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The synthesis, SAR, and preclinical evaluation of 17-cyanated 2-substituted estra-1,3,5(10)-trienes as anticancer agents are discussed. 2-Methoxy-17beta-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 MDA-MB-231 human breast cancer xenograft model.

Original publication

DOI

10.1021/jm701319c

Type

Journal article

Journal

J Med Chem

Publication Date

13/03/2008

Volume

51

Pages

1295 - 1308

Keywords

Angiogenesis Inhibitors, Animals, Antineoplastic Agents, Carbonic Anhydrase II, Carbonic Anhydrase Inhibitors, Cell Line, Tumor, Crystallography, X-Ray, Drug Screening Assays, Antitumor, Estradiol, Estrenes, Female, Humans, Mice, Mice, Nude, Models, Molecular, Molecular Conformation, Neoplasm Transplantation, Nitriles, Stereoisomerism, Steryl-Sulfatase, Structure-Activity Relationship, Transplantation, Heterologous, Tubulin Modulators