title: Conformationally tailored N-[(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)carbonyl]proline templates as molecular tools for the design of peptidomimetics. Design and synthesis of fibrinogen receptor antagonists.
abstract: The proline peptide bond was shown by 2D proton NMR studies to exist exclusively in the trans conformation in benzyl (2S)-1-[[(2S)-2-methyl-6-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl]-2-pyrrolidinecarboxylate [(S,S)-11], benzyl (2S)-1-[[(2S)-2-methyl-7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl]-2-pyrrolidinecarboxylate [(S,S)-9], and in the corresponding 6-amino and 7-amino carboxylic acids (S,S)-3 and (S,S)-4. On the other hand, the diastereomers (R,S)-11 and (R,S)-9 containing an (R)[2-methyl-6/7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl moiety, and the diastereoisomers (R,S)-3 and (R,S)-4 incorporating an (R)[6/7-amino-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl moiety were found to exist as equilibria of trans(63-83%) and cis(17-37%) isomers. These conformationally defined templates were applied in the construction of RGD mimetics possessing antagonistic activity at the platelet fibrinogen receptor.
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, Slovenia.
authors.forename: Petra
authors.initials: P
authors.lastname: Stefanic
authors.forename: Zvone
authors.initials: Z
authors.lastname: Simoncic
authors.forename: Matej
authors.initials: M
authors.lastname: Breznik
authors.forename: Janez
authors.initials: J
authors.lastname: Plavec
authors.forename: Marko
authors.initials: M
authors.lastname: Anderluh
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Addicks
authors.forename: Athanassios
authors.initials: A
authors.lastname: Giannis
authors.forename: Danijel
authors.initials: D
authors.lastname: Kikelj
mesh_terms: D001667:Binding, Competitive; D016023:Integrins / Q000737:chemistry; D008163:Luminescent Measurements; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry; D039341:Receptors, Fibrinogen / Q000037:antagonists & inhibitors* / Q000737:chemistry; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D016023:Integrins; D009842:Oligopeptides; D010455:Peptides; D039341:Receptors, Fibrinogen; D019030:Receptors, Vitronectin; D011392:Proline; C046617:arginyl-glycyl-aspartyl-serine