SYNTHESIS OF 5-DEOXY-5-EPIFLUORO DERIVATIVES OF ARBEKACIN, AMIKACIN, AND 1-N-[(S)-4-AMINO-2-HYDROXYBUTANOYL]TOBRAMYCIN (STUDY ON STRUCTURE-TOXICITY RELATIONSHIPS)

As part of a study on fluorination-toxicity relationships for aminoglycoside antibiotics, 5,3'-dideoxy-5-epifluorokanamycin B (10), 5,3',4'-trideoxy-5-epifluorokanamycin B (11), 1-N-[(S)-4-amino-2-hydroxybutanoyl]-5-deoxy-5-epifluorotobramycin (19), 5-deoxy-5-epifluoroarbekacin (20), and 5-deoxy-5-epifluoroamikacin (21) have been prepared. The acute toxicities of these three 5-deoxy-5-epifluoro compounds showed values almost identical or similar to those for arbekacin (ABK) and amikacin (15), making a sharp contrast with the toxicities of the corresponding 5-deoxy-5-fluoro derivatives. This fact is explained on the basis of basicity changes (retention for the 5-epifluoro derivatives and reduction for the 5-fluoro derivatives) at the H2N-3 groups of the fluorinated compounds compared to the parent compounds; this hypothesis was substantiated by the pKa values at the H3N+-1, 3 groups (determined by the shift changes depending on pD values at C-2 and C-4, 6 in their C-13 NMR spectral of 2,5-dideoxy-5-epifluorostreptamine (23) and 2,5-dideoxy-5-fluorostreptamine (24), chosen as model compounds, and 2-deoxystreptamine (DST).