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Structural characterization of a cyclic dipeptidomimetic: The effect of ring size on a 1,2,5‐trisubstituted‐3‐oxo‐1,4‐diazepine system
Author(s) -
Piserchio Andrea,
Han Yinglin,
Chorev Michael,
Mierke Dale F.
Publication year - 2002
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.10080
Subject(s) - chemistry , diazepine , ring (chemistry) , amide , heteronuclear molecule , stereochemistry , side chain , ring size , drug discovery , peptide , combinatorial chemistry , nuclear magnetic resonance spectroscopy , organic chemistry , biochemistry , polymer
Abstract A series of dipeptidomimetics derived from C α i ‐to‐N i −1 side chain‐to‐backbone amide cyclization of adjacent amino acids are structurally characterized. The resulting ring systems are either 1,2,5‐trisubstituted‐3‐oxo‐1,4‐diazepine (DAP) structurally related to benzodiazepines, commonly used in drug candidates and therapeutic agents, or higher homologs of it. Here, we examine the structural consequences of enlarging the ring size from seven members to eight‐, nine‐, and ten‐membered rings. The structural features determined by high‐resolution NMR methods, relying largely on homo‐ and heteronuclear coupling constants, indicate that variation of the ring leads to alternative conformations and topological orientations of the attached chemical moieties or functional groups. Controlling the topological display of the ring substituents required for biological action, using a molecular scaffold made up entirely of functional groups found in peptides, should facilitate the rational, stepwise transformation of peptide lead candidate into a nonpeptidic drug candidate. © 2002 Wiley Periodicals, Inc. Biopolymers 64: 16–25, 2002