Solution phase synthesis of Saccharomyces cerevisiae a-mating factor and its analogs.
The solution phase synthesis of the Saccharomyces cerevisiae a-mating factor and nonfarnesylated and nonmethylated a-factor analogs are reported. The a-factor, a lipopeptide with the sequence Tyr-Ile-Ile-Lys-Gly-Val-Phe-Trp-Asp-Pro-Ala-Cys(S-Farnesyl)OCH3 was synthesized by the condensation of the amine terminal protected decapeptide with the carboxyl terminal farnesylated dipeptide using benzotriazol-l-yloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent) as the coupling agent. The synthesis of the decapeptide involved 5 + 5 fragment coupling with the BOP reagent and the successful application of 9-fluorenylmethyl ester(OFm) and 9-fluorenylmethoxycarbonyl(Fmoc) groups for the protection of Asp and Lys side chains and Tyr alpha-amine and of phenacyl esters (OPa) for alpha-carboxyl protection. The OFm and Fmoc groups tolerated repeated couplings and were completely stable to zinc powder in acetic acid, a condition under which the OPa group was removed. The synthesis of the nonfarnesylated alpha-factor was accomplished by the coupling of the decapeptide with tetrapeptide (Ala-CysOCH3)2 followed by the deprotection of the OFm and Fmoc groups with piperidine and the cleavage of the disulfide bond with zinc powder in acetic acid. The nonmethylated a-factor was prepared by 10 + 2 fragment coupling using OFm protection of the dipeptide carboxyl group followed by removal of all protecting groups with piperidine. Attempts to saponify a-factor were not successful. The synthetic nonfarnesylated and nonmethylated a-mating pheromones were 100-1000 times less active than the a-factor, indicating that although the methyl ester and the farnesyl group are not essential for biological activity, they are necessary for high potency.
Xue
C B
CB
Department of Chemistry, College of Staten Island, City University of New York.
Ewenson
A
A
Becker
J M
JM
Naider
F
F
D000595:Amino Acid Sequence; D002851:Chromatography, High Pressure Liquid; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D000072235:Mating Factor; D008969:Molecular Sequence Data; D009904:Optical Rotation; D010455:Peptides / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology; D010675:Pheromones / Q000138:chemical synthesis*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D010455:Peptides; D010675:Pheromones; D000072235:Mating Factor