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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


Kato, T; Yang, G; Youjin, T; Juskeviciene, R; Perez-Fernandez, D; Shinde, HM; Salian, S; Bernet, B; Vasella, A; Böttger, EC; Crich, D (2015). 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. ACS Infectious Diseases, 1(10):479-486.

Abstract

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.

Abstract

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Microbiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2015
Deposited On:21 Dec 2015 14:39
Last Modified:05 Apr 2016 19:43
Publisher:American Chemical Society (ACS)
ISSN:2373-8227
Publisher DOI:https://doi.org/10.1021/acsinfecdis.5b00069

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