha- ras transformed. Compound 3(A) derived from lead compound 1(A), showed an appreciable selectivity against transformed cells. In contrast, compounds derived from derivative 1(B) had only a modest cellular activity.

Original languageEnglish
Pages (from-to)785-790
Number of pages6
JournalFarmaco
Volume54
Issue number11-12
DOIs
Publication statusPublished - Nov 9 1999

Keywords

  • Cellular in vitro activity
  • Phenol derivative
  • Ras farnesyltransferase inhibitor

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmaceutical Science

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