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.
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.
Stefanic
Petra
P
University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, Slovenia.
Simoncic
Zvone
Z
Breznik
Matej
M
Plavec
Janez
J
Anderluh
Marko
M
Addicks
Elisabeth
E
Giannis
Athanassios
A
Kikelj
Danijel
D
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
D016023:Integrins; D009842:Oligopeptides; D010455:Peptides; D039341:Receptors, Fibrinogen; D019030:Receptors, Vitronectin; D011392:Proline; C046617:arginyl-glycyl-aspartyl-serine