Piserchio Andrea, Han Yinglin, Chorev Michael, Mierke Dale F
Department of Chemistry, Brown University, Providence, RI 02912, USA.
Biopolymers. 2002 Jun;64(1):16-25. doi: 10.1002/bip.10080.
A series of dipeptidomimetics derived from C(alpha)(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.
一系列通过相邻氨基酸的C(α)(i)-至-N(i-1)侧链至主链酰胺环化衍生的二肽模拟物得到了结构表征。所得的环系要么是与苯二氮䓬结构相关的1,2,5-三取代-3-氧代-1,4-二氮杂䓬（DAP），常用于候选药物和治疗剂，要么是其更高的同系物。在此，我们研究了将环大小从七元环扩大到八元、九元和十元环的结构后果。通过高分辨率核磁共振方法确定的结构特征，很大程度上依赖于同核和异核耦合常数，表明环的变化会导致连接的化学部分或官能团的替代构象和拓扑取向。使用完全由肽中发现的官能团组成的分子支架来控制生物活性所需的环取代基的拓扑展示，应该有助于将肽类候选先导物合理、逐步地转化为非肽类候选药物。
