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.
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.
Department of Chemistry, Wayne State University , Detroit, Michigan 48202, United States.
Takayuki
T
Kato
Department of Chemistry, Wayne State University , Detroit, Michigan 48202, United States.
Guanyu
G
Yang
Institut für Medizinische Mikrobiologie, Universität Zürich , 8006 Zürich, Switzerland.
Youjin
Y
Teo
Institut für Medizinische Mikrobiologie, Universität Zürich , 8006 Zürich, Switzerland.
Reda
R
Juskeviciene
Laboratorium für Organische Chemie, ETH Zürich , 8093 Zürich, Switzerland.
Déborah
D
Perez-Fernandez
Laboratorium für Organische Chemie, ETH Zürich , 8093 Zürich, Switzerland.
Harish M
HM
Shinde
Laboratorium für Organische Chemie, ETH Zürich , 8093 Zürich, Switzerland.
Sumanth
S
Salian
Laboratorium für Organische Chemie, ETH Zürich , 8093 Zürich, Switzerland.
Bruno
B
Bernet
Laboratorium für Organische Chemie, ETH Zürich , 8093 Zürich, Switzerland.
Andrea
A
Vasella
Institut für Medizinische Mikrobiologie, Universität Zürich , 8006 Zürich, Switzerland.
Erik C
EC
Böttger
Department of Chemistry, Wayne State University , Detroit, Michigan 48202, United States.
David
D
Crich
antibacterial activity; decoding A site; mitochondrial rRNA; ototoxicity; ribosomal selectivity