posted on 2000-11-16, 00:00authored byHaibo Xie, Ying Shao, Jeffrey M. Becker, Fred Naider, Richard A. Gibbs
The a-factor of Saccharomyces cerevisiae is a dodecapeptide pheromone (YIIKGVFWDPAC(Farnesyl)-OCH3, 1), in which post-translational modification with a farnesyl isoprenoid and
carboxymethyl group is required for full biological activity. This peptide has been used as a model
system to explore the biological function of the farnesylcysteine moiety, which is found on and
required for the biological activity of many key mammalian proteins. The objective of this particular
study was the determination of the biological effect of double bond isomerization of the natural
E,E-farnesyl moiety on the biological activity of the a-factor. A unified, stereoselective synthetic
route to the three geometric isomers of E,E-farnesol (12, 13, and 14) has been developed. The key
feature of this synthesis is the ability to control the stereochemistry of triflation of the β-ketoester
22 to give either 23 or 25. The three farnesol isomers were converted to the corresponding isomeric
a-factors (9, 10 and 11) via a modified version of a previously utilized synthetic route. Biological
evaluation of these peptides indicates that, surprisingly, all three possess nearly equivalent activity
to the natural a-factor bearing the E,E-farnesyl moiety.