New derivatives of kanamycin B obtained by combined modifications in positions 1 and 6". Synthesis, microbiological properties, and in vitro and computer-aided toxicological evaluation

Vanschepdael, Ann;Busson, Roger;Vanderhaeghe, HJ.;Claes, PJ.;Tulkens, Paul M.;et.al.
(1991) Journal of Medicinal Chemistry — Vol. 34, n° 4, p. 1483-1492 (1991)

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  • Vanschepdael, Ann
    Author
  • Busson, RogerKUL
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  • Vanderhaeghe, HJ.
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  • Claes, PJ.
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  • Mingeot-Leclercq, Marie-PauleUCLouvain
    Author
  • Tulkens, Paul M.UCLouvain
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Abstract
Substitution of the C-1 atom in the 2-deoxystreptamine moiety of gentamicin C2, a broad-spectrum aminoglycoside antibiotic, by an axial hydroxymethyl group has been reported to confer protection against most clinically important bacterial enzymes inactivating aminoglycosides, while simultaneously reducing the nephrotoxic potential of this drug. We report here on a similar modification of kanamycin B. Microbiological evaluation, however, revealed no useful protection, as established by the almost complete lack of activity of 1-C-(hydroxymethyl)kanamycin B against an array of organisms producing defined types of aminoglycoside-inactivating enzymes and against which 1-C-(hydroxymethyl)gentamicin C2 and amikacin (1-N-[(S)-2-hydroxy-4-aminobutyryl]kanamycin A) are active. Moreover, toxicological evaluation, based on the in vitro measurement of the drug inhibitory potential toward lysosomal phospholipases, a predictive test of the intrinsic nephrotoxic potential of aminoglycosides, showed not decreased but rather increased toxicity. Comparative conformational analysis of the interactions of the drug with a phosphatidylinositol monolayer explained the lack of protective effect, since no significant change of the mode of insertion of the derivative in this monolayer was detected compared to that of kanamycin B. Combination of a 1-C-(hydroxymethyl) substituent with a 6"-chloro, 6"-azido, or 6"-acetamido substituent resulted in a partial improvement of the toxicological behavior with no loss of activity for the 6"-chloro and the 6"-azido derivatives, but not to the extent of obtaining better derivatives than kanamycin B itself. We, therefore, suggest that the advantages of an axial hydroxymethyl substituent at C-1 are probably restricted to the gentamicin family and do not extend to kanamycins. It might be concluded that the structural differences between gentamicins and kanamycins play an important, still undescribed role both in their effective recognition by aminoglycoside-inactivating enzymes, which are responsible for most of the clinically important cases of resistance to aminoglycosides, and also in the interactions with phospholipids, which in turn cause nephrotoxicity.
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Vanschepdael, A., Busson, R., Vanderhaeghe, HJ., Claes, PJ., Verbist, L., Mingeot-Leclercq, M.-P., Brasseur, R., & Tulkens, P. M. (1991). New derivatives of kanamycin B obtained by combined modifications in positions 1 and 6″. Synthesis, microbiological properties, and in vitro and computer-aided toxicological evaluation. Journal of Medicinal Chemistry, 34(4), 1483-1492. https://doi.org/10.1021/jm00108a037 (Original work published 1991)