New Ras CAAX mimetics: design, synthesis, antiproliferative activity, and RAS prenylation inhibition.
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.
Bolchi
Cristiano
C
Dipartimento di Scienze Farmaceutiche 'Pietro Pratesi', Università degli Studi di Milano, via Mangiagalli 25, I-20133 Milano, Italy.
Pallavicini
Marco
M
Fumagalli
Laura
L
Ferri
Nicola
N
Corsini
Alberto
A
Rusconi
Chiara
C
Valoti
Ermanno
E
D001011:Aorta / Q000166:cytology; D032701:Biomimetics; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D054876:Prenylation / Q000187:drug effects*; D018631:ras Proteins / Q000737:chemistry* / Q000378:metabolism*
D010455:Peptides; D018631:ras Proteins