title: Modification of the antibiotic olivomycin I at the 2'-keto group of the side chain. Novel derivatives, antitumor and topoisomerase I-poisoning activity.
abstract: A novel way of chemical modification of the antibiotic olivomycin I at the 2'-keto group of the side chain of the aglycone moiety was developed. Reaction of olivomycin I with the carboxymethoxylamine hemihydrochloride gave the key intermediate, 2'-carboxymethoxime-olivomycin I, which was further reacted with different amines in the presence of benzotriazol-1-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate to give the corresponding amides. The antiproliferative and topoisomerase I (Topo-I)-poisoning activities of the novel derivatives were examined. One of the novel derivatives showed a marked inhibitory activity against Topo-I, a pronounced antitumor activity in in vivo experiments on mice bearing leukemia P-388 and lower toxic side effects compared with the parent olivomycin I.
authors.affiliation: Laboratory of Chemical Transformation of Antibiotics, Gause Institute of New Antibiotics Russian Academy of Medical Sciences, Moscow, Russia.
authors.forename: Anna N
authors.initials: AN
authors.lastname: Tevyashova
authors.forename: Eugenia N
authors.initials: EN
authors.lastname: Olsufyeva
authors.forename: Eugenia N
authors.initials: EN
authors.lastname: Zbarsky
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Shtil
authors.forename: Lyubov G
authors.initials: LG
authors.lastname: Dezhenkova
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Bukhman
authors.forename: Victor B
authors.initials: VB
authors.lastname: Zbarsky
authors.forename: Maria N
authors.initials: MN
authors.lastname: Preobrazhenskaya
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002240:Carbohydrate Sequence; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007659:Ketones / Q000737:chemistry; D007941:Leukemia P388; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008969:Molecular Sequence Data; D009848:Olivomycins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors
chemical_list: D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D007659:Ketones; D059004:Topoisomerase I Inhibitors; D009848:Olivomycins