Insertion of multiple alpha-amino gamma-lactam (Agl) residues into a peptide sequence by solid-phase synthesis on synphase lanterns.
The insertion of lactams into peptide analogs can enhance potency and improve receptor selectivity. The synthesis of lactam-bridged peptide sequences has been accomplished by a solid-phase approach on SynPhase lanterns using cyclic (R)- and (S)-oxathiazinane ester (2) to annulate the amino lactam residue onto the peptide chain. Parallel synthesis of alpha-amino gamma-lactam analogs of the allosteric modulator of IL-1 receptor 101.10 (D-Arg-D-Tyr-D-Thr-D-Val-D-Glu-D-Leu-D-Ala: rytvela) was performed by split-mix chemistry on the lanterns. In particular, the double insertion of alpha-amino gamma-lactams in the same peptide sequence has been accomplished by this effective method for the solid-supported combinatorial synthesis of lactam-bridged peptides. Peptides bearing an Agl residue exhibited curve shapes indicative of turn conformations in their circular dichroism spectra.
Départment de Chimie, Universitè de Montréal, C.P, 6128, Succursale Centre-Ville, Montréal, Québec H3C 3J7, Canada.
Luisa
L
Ronga
Andrew G
AG
Jamieson
Kim
K
Beauregard
Christiane
C
Quiniou
Sylvain
S
Chemtob
William D
WD
Lubell
D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D020650:Combinatorial Chemistry Techniques; D004338:Drug Combinations; D004997:Ethinyl Estradiol / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000737:chemistry*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors; D007769:Lactams / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D009640:Norethindrone / Q000737:chemistry* / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology
C529594:101.10 peptide; D004338:Drug Combinations; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D007769:Lactams; D010455:Peptides; C020416:norethindrone acetate, ethinyl estradiol, ferrous fumarate drug combination; D004997:Ethinyl Estradiol; D009640:Norethindrone