Modification of the antibiotic olivomycin I at the 2'-keto group of the side chain. Novel derivatives, antitumor and topoisomerase I-poisoning activity.
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.
Tevyashova
Anna N
AN
Laboratory of Chemical Transformation of Antibiotics, Gause Institute of New Antibiotics Russian Academy of Medical Sciences, Moscow, Russia.
Olsufyeva
Eugenia N
EN
Zbarsky
Eugenia N
EN
Balzarini
Jan
J
Shtil
Alexander A
AA
Dezhenkova
Lyubov G
LG
Bukhman
Vladimir M
VM
Zbarsky
Victor B
VB
Preobrazhenskaya
Maria N
MN
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
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D007659:Ketones; D059004:Topoisomerase I Inhibitors; D009848:Olivomycins