SYNTHESIS OF 4S)-5-AMINO-4-FLUORO-2-HYDROXYPENTANOYL]DIBEKACINS AND 4R)-5-AMINO-4-FLUORO-2-HYDROXYPENTANOYL]DIBEKACINS (STUDY ON STRUCTURE-TOXICITY RELATIONSHIPS)

(2S,4S)- and 4R)-5-azido-2-O-benzyl-4-fluoro-2-hydroxypentanoic acids (15 and 19) have been prepared from L-malic acid (1), and coupled to t he H2N-1 group of 3,2',6'-tris(N-benzyloxycarbonyl)-3 ''-N-(trifluoroa cetyl)dibekacin (23), to give, after reduction and deblocking, 1-N-[(2 S,4S)- and 4R)-5-amino-4-fluoro-2-hydroxypentanoyl]dibekacins (26 and 27). The fluorinated arbekacin analogs showed almost the same antibact erial activities as that of arbekacin, but lower toxicity. Comparision of the toxicity between 26 (and 27) and the arbekacin analogs (28-30) with change of the 1N-side-chain indicates that the observed decrease in toxicity was a function of the chain length rather than the introd uction of flourine. (C) 1998 Elsevier Science Ltd. All rights reserved .