Herzog Ido M, Louzoun Zada Sivan, Fridman Micha
School of Chemistry, Raymond and Beverley Sackler Faculty of Exact Sciences, Tel Aviv University , Tel Aviv 6997801, Israel.
J Med Chem. 2016 Sep 8;59(17):8008-18. doi: 10.1021/acs.jmedchem.6b00793. Epub 2016 Aug 19.
We studied six pairs of aminoglycosides and their corresponding ribosylated derivatives synthesized by attaching a β-O-linked ribofuranose to the 5-OH of the deoxystreptamine ring of the parent pseudo-oligosaccharide antibiotic. Ribosylation of the 4,6-disubstituted 2-deoxystreptamine aminoglycoside kanamycin B led to improved selectivity for inhibition of prokaryotic relative to cytosolic eukaryotic in vitro translation. For the pseudodisaccharide aminoglycoside scaffolds neamine and nebramine, ribosylated derivatives were both more potent antimicrobials and more selective to inhibition of prokaryotic translation. On the basis of the results of this study, we suggest that modification of the 5-OH position of the streptamine ring of other natural or semisynthetic pseudodisaccharide aminoglycoside scaffolds containing an equatorial amine at the 2' sugar position with a β-O-linked ribofuranose is a promising avenue for the development of novel aminoglycoside antibiotics with improved efficacy and reduced toxicity.
我们研究了六对氨基糖苷类及其相应的核糖基化衍生物，这些衍生物是通过将β - O - 连接的呋喃核糖连接到母体假寡糖抗生素脱氧链霉胺环的5 - OH上合成的。4,6 - 二取代的2 - 脱氧链霉胺氨基糖苷卡那霉素B的核糖基化导致相对于胞质真核生物体外翻译，对原核生物抑制的选择性提高。对于假二糖氨基糖苷支架新霉素和异新霉素，核糖基化衍生物既是更强效的抗菌剂，对原核生物翻译的抑制也更具选择性。基于本研究结果，我们认为，用β - O - 连接的呋喃核糖修饰在2'糖位置含有平伏胺的其他天然或半合成假二糖氨基糖苷支架的链霉胺环的5 - OH位置，是开发具有更高疗效和更低毒性的新型氨基糖苷类抗生素的一条有前景的途径。
