Peptidomimetic inhibitors of farnesyltransferase with high in vitro activity and significant cellular potency.

2-o-Tolyl or 2-o-anisyl substituted 4-hydroxy- and 4-carboxybenzamides of methionine, etherified and amidified with 2-hydroxymethyl- and 2-aminomethylpyridodioxane, respectively, are described as inhibitors of Ras protein farnesyltransferase (FTase). Of the sixteen compounds, resulting from the substitution pattern of benzamide and the configuration of the two stereocenters, seven inhibited FTase activity with potencies in the nanomolar range. They were all 2-oxymethylpyridodioxane ethers and, among them, the four o-tolyl substituted stereoisomers also showed micromolar antiproliferative effect on human aortic smooth muscle cells interfering with Ras farnesylation. The docking analysis enlightened significant differences in enzyme interaction between oxymethylpyridodioxane and aminomethylpyridodioxane derivatives.