Hirano Shinpei, Ichikawa Satoshi, Matsuda Akira
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
J Org Chem. 2008 Jan 18;73(2):569-77. doi: 10.1021/jo702264e. Epub 2007 Dec 20.
Synthesis of palmitoyl caprazol 7, which possesses a simple fatty acyl side chain at the 3' ''-position of the diazepanone moiety, was carried out and their antibacterial activity was evaluated. The key elements of our approach include the improved synthesis of the key 5'-beta-O-aminoribosyl-glycyluridine derivative, installation of the palmitoyl side chain to the cyclization precursor, and the construction of the diazepanone by an intramolecular reductive amination. The second generation synthesis of (+)-caprazol was also established. Palmitoyl caprazol 7 exhibited antibacterial activity against Mycobacterium smegmatis ATCC607 (MIC = 6.25 microg/mL) with potency similar to that of the caprazamycins (CPZs). Palmitoyl caprazol 7 and N6'-desmethyl palmitoyl caprazol 28 also exhibited antibacterial activity against drug-resistant bacteria including methyciline-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) strains (MIC = 3.13-12.5 microg/mL).
合成了在二氮杂环庚酮部分的3''' - 位具有简单脂肪酰基侧链的棕榈酰卡普唑7，并评估了它们的抗菌活性。我们方法的关键要素包括关键的5'-β-O-氨基核糖基 - 甘氨酰尿苷衍生物的改进合成、将棕榈酰侧链安装到环化前体上以及通过分子内还原胺化构建二氮杂环庚酮。还建立了(+)-卡普唑的第二代合成方法。棕榈酰卡普唑7对耻垢分枝杆菌ATCC607表现出抗菌活性（MIC = 6.25μg/mL），其效力与卡普霉素（CPZs）相似。棕榈酰卡普唑7和N6'-去甲基棕榈酰卡普唑28对包括耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素肠球菌（VRE）菌株在内的耐药菌也表现出抗菌活性（MIC = 3.13 - 12.5μg/mL）。
