Rebeccamycin analogues bearing amine substituents or other groups on the sugar moiety.
In the course of structure-activity relationship studies on rebeccamycin analogues, a series of compounds bearing an amino function on the sugar moiety were synthesized with the aim of improving the solubility and interaction with the macromolecular target(s). The syntheses of amino derivatives and the corresponding chloro, iodo and azido intermediates are described. Their interaction with DNA and effects on human DNA topoisomerases I and II were investigated. Their antimicrobial activities against two Gram-positive bacteria, Bacillus cereus and Streptomyces chartreusis, a Gram-negative bacterium Escherichia coli and a yeast Candida albicans were also determined. 6'-Amino compound 7 and 6'-N-methylamino 14 very efficiently inhibit the growth of E. coli. The introduction of an amino group at the 6'-position strongly enhances the capacity of the drugs to interact with DNA but almost abolishes their poisoning effect on topoisomerase I. Unlike the vast majority of rebeccamycin analogues previously studied, the newly designed compounds do not stimulate DNA cleavage by topoisomerase I. The enhanced capacity of the 6'-amino glycosyl rebeccamycin derivatives to bind to DNA likely account for the improved biological profiles. DNA and topoisomerase I represent two independent targets which can both be used for the development of antitumor rebeccamycin derivatives.
Anizon
Fabrice
F
Université Blaise Pascal, Synthèse et Etude de Systèmes à Intérêt Biologique, UMR 6504 du CNRS, 63177, Aubière, France.
Moreau
Pascale
P
Sancelme
Martine
M
Laine
William
W
Bailly
Christian
C
Prudhomme
Michelle
M
D000588:Amines / Q000138:chemical synthesis; D000617:Aminoglycosides / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003851:Deoxyribonucleases / Q000378:metabolism; D005947:Glucose / Q000138:chemical synthesis / Q000737:chemistry; D005960:Glucosides; D006031:Glycosylation; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000588:Amines; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D002227:Carbazoles; D005960:Glucosides; D007211:Indoles; D059005:Topoisomerase II Inhibitors; C053339:rebeccamycin; C093269:becatecarin; D003851:Deoxyribonucleases; D005947:Glucose