Hanessian Stephen, Szychowski Janek, Adhikari Susanta Sekhar, Vasquez Guillermo, Kandasamy Pachamuthu, Swayze Eric E, Migawa Michael T, Ranken Ray, François Boris, Wirmer-Bartoschek Julia, Kondo Jiro, Westhof Eric
Department of Chemistry, Université de Montréal, C. P. 6128, Succ. Centre-Ville, Montréal, P. Q., Canada.
J Med Chem. 2007 May 17;50(10):2352-69. doi: 10.1021/jm061200+. Epub 2007 Apr 26.
A series of 2"-O-substituted ether analogues of paromomycin were prepared based on new site-selective functionalizations. X-ray cocrystal complexes of several such analogues revealed a new mode of binding in the A-site rRNA, whereby rings I and II adopted the familiar orientation and position previously observed with paromomycin, but rings III and IV were oriented differently. With few exceptions, all of the new analogues showed potent inhibitory activity equal or better than paromomycin against a sensitive strain of S. aureus. Single digit microM MIC values were obtained against E. coli, with some of the ether appendages containing polar or basic end groups. Two analogues showed excellent survival rate in a mouse septicemia protection assay. Preliminary histopathological analysis of the kidney showed no overt signs of toxicity, while controls with neomycin and kanamycin were toxic at lower doses.
基于新的位点选择性官能化反应，制备了一系列巴龙霉素的2''-O-取代醚类似物。几种此类类似物的X射线共晶体复合物揭示了在A位点rRNA中的一种新结合模式，即环I和环II采用了先前在巴龙霉素中观察到的常见取向和位置，但环III和环IV的取向不同。除少数例外，所有新类似物对金黄色葡萄球菌敏感菌株均表现出与巴龙霉素相当或更好的强效抑制活性。对大肠杆菌的最低抑菌浓度（MIC）值达到个位数微摩尔，其中一些醚类附属基团含有极性或碱性端基。两种类似物在小鼠败血症保护试验中显示出优异的存活率。对肾脏的初步组织病理学分析未发现明显的毒性迹象，而新霉素和卡那霉素对照组在较低剂量下具有毒性。
