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Structure-activity relationships of C-17 cyano-substituted estratrienes as anticancer agents


Reference:

Leese, M. P., Jourdan, F. L., Gaukroger, K., Mahon, M. F., Newman, S. P., Foster, P. A., Stengel, C., Regis-Lydi, S., Ferrandis, E., Di Fiore, A., De Simone, G., Supuran, C. T., Purohit, A., Reed, M. J. and Potter, B. V. L., 2008. Structure-activity relationships of C-17 cyano-substituted estratrienes as anticancer agents. Journal of Medicinal Chemistry, 51 (5), pp. 1295-1308.

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Official URL:

http://dx.doi.org/10.1021/jm701319c

Abstract

The synthesis, SAR, and preclinical evaluation of 17-cyanated 2-substituted estra-1,3,5(10)-trienes as anticancer agents are discussed. 2-Methoxy-17 beta-cyanomethylestra-1,3,5(10)-trien-3-ol (14), but not the related 2-ethyl derivative 7, and the related 3-O-sulfamates 8 and 15 display potent antiproliferative effects (MCF-7 GI(50) 300, 60 and 70 nM, respectively) against human cancer cells in vitro. Investigation of the SAR reveals that a sterically unhindered hydrogen bond acceptor attached to C-17 is most likely key to the enhanced activity. Compound 8 displayed significant in vitro antiangiogenic activity, and its ability to act as a microtubule disruptor was confirmed. Inhibitory activity of the sulfamate derivatives against steroid sulfatase and carbonic anhydrase II (hCAII) was also observed, and the interaction between 15 and hCAII was investigated by protein crystallography. The potential of these multimechanism anticancer agents was confirmed in vivo, with promising activity observed for both 14 and 15 in an athymic nude mouse MDAMB-231 human breast cancer xenograft model.

Details

Item Type Articles
CreatorsLeese, M. P., Jourdan, F. L., Gaukroger, K., Mahon, M. F., Newman, S. P., Foster, P. A., Stengel, C., Regis-Lydi, S., Ferrandis, E., Di Fiore, A., De Simone, G., Supuran, C. T., Purohit, A., Reed, M. J. and Potter, B. V. L.
DOI10.1021/jm701319c
DepartmentsFaculty of Science > Pharmacy & Pharmacology
Faculty of Science > Chemistry
RefereedYes
StatusPublished
ID Code4485

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