Jia Yanxing, Ma Nianchun, Liu Zuosheng, Bois-Choussy Michèle, Gonzalez-Zamora Eduardo, Malabarba Adriano, Brunati Cristina, Zhu Jieping
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France.
Chemistry. 2006 Jul 5;12(20):5334-51. doi: 10.1002/chem.200600137.
16-membered meta,para-cyclophanes mimicking the vancomycin binding pocket (D-O-E ring) were designed and synthesized. The structural key features of these biaryl ether containing macrocycles are (1) the presence of beta-amino-alpha-hydroxy acid or alpha,beta-diamino acid as the C-terminal component of the cyclopeptide and (2) the presence of a hydrophobic chain or lipidated aminoglucose at the appropriate position. Cycloetherification by an intramolecular nucleophilic aromatic substitution reaction (S(N)Ar) is used as the key step for the construction of the macrocycle. The atropselectivity of this ring-closure reaction is found to be sensitive to the peptide backbone and chemoselective cyclization (phenol versus primary amine) is achievable. Glycosylation of phenol was realized with freshly prepared 3,4,6-tri-O-acetyl-2-N-lauroyl-2-amino-2-deoxy-alpha-D-glucopyranosyl bromide under phase-transfer conditions. Minimum inhibitory concentrations for all of the derivatives are measured by using a standard microdilution assay, and potent bioactivities against both sensitive and resistant strains are found for some of these compounds (MIC (minimum inhibitory concentration) = 4 microg mL(-1) against VRE). From these preliminary SAR studies, it was anticipated that both the presence of a hydrophobic substituent and an appropriate structure of the macrocycle were required for this series of compounds to be active against VRE.
设计并合成了模拟万古霉素结合口袋（D - O - E环）的16元间、对环芳烷。这些含联芳基醚大环化合物的结构关键特征为：（1）环肽的C末端组分存在β - 氨基 - α - 羟基酸或α,β - 二氨基酸；（2）在适当位置存在疏水链或脂化氨基葡萄糖。通过分子内亲核芳香取代反应（S(N)Ar）进行环醚化反应是构建大环的关键步骤。发现该闭环反应的阻转选择性对肽主链敏感，并且可实现化学选择性环化（苯酚与伯胺）。在相转移条件下，用新制备的3,4,6 - 三 - O - 乙酰基 - 2 - N - 月桂酰基 - 2 - 氨基 - 2 - 脱氧 - α - D - 吡喃葡萄糖基溴实现了苯酚的糖基化。通过标准微量稀释法测定所有衍生物的最低抑菌浓度，发现其中一些化合物对敏感菌株和耐药菌株均具有强效生物活性（对耐万古霉素肠球菌的最低抑菌浓度（MIC） = 4 μg mL⁻¹）。从这些初步的构效关系研究中可以预期，该系列化合物要对耐万古霉素肠球菌具有活性，既需要存在疏水取代基又需要大环具有合适的结构。
