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-epifluorotobramyc in (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 13C NMR spectra) of 2,5-dideoxy-5-epifluorostreptamine (23) and 2,5-dideoxy-5-fluorostreptamine (24), chosen as model compounds, and 2-deoxystreptamine (DST).
Institute of Bioorganic Chemistry, Kawasaki, Japan.
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Shitara
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Umemura
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Tsuchiya
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Matsuno
D000583:Amikacin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D003982:Dibekacin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D017611:Fluorine Compounds / Q000138:chemical synthesis / Q000633:toxicity; D051379:Mice; D008969:Molecular Sequence Data; D014031:Tobramycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D017611:Fluorine Compounds; D003982:Dibekacin; D000583:Amikacin; C031986:arbekacin; D014031:Tobramycin