3,17-disubstituted 2-alkylestra-1,3,5(10)-trien-3-ol derivatives : synthesis, in vitro and in vivo anticancer activity

Reference:

Bubert, C., Leese, M. P., Mahon, M. F., Ferrandis, E., Regis-Lydi, S., Kasprzyk, P. G., Newman, S. P., Ho, Y. T., Purohit, A., Reed, M. J. and Potter, B. V. L., 2007. 3,17-disubstituted 2-alkylestra-1,3,5(10)-trien-3-ol derivatives : synthesis, in vitro and in vivo anticancer activity. Journal of Medicinal Chemistry, 50 (18), pp. 4431-4443.

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Official URL:

http://dx.doi.org/10.1021/jm070405v

Abstract

Estradiol-3,17-O,O-bis-sulfamates inhibit steroid sulfatase (STS), carbonic anhydrase (CA), and, when substituted at C-2, cancer cell proliferation and angiogenesis. C-2 Substitution and 17-sulfamate replacement of the estradiol-3,17-O,O-bis-sulfamates were explored with efficient and practical syntheses developed. Evaluation against human cancer cell lines revealed the 2-methyl derivative 27 (DU145 GI(50) = 0.38,mu M) as the most active novel bis-sulfamate, while 2-ethyl-17-carbamate derivative 52 (GI(50) = 0.22 mu M) proved most active of its series (cf. 2-ethylestradiol-3,17-O,O-bis-sulfamate 4 GI(50) = 0.21 mu M). Larger C-2 substituents were deleterious to activity. 2-Methoxy-17-carbamate 50 was studied by X-ray crystallography and was surprisingly 13-fold weaker as an STS inhibitor compared to parent bis-sulfamate 3. The potential of 4 as an orally dosed anti-tumor agent is confirmed using breast and prostate cancer xenografts. In the MDA-MB-231 model, dramatic reduction in tumor growth or regression was observed, with effects sustained after cessation of treatment. 3-O-Sulfamoylated 2-alkylestradiol-17-O-carbamates and sulfamates have considerable potential as anticancer agents.

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