[en] Amino acid and peptide derivatives of aminoglycosides have been obtained by
substitution of the 1-N or 6'-N amino functions of kanamycin A and netilmicin via
the temporary complexation of vicinal and nonvicinal amino and hydroxy functions
by copper ion [1-N kanamycin A derivatives: L-Ala (6a), D-Ala (6b), Gly (6c),
L-Asp (6d), L-Ala-L-Ala (6e). 6'-N kanamycin A derivatives: L-Ala (3a), D-Ala
(3b), Gly (3c), L-Ala-L-Ala (3e), L-Leu (3f). 6'-N netilmicin derivatives: L-Ala
(9a), D-Ala (9b), Gly (9c), L-Asp (9d), L-Ala-L-Ala (9e)]. Characterization was
made by FAB-MS, IR, 1H-NMR, and 13C-NMR. All derivatives were essentially
inactive. The nephrotoxic potential of the derivatives obtained in sufficient
quantities (3b,e and 9a-e) was assessed by measuring their inhibitory potential
toward the activity of lysosomal phospholipase A1 acting on phosphatidylcholine
embedded in negatively-charged membranes. One compound, 6'-N-L-Ala-netilmicin
(9a), showed a 2-fold decrease of inhibitory potency compared to its parent drug.
A conformational analysis revealed that it adopts two equally probable
conformations and orientations when interacting with phosphatidylinositol. The
first in which the drug lies parallel to the hydrophobic-hydrophilic interface,
is similar to that of netilmicin. The second, in which the drug inserts itself in
the bilayer across the hydrophilic/hydrophobic interface, is similar to that
described for streptomycin, an almost non-nephrotoxic aminoglycoside.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Kotretsou, S.
Mingeot-Leclercq, Marie-Paule
Constantinoukokotou, V.
Brasseur, Robert ; Université de Liège - ULiège > Gembloux Agro-Bio Tech
Georgiadis, Mp.
Tulkens, Pm.
Language :
English
Title :
Synthesis And Antimicrobial And Toxicological Studies Of Amino-Acid And Peptide Derivatives Of Kanamycin-A And Netilmicin
Publication date :
1995
Journal title :
Journal of Medicinal Chemistry
ISSN :
0022-2623
eISSN :
1520-4804
Publisher :
American Chemical Society, Washington, United States - District of Columbia
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