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Issue 22, 2008
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Effects of C-17 heterocyclic substituents on the anticancer activity of 2-ethylestra-1,3,5(10)-triene-3-O-sulfamates: synthesis, in vitro evaluation and computational modelling

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Abstract

The potent activity of 2-substituted estra-1,3,5(10)-triene-3-O-sulfamates against the proliferation of cancer cellsin vitro and tumours in vivo highlights the therapeutic potential of such compounds. Optimal activity is derived from a combination of a 2-XMe group (where X = CH2, O or S), a 3-O-sulfamate group in the steroidal A-ring and a H-bond acceptor around C-17 of the D-ring. Herein, we describe the synthesis and anti-proliferative activities of a series of novel 2-substituted estra-1,3,5(10)-triene-3-O-sulfamates bearing heterocyclic substituents (oxazole, tetrazole, triazole) tethered to C-17. In vitro evaluation of these molecules revealed that high anti-proliferative activity in breast and prostate cancer cells lines (GI50 of 340–850 nM) could be retained when the heterocyclic substituent possesses H-bond acceptor properties. A good correlation between the calculated electron density of the heterocyclic ring and anti-proliferative activity was observed. Docking of the most active compounds into their putative site of action, the colchicine binding site of tubulin, suggests that they bind through a different mode to the previously described bis-sulfamate derivatives 1 and 2, which possess similar in vitro activity.

Graphical abstract: Effects of C-17 heterocyclic substituents on the anticancer activity of 2-ethylestra-1,3,5(10)-triene-3-O-sulfamates: synthesis, in vitro evaluation and computational modelling

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Publication details

The article was received on 17 Jun 2008, accepted on 22 Aug 2008 and first published on 22 Sep 2008


Article type: Paper
DOI: 10.1039/B810300C
Citation: Org. Biomol. Chem., 2008,6, 4108-4119
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    Effects of C-17 heterocyclic substituents on the anticancer activity of 2-ethylestra-1,3,5(10)-triene-3-O-sulfamates: synthesis, in vitro evaluation and computational modelling

    F. Jourdan, C. Bubert, M. P. Leese, A. Smith, E. Ferrandis, S. Regis-Lydi, S. P. Newman, A. Purohit, M. J. Reed and B. V. L. Potter, Org. Biomol. Chem., 2008, 6, 4108
    DOI: 10.1039/B810300C

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