Studies on conformational consequences of i to i + 3 side-chain cyclization in model cyclic tetrapeptides.
In an effort to explore the effect of ring size on the biologically active conformation of cyclic analogs of the mating pheromone alpha-factor (WHWLQLKPGQPMY) from Saccharomyces cerevisiae, eight cyclic tetrapeptides corresponding to the KPGQ portion of alpha-factor were synthesized. These N-alpha-acetyl/carboxyl amide terminal cyclic tetrapeptides were prepared on a 4-methylbenzhydrylamine resin using orthogonal Boc, Fmoc, OFm and OtBut protecting groups and HOBt-DIPC accelerated active esters or urethane-protected N-carboxyanhydrides. On-resin cyclization of the side-chain amino and carboxyl groups of the first and fourth residues, respectively, was performed with the BOP reagent to generate lactams containing 14-18 atoms. HF cleavage resulted in two products, the desired cyclic tetrapeptide and a major side product. All peptides were purified to near homogeneity (> 99%) by using reversed-phase HPLC and were characterized by FBMS and 1H NMR. Certain constrained cyclic tetrapeptides appear to be a mixture of isomers at room temperature as evidenced by HPLC and NMR. The major side product has been identified as a cyclo dimer, obtained as a consequence of interchain cyclization on the resin. CD analysis in several solvents gives evidence that some of the cyclic tetrapeptides exist in beta-turn conformations.
Rao
M H
MH
Department of Chemistry, College of Staten Island, City University of New York, USA.
Yang
W
W
Joshua
H
H
Becker
J M
JM
Naider
F
F
D000595:Amino Acid Sequence; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D007769:Lactams / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry*; D011487:Protein Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D007769:Lactams; D009842:Oligopeptides; D010455:Peptides; D010456:Peptides, Cyclic