Synthesis and antimicrobial and toxicological studies of amino acid and peptide derivatives of kanamycin A and netilmicin.
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.
D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001419:Bacteria / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005839:Gentamicins / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D007612:Kanamycin / Q000031:analogs & derivatives*; D008247:Lysosomes / Q000201:enzymology; D008968:Molecular Conformation; D009428:Netilmicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D010455:Peptides / Q000737:chemistry*; D010713:Phosphatidylcholines / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism; D054466:Phospholipases A1; D051381:Rats; D013816:Thermodynamics
C096779:6'-N-alanylnetilmicin; D000596:Amino Acids; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D005839:Gentamicins; D010455:Peptides; D010713:Phosphatidylcholines; D009428:Netilmicin; D007612:Kanamycin; D010741:Phospholipases A; D054466:Phospholipases A1