Synthesis, antitubulin, and antiproliferative SAR of analogues of 2-Methoxyestradiol-3,17-O,O-bis-sulfamate

Fabrice Jourdan, Mathew P. Leese, Wolfgang Dohle, Ernest Hamel, Eric Ferrandis, Simon P. Newman, Atul Purohit, M. J. Reed, Barry V. L. Potter

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

The synthesis and antiproliferative activity of analogues of estradiol 3,17-O,O-bis-sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent reveal that an H-bond acceptor is essential for high antiproliferative activity. The local environment in which this H-bond acceptor lies can be varied to an extent. The C-17-oxygen linker can be deleted or substituted with an electronically neutral methylene group, and replacement of the terminal NH2 with a methyl group is also acceptable. Mesylates 10 and 14 prove equipotent to the E2bisMATEs 2 and 3, while sulfones 20 and 35 display enhanced in vitro antiproliferative activity. In addition, the SAR of 2-substituted estradiol-3-O-sulfamate derivatives as inhibitors of tubulin polymerization has been established for the first time. These agents inhibit the binding of radiolabeled colchicine to tubulin.
Original languageEnglish
Pages (from-to)2942-2951
JournalJournal of Medicinal Chemistry
Volume53
Issue number7
DOIs
Publication statusPublished - 8 Apr 2010

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Tubulin Modulators
Sulfones
Mesylates
Colchicine
Tubulin
Estradiol
Oxygen
estradiol-3-O-sulfamate
In Vitro Techniques
sulfamic acid
2-methoxyestradiol-3,17-O,O-bis(sulfamate)

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Synthesis, antitubulin, and antiproliferative SAR of analogues of 2-Methoxyestradiol-3,17-O,O-bis-sulfamate. / Jourdan, Fabrice; Leese, Mathew P.; Dohle, Wolfgang; Hamel, Ernest; Ferrandis, Eric; Newman, Simon P.; Purohit, Atul; Reed, M. J.; Potter, Barry V. L.

In: Journal of Medicinal Chemistry, Vol. 53, No. 7, 08.04.2010, p. 2942-2951.

Research output: Contribution to journalArticle

Jourdan, F, Leese, MP, Dohle, W, Hamel, E, Ferrandis, E, Newman, SP, Purohit, A, Reed, MJ & Potter, BVL 2010, 'Synthesis, antitubulin, and antiproliferative SAR of analogues of 2-Methoxyestradiol-3,17-O,O-bis-sulfamate', Journal of Medicinal Chemistry, vol. 53, no. 7, pp. 2942-2951. https://doi.org/10.1021/jm9018806
Jourdan, Fabrice ; Leese, Mathew P. ; Dohle, Wolfgang ; Hamel, Ernest ; Ferrandis, Eric ; Newman, Simon P. ; Purohit, Atul ; Reed, M. J. ; Potter, Barry V. L. / Synthesis, antitubulin, and antiproliferative SAR of analogues of 2-Methoxyestradiol-3,17-O,O-bis-sulfamate. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 7. pp. 2942-2951.
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abstract = "The synthesis and antiproliferative activity of analogues of estradiol 3,17-O,O-bis-sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent reveal that an H-bond acceptor is essential for high antiproliferative activity. The local environment in which this H-bond acceptor lies can be varied to an extent. The C-17-oxygen linker can be deleted or substituted with an electronically neutral methylene group, and replacement of the terminal NH2 with a methyl group is also acceptable. Mesylates 10 and 14 prove equipotent to the E2bisMATEs 2 and 3, while sulfones 20 and 35 display enhanced in vitro antiproliferative activity. In addition, the SAR of 2-substituted estradiol-3-O-sulfamate derivatives as inhibitors of tubulin polymerization has been established for the first time. These agents inhibit the binding of radiolabeled colchicine to tubulin.",
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AU - Hamel, Ernest

AU - Ferrandis, Eric

AU - Newman, Simon P.

AU - Purohit, Atul

AU - Reed, M. J.

AU - Potter, Barry V. L.

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AB - The synthesis and antiproliferative activity of analogues of estradiol 3,17-O,O-bis-sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent reveal that an H-bond acceptor is essential for high antiproliferative activity. The local environment in which this H-bond acceptor lies can be varied to an extent. The C-17-oxygen linker can be deleted or substituted with an electronically neutral methylene group, and replacement of the terminal NH2 with a methyl group is also acceptable. Mesylates 10 and 14 prove equipotent to the E2bisMATEs 2 and 3, while sulfones 20 and 35 display enhanced in vitro antiproliferative activity. In addition, the SAR of 2-substituted estradiol-3-O-sulfamate derivatives as inhibitors of tubulin polymerization has been established for the first time. These agents inhibit the binding of radiolabeled colchicine to tubulin.

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