Synthetic approaches to peptides containing the L-Gln-L-Val-D(S)-Dmt motif.
The pseudoprolines S-Dmo (5,5-dimethyl-4-oxaproline) and R-Dmt (5,5-dimethyl-4-thiaproline) have been used to study the effects of forcing a fully cis conformation in peptides. Synthesis of peptides containing these (which have the same configuration as L-Pro) is straightforward. However, synthesis of peptides containing S-Dmt is difficult, owing to the rapid cyclisation of L-Aaa-S-Dmt amides and esters to form the corresponding diketopiperazines (DKP); thus the intermediacy of L-Aaa-S-Dmt amides and esters must be avoided in the synthetic sequence. Peptides containing the L-Gln-L-Val-D(S)-Dmt motif are particularly difficult, owing to the insolubility of coupling partners containing Gln. Introduction of Gln as N-Boc-pyroglutamate overcame the latter difficulty and the dipeptide active ester BocPygValOC(6)F(5) coupled in good yield with S-DmtOH. BocPygVal-S- DmtNH(CH(2))(2)C(6)H(4)NO(2) was converted quantitatively to BocGlnVal-S-DmtNH(CH(2))(2)C(6)H(4)NO(2) with ammonia, demonstrating the utility of this approach. Two peptide derivatives (CbzSerLysLeuGlnVal-S-DmtNH(CH(2))(2)C(6)H(4)NO(2) and CbzSerSerLysLeuGlnVal-S- DmtNH(CH(2))(2)C(6)H(4)NO(2)) were assembled, using these new methods of coupling a dipeptide acid active ester with S-DmtOH and introduction of Gln as Pyg, followed by conventional peptide couplings. The presence of the Val caused these peptides to be cleaved very slowly by prostate-specific antigen (PSA) at Leu Gln, rather than the expected Gln Val.
Suaifan
Ghadeer A R Y
GA
Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
Arafat
Tawfiq
T
Threadgill
Michael D
MD
D002851:Chromatography, High Pressure Liquid; D010450:Endopeptidases / Q000737:chemistry; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000138:chemical synthesis*; D010455:Peptides / Q000138:chemical synthesis*; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors / Q000737:chemistry; D013055:Spectrophotometry, Infrared
D007202:Indicators and Reagents; C520659:L-glutaminyl-L-valyl-D(S)-5,5-dimethyl-4-thiaproline; D009842:Oligopeptides; D010455:Peptides; D010450:Endopeptidases; D017430:Prostate-Specific Antigen