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 (YIIKGVFWDPAC(Farnesyl)-OCH(3), 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 beta-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.
Xie
H
H
Department of Chemistry, College of Staten Island, and the Doctoral Program in Chemistry of the City University of New York, Staten Island, New York 10314, USA.
Shao
Y
Y
Becker
J M
JM
Naider
F
F
Gibbs
R A
RA
D000595:Amino Acid Sequence; D005204:Farnesol / Q000737:chemistry; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D000072235:Mating Factor; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D012441:Saccharomyces cerevisiae / Q000737:chemistry*
D010446:Peptide Fragments; D010455:Peptides; D005204:Farnesol; D000072235:Mating Factor