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: Anna N Tevyashova, Eugenia N Olsufyeva, Eugenia N Zbarsky, Jan Balzarini, Alexander A Shtil, Lyubov G Dezhenkova, Vladimir M Bukhman, Victor B Zbarsky, Maria N Preobrazhenskaya
• Journal: The Journal of antibiotics (J Antibiot (Tokyo)) Vol. 62 Issue 1 Pg. 37-41 (Jan 2009) ISSN: 1881-1469 [Electronic] England
• PMID: 19132061 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Enzyme Inhibitors
• Ketones
• Topoisomerase I Inhibitors
• Olivomycins

Topics

• Animals
• Antibiotics, Antineoplastic (chemical synthesis, chemistry, pharmacology)
• Carbohydrate Sequence
• Cell Line, Tumor
• Chromatography, High Pressure Liquid
• Chromatography, Thin Layer
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Ketones (chemistry)
• Leukemia P388
• Male
• Mass Spectrometry
• Mice
• Molecular Sequence Data
• Olivomycins (chemical synthesis, chemistry, pharmacology)
• Topoisomerase I Inhibitors