Synthesis and antimicrobial and toxicological studies of amino acid and peptide derivatives of kanamycin A and netilmicin

dc.contributor.author	Kotretsou, S	en
dc.contributor.author	Mingeot-Leclercq, MP	en
dc.contributor.author	Constantinou-Kokotou, V	en
dc.contributor.author	Brasseur, R	en
dc.contributor.author	Georgiadis, MP	en
dc.contributor.author	Tulkens, PM	en
dc.date.accessioned	2014-06-06T06:42:59Z
dc.date.available	2014-06-06T06:42:59Z
dc.date.issued	1995	en
dc.identifier.issn	00222623	en
dc.identifier.uri	http://62.217.125.90/xmlui/handle/123456789/928
dc.relation.uri	http://www.scopus.com/inward/record.url?eid=2-s2.0-0028842520&partnerID=40&md5=c1c842d4315e3180a35334ec3c1868bc	en
dc.subject.other	amino acid derivative	en
dc.subject.other	kanamycin a	en
dc.subject.other	kanamycin derivative	en
dc.subject.other	netilmicin	en
dc.subject.other	peptide derivative	en
dc.subject.other	amino acid substitution	en
dc.subject.other	antibiotic resistance	en
dc.subject.other	antimicrobial activity	en
dc.subject.other	article	en
dc.subject.other	conformational transition	en
dc.subject.other	drug synthesis	en
dc.subject.other	enzyme inactivation	en
dc.subject.other	enzyme inhibition	en
dc.subject.other	enzyme modification	en
dc.subject.other	infection	en
dc.subject.other	nephrotoxicity	en
dc.subject.other	nonhuman	en
dc.subject.other	ototoxicity	en
dc.subject.other	Amino Acids	en
dc.subject.other	Animal	en
dc.subject.other	Antibiotics, Aminoglycoside	en
dc.subject.other	Bacteria	en
dc.subject.other	Chemistry, Physical	en
dc.subject.other	Enzyme Inhibitors	en
dc.subject.other	Gentamicins	en
dc.subject.other	Kanamycin	en
dc.subject.other	Lysosomes	en
dc.subject.other	Molecular Conformation	en
dc.subject.other	Netilmicin	en
dc.subject.other	Peptides	en
dc.subject.other	Phosphatidylcholines	en
dc.subject.other	Phospholipases A	en
dc.subject.other	Rats	en
dc.subject.other	Support, Non-U.S. Gov't	en
dc.subject.other	Thermodynamics	en
dc.title	Synthesis and antimicrobial and toxicological studies of amino acid and peptide derivatives of kanamycin A and netilmicin	en
heal.type	journalArticle	en
heal.publicationDate	1995	en
heal.abstract	Amino 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. © 1995 American Chemical Society.	en
heal.journalName	Journal of Medicinal Chemistry	en
dc.identifier.issue	23	en
dc.identifier.volume	38	en
dc.identifier.spage	4710	en
dc.identifier.epage	4719	en