title: Design and synthesis of amidine-type peptide bond isosteres: application of nitrile oxide derivatives as active ester equivalents in peptide and peptidomimetics synthesis.
abstract: Amidine-type peptide bond isosteres were designed based on the substitution of the peptide bond carbonyl (C=O) group with an imino (C=NH) group. The positively-charged property of the isosteric part resembles a reduced amide-type peptidomimetic. The peptidyl amidine units were synthesized by the reduction of a key amidoxime (N-hydroxyamidine) precursor, which was prepared from nitrile oxide components as an aminoacyl or peptidyl equivalent. This nitrile oxide-mediated C-N bond formation was also used for peptide macrocyclization, in which the amidoxime group was converted to peptide bonds under mild acidic conditions. Syntheses of the cyclic RGD peptide and a peptidomimetic using both approaches, and their inhibitory activity against integrin-mediated cell attachment, are presented.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Inokuchi
authors.forename: Ai
authors.initials: A
authors.lastname: Yamada
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hozumi
authors.forename: Kenji
authors.initials: K
authors.lastname: Tomita
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ohno
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Nomizu
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D000578:Amidines / Q000737:chemistry*; D000596:Amino Acids / Q000737:chemistry; D015195:Drug Design; D004952:Esters / Q000737:chemistry*; D007477:Ions / Q000737:chemistry; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry*; D010087:Oxides / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis*; D057786:Peptidomimetics / Q000138:chemical synthesis*
chemical_list: D000578:Amidines; D000596:Amino Acids; D004952:Esters; D007477:Ions; D009570:Nitriles; D010087:Oxides; D010455:Peptides; D057786:Peptidomimetics