Mimetics of the C-terminal CAAX tetrapeptide of Ras protein were designed replacing cysteine (C) by 2-hydroxymethylbenzodioxane or 2-aminomethylbenzodioxane, respectively etherified and amidified with 2′-methyl or 2′-methoxy substituted 2-carboxy-4-hydroxybiphenyl and 2,4-dicarboxybiphenyl. These pluri-substituted biphenyl systems, used as internal spacer and AA dipeptide bioisoster, were linked to the methyl ester of l-methionine, glycine or l-leucine by an amide bond. The resultant twelve pairs of stereoisomers at the dioxane C-2 were tested for antiproliferative effect finding the maximum activity for derivatives with methyleneoxy linker between benzodioxane and 2′-methylbiphenyl. Of these compounds, the one with terminal methionine and S configuration proved a good Ras prenylation inhibitor in a cell-based assay.
|Titolo:||New Ras CAAX mimetics : design, synthesis, antiproliferative activity, and RAS prenylation inhibition|
|Parole Chiave:||Peptidomimetic inhibitors; Antiproliferative agents; Antitumors; Prenylation inhibitors|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
Settore BIO/14 - Farmacologia
|Data di pubblicazione:||2009|
|Digital Object Identifier (DOI):||10.1016/j.bmcl.2009.07.065|
|Appare nelle tipologie:||01 - Articolo su periodico|