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

Article Details


Leese MP, Jourdan FL, Gaukroger K, Mahon MF, Newman SP, Foster PA, Stengel C, Regis-Lydi S, Ferrandis E, Di Fiore A, De Simone G, Supuran CT, Purohit A, Reed MJ, Potter BV

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

J Med Chem. 2008 Mar 13;51(5):1295-308. doi: 10.1021/jm701319c. Epub 2008 Feb 9.

PubMed ID
18260615 [ View in PubMed

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.

DrugBank Data that Cites this Article

NameUniProt ID
Carbonic anhydrase 2P00918Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
(17beta)-17-(cyanomethyl)-2-methoxyestra-1(10),2,4-trien-3-yl sulfamateCarbonic anhydrase 2IC 50 (nM)1500N/AN/ADetails
(9BETA,13ALPHA,14BETA,17ALPHA)-2-METHOXYESTRA-1,3,5(10)-TRIENE-3,17-DIYL DISULFAMATECarbonic anhydrase 2IC 50 (nM)379N/AN/ADetails