Mitochondrial mutant bonds to the N7 and a phosphate oxygen of G1405 that must be maintained for activity. At this position restrictions on the size and geometry of a substituent limits other allowable modifications.A hydrogen bond exists between the hydroxyl at C4" and a phosphate oxygen of U1406. Some natural variations exist at C4"; a hydroxyl group (in either configuration) is usually present but sometimes is replaced by a methoxy (41).

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" modifications of 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 30S explains why a variety of small substitutions is permissible.

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