Abstract
The jadomycins are a unique family of angucycline-derived antibiotics with interesting cytotoxic activities. In this work, six new jadomycin derivatives were produced in vivo by providing non-natural amino acids in fermentation media. They were further purified and identified by MS and NMR analyses. The cytotoxicities of these derivatives were evaluated against tumor cell lines MCF-7 and HCT116, as well as the normal human microvascular epithelial cells. The derivatives with alkyl side chains showed similar levels of cytotoxicity as jadomycin B and other known derivatives with nonpolar side chains, with IC50 ranging from 1.3 to 10 μM; but the activities are not selective as these compounds also showed similar levels of cytotoxicity toward the normal human microvascular epithelial cells in the same concentration range. For the first time, derivatives with amino side chains (jadomycin Orn and K) were prepared and evaluated. Significantly, jadomycin Orn showed differential activity against normal and tumor cell lines. This result points to a new direction to modify jadomycin structure. The insights on the structure–activity relationship of jadomycins will guide further efforts to generate new and improved jadomycin derivatives against tumor cells.
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Acknowledgements
We thank Professor Keith F Chater (John Innes Centre, Norwich, United Kindom) and Dr Mikko Metsä-Ketelä (Department of Biochemistry and Food Chemistry, University of Turku, Turku, Finland) for critical reading in preparation of this manuscript. This work was supported by grants from the National Natural Science Foundation of China (grant no. 31130001 and 30670017) and the National Natural Science Foundation of China for Distinguished Young Scholars (grant no. 30725046).
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Fan, K., Zhang, X., Liu, H. et al. Evaluation of the cytotoxic activity of new jadomycin derivatives reveals the potential to improve its selectivity against tumor cells. J Antibiot 65, 449–452 (2012). https://doi.org/10.1038/ja.2012.48
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DOI: https://doi.org/10.1038/ja.2012.48
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