Synthesis of low-toxicity, 5-deoxy-5-fluoro and 5-deoxy-5,5-difluoro derivatives of arbekacin and its analogs, and study of structure-toxicity relationships

✍ Scribed by Tsutomu Tsuchiya; Tetsuo Shitara; Sumio Umezawa; Tomio Takeuchi; Masa Hamada; Noriko Tomono; Eijiro Umemura

• Publisher: Elsevier Science
• Year: 1993
• Tongue: English
• Weight: 379 KB
• Volume: 240
• Category: Article
• ISSN: 0008-6215
• DOI: 10.1016/0008-6215(93)84194-b

✦ Synopsis

Studies on structure-toxicity relationships of aminoglycoside antibiotics have rarely been reported, and, to the best of our knowledge, no studies except for ours1.2 have been rep orted on the relationship between the basicity of a particular amino group in the molecule and the toxicity of the antibiotic. Lately we reported the synthesis of several 2 '-(ref. 3), 3'-(refs. 4-7), 4'-(ref. S), 6"-(ref. 9), and 5-deoxyfluoro (and 5-deoxy-5,5-difluoro) analogs" of kanamycins. The last group of compounds were especially found to show remarkably decreased acute toxicity (by intravenous injection in mice), with similar or sometimes improved antibacterial activity as compared to the parent antibiotics. This decrease of toxicity was considered to result" from the lowered basicity (induced by the strongly electronegative fluorine(s)" at C-5) of the amino groups at C-l and C-3 of the deoxyfluorinated derivatives of kanamycin B analogs, relative to the parent compounds. The present study extends this research and describes the synthesis of the l-N-t(S)-4-amino-2-hydroxybutanoyl] (AHB) derivatives of the deoxyfluorinated derivatives. As was seen in amikacin13 (1-N-AHB-kanamycin A) and arbekacin14 (l-N-AHB-3',4'-dideoxykanamycin B), attachment of an AHB group to the NH,-1 group of kanamycins gave compounds of remarkably enhanced antibacterial activity, against both sensitive and resistant bacteria, relative to the parent antibiotics. However, a serious drawback in clinical use of arbekacin, for example, is its high toxicity (renal and otic toxicities, in general). Thus reduction of the toxicity of arbekacin and related aminoglycoside antibiotics is an urgent problem to be