New derivatives of kanamycin B obtained by modifications and substitutions in position 6''. 2. In vitro and computer-aided toxicological evaluation with respect to interactions with phosphatidylinositol

Mingeot-Leclercq, Marie-Paule;Van Schepdael, Ann;Brasseur, Robert;Busson, Roger;Tulkens, Paul M.;et.al.
(1991) Journal of Medicinal Chemistry — Vol. 34, n° 4, p. 1476-1482 (1991)

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  • Mingeot-Leclercq, Marie-PauleUCLouvain
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  • Van Schepdael, AnnUCLouvain
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  • Brasseur, Robert
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  • Busson, RogerKUL
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  • Claes, PaulUCLouvain
    Author
  • Tulkens, Paul M.UCLouvain
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Abstract
In a companion paper (previous paper in this issue), we report on the synthesis and microbiological evaluation of new derivatives of the aminoglycoside antibiotic kanamycin B carrying substitutions in 6" (halogeno, or amino, amido, thioalkyl, and alkoxy groups, each series with increasingly bulkier chains). These modifications were intended to potentially modulate the interactions of kanamycin B with phospholipids since these are related to inhibition of lysosomal phospholipase activities and lysosomal phospholipidosis, an early and predictive index of the nephrotoxic potential of aminoglycosides. The new derivatives were therefore examined for inhibitory potency in vitro toward lysosomal phospholipase A1 acting on phosphatidylcholine included in negatively charged liposomes. No simple correlation was observed between the nature or the size of the 6''-substituent and the inhibitory potencies of the corresponding derivatives, although certain groups (diethylamino, isopropylthio) caused a significant increase in inhibitory potency, whereas an N-acetyl-N-methylamino substituent had the opposite effect. 6''-Deoxy-6''-chlorokanamycin B, however, was the only derivative showing both a decrease (albeit limited) of inhibitory potency toward phospholipase A1 associated with the maintenance of a satisfactory microbiological activity (actually equal or slightly better than that of kanamycin B). Computer-aided conformational analysis showed that this chloro substituent did not allow the molecule to insert itself very differently compared to kanamycin B or 6''-deoxykanamycin B in a monolayer of phosphatidylinositol, all three drugs adopting an orientation largely parallel to the hydrophobic-hydrophilic interface and being largely "embedded" in the bilayer at that level. In contrast, the N-acetyl-N-methylamino and isopropylthio substituents caused the corresponding derivatives to adopt an orientation largely perpendicular to the interface, because of the attraction of this substituent, and therefore of the 3''-amino sugar moiety of kanamycin B into the hydrophobic domain of the monolayer, whereas the opposite part of the drug (2',6'-diamino sugar) protruded into the aqueous phase. No simple correlation, however, could be drawn between these changes of conformation and the relative inhibitory potencies of the derivatives.
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Mingeot-Leclercq, M.-P., Van Schepdael, A., Brasseur, R., Busson, R., Vanderhaeghe, H. J., Claes, P., & Tulkens, P. M. (1991). New derivatives of kanamycin B obtained by modifications and substitutions in position 6″. 2. In vitro and computer-aided toxicological evaluation with respect to interactions with phosphatidylinositol. Journal of Medicinal Chemistry, 34(4), 1476-1482. https://doi.org/10.1021/jm00108a036 (Original work published 1991)