Synthesis and biological evaluation of the geometric farnesylated analogues of the a-factor mating peptide of Saccharomyces cerevisiae

The a-factor of Saccharomyces cerevisiae is a dodecapeptide pheromone (YIIK GVFWDPAC-(Farnesyl)-OCH3, 1), in which post-translational modification with a farnesyl isoprenoid and carboxymethyl group is required for foil biologi cal activity. This peptide has been used as a model system to explore the b iological funct ion of the farnesylcysteine moiety, which is found on and r equired for the biological activity of many key mammalian proteins. The obj ective of this particular study was the determination of the biological eff ect of double bond isomerization of the natural E,E-farnesyl moiety on the biological activity of the a-factor. A unified, stereoselective synthetic r oute to the three geometric isomers of E,E-farnesol (12, 13, and 14) has be en developed. The key feature of this synthesis is the ability to control t he stereochemistry of triflation of the beta -ketoester 22 to give either 2 3 or 25. The three farnesol isomers were converted to-the corresponding iso meric a-factors (9, 10 and II) via a modified version of a previously utili zed synthetic route. Biological evaluation of these peptides indicate's tha t, surprisingly, all three possess nearly equivalent activity to the natura l a-factor bearing the E,E-farnesyl moiety.