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.
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Acknowledgements
This study was supported by the Russian Fond of Fundamental Research (Grant no. 06-04-08127 for 2006-2007), a grant of the President of Russian Federation for the support of young Russian scientists (AN Tevyashova, MK-5422.2007.4) and the Geconcerteerde Onderzoeksacties (GOA) of the KU Leuven. We thank Mrs Lizette van Berckelaer (Rega Institute, Leuven) for excellent technical assistance, and Dr Marina I Reznikova and Nataly M Malutina (Gause Institute, Moscow) for HPLC analysis.
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Tevyashova, A., Zbarsky, E., Balzarini, J. et al. Modification of the antibiotic olivomycin I at the 2′-keto group of the side chain. Novel derivatives, antitumor and topoisomerase I-poisoning activity. J Antibiot 62, 37–41 (2009). https://doi.org/10.1038/ja.2008.7
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DOI: https://doi.org/10.1038/ja.2008.7
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