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

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

doi:10.1021/acsinfecdis.5b00069

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 Infect Dis. 2015 Oct 9;1(10):479-86. doi: 10.1021/acsinfecdis.5b00069. Epub 2015 Aug 6.

Affiliations

¹ Department of Chemistry, Wayne State University , Detroit, Michigan 48202, United States.
² Institut für Medizinische Mikrobiologie, Universität Zürich , 8006 Zürich, Switzerland.
³ Laboratorium für Organische Chemie, ETH Zürich , 8093 Zürich, Switzerland.

PMID: 27623314
DOI: 10.1021/acsinfecdis.5b00069

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.

Keywords: antibacterial activity; decoding A site; mitochondrial rRNA; ototoxicity; ribosomal selectivity.