Kanamycin, azido derivatives

Dideoxy-2 -fluorokanamycin A (Ref. 170), a kanamycin derivative in which the OH-2 or NH2-2 of kanamycin A and B, respectively, is replaced by a fluorine atom, was prepared by condensation of 6-azido-4-0-benzoyl-2,3,6-trideoxy-2-fluoro-a-D-n77ohexopyranosyl bromide, derived from 179 (see Section 11,2), with the pseudodisaccharide component of kanamycin. The compound showed mediocre antibacterial activity however, on attachment of an (5)-4-amino-2-hydroxybutanoyl residue, as in amikacin, to the NHj-l group, the derivative showed considerably enhanced activity. ... 

For gentamycin derivatives, the introduction of an axial hydroxymethyl substituent at C-1 in the 2-deoxystreptamine moiety reportedly ameliorates nephrotoxicity and confers protection against inactivation by bacterial enzymes. The Belgium team investigated a similar modification in the kanamycin B series [265]. As expected, l-C-(hydroxymethyl)kanamycin B (212) proved equipotent with the parent aminoglycoside (208) against kanamycin B-sensitive bacteria and the introduction of a 6"-azido, 6"-chloro, or 6"-acetamido group (213)-(215), did not reduce antibacterial activity Table 3.19). However, the introduction of a l-C-(hydroxymethyl)... 

A wide variety of natural and synthetic variations is permissible at C5", and at C6" for C 5 branched compounds (41). An extensive study of C6" modificationsof kanamycin B revealed that halogeno, azido, amino, alkylthio, and alkoxy substitutions are all well tolerated until they become very bulky (70). For example, only the N-hexanoyl-N-butylarnino derivative was essentially inactive against all bacteria tested, but the smaller substituents retained good activity. The NMR structure of gentamicin Cla (which is 5 deoxy) indicates that any modification at C 5 would be directed away from 30S (60). The predicted lack of interaction between C5" substituents and 308 explains why a variety of small substitutions is permissible. 

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