Synthesis and Antiribosomal Activities of 4′-O-, 6′-O-, 4″-O-, 4′,6′-O- and 4″,6″-O-Derivatives in the Kanamycin Series Indicate Differing Target Selectivity Patterns between the 4,5- and 4,6-Series of Disubstituted 2-Deoxystreptamine Aminoglycoside Antibiotics

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• 作者：Takayuki Kato ; Guanyu Yang ; Youjin Teo ; Reda Juskeviciene ; Déborah Perez-Fernandez ; Harish M. Shinde ; Sumanth Salian ; Bruno Bernet ; Andrea Vasella ; Erik C. Böttger ; David Crich
• 刊名：ACS Infectious Diseases
• 出版年：2015
• 出版时间：October 9, 2015
• 年：2015
• 卷：1
• 期：10
• 页码：479-486
• 全文大小：486K
• ISSN：2373-8227

文摘

Chemistry for the efficient modification of the kanamycin class of 4,6-aminoglycosides at the 4′-position is presented. In all kanamycins but kanamycin B, 4′-O-alkylation is strongly detrimental to antiribosomal and antibacterial activity. Ethylation of kanamycin B at the 4″-position entails little loss of antiribosomal and antibacterial activity, but no increase of ribosomal selectivity. These results are contrasted with those for the 4,5-aminoglycosides, where 4′-O-alkylation of paromomycin causes only a minimal loss of activity but results in a significant increase in selectivity with a concomitant loss of ototoxicity.