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

Mathew P Leese, Fabrice L Jourdan, Keira Gaukroger, Mary F Mahon, Simon P Newman, Paul A Foster, Chloe Stengel, Sandra Regis-Lydi, Eric Ferrandis, Anna Di Fiore, Giuseppina De Simone, Claudiu T Supuran, Atul Purohit, Michael J Reed, Barry V L Potter

    Research output: Contribution to journalArticlepeer-review

    49 Citations (Scopus)


    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 languageEnglish
    Pages (from-to)1295-308
    Number of pages14
    JournalJournal of Medicinal Chemistry
    Issue number5
    Publication statusPublished - 2008


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