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

doi:10.1021/jm701319c

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 journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	1295-1308
Journal	Journal of Medicinal Chemistry
Volume	51
Issue number	5
DOIs	https://doi.org/10.1021/jm701319c
Publication status	Published - 2008

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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., & Potter, B. V. L. (2008). Structure-activity relationships of C-17 cyano-substituted estratrienes as anticancer agents. Journal of Medicinal Chemistry, 51(5), 1295-1308. https://doi.org/10.1021/jm701319c

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, BVL 2008, 'Structure-activity relationships of C-17 cyano-substituted estratrienes as anticancer agents', Journal of Medicinal Chemistry, vol. 51, no. 5, pp. 1295-1308. https://doi.org/10.1021/jm701319c

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title = "Structure-activity relationships of C-17 cyano-substituted estratrienes as anticancer agents",

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.",

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

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doi = "10.1021/jm701319c",

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T1 - Structure-activity relationships of C-17 cyano-substituted estratrienes as anticancer agents

AU - Leese, Mathew P.

AU - Jourdan, Fabrice L.

AU - Gaukroger, Keira

AU - Mahon, Mary F.

AU - Newman, Simon P.

AU - Foster, Paul A.

AU - Stengel, Chloe

AU - Regis-Lydi, Sandra

AU - Ferrandis, Eric

AU - Di Fiore, Anna

AU - De Simone, Giuseppina

AU - Supuran, Claudiu T.

AU - Purohit, Atul

AU - Reed, Michael J.

AU - Potter, Barry V. L.

PY - 2008

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N2 - 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.

AB - 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.

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

Abstract

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