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Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template


Reference:

Woo, L. .W. L., Jackson, T., Putey, A., Cozier, G., Leonard, P., Acharya, K. R., Chander, S. K., Purohit, A., Reed, M. J. and Potter, B. V. L., 2010. Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template. Journal of Medicinal Chemistry, 53 (5), pp. 2155-2170.

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Official URL:

http://dx.doi.org/10.1021/jm901705h

Abstract

Single agents against multiple drug targets are of increasing interest. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS). The aromatase inhibitory pharmacophore was thus introduced into a known biphenyl STS inhibitor to give a series of novel dual aromatase-sulfatase inhibitors (DASIs). Several compounds are good aromatase or STS inhibitors and DASI 20 (IC50: aromatase, 2.0 nM; STS, 35 nM) and its chlorinated congener 23 (IC50: aromatase, 0.5 nM; STS, 5.5 nM)are examples that show exceptional dual potency in JEG-3 cells. Both biphenyls share a para-sulfamate-containing ring B and a ring A, which contains a triazol-1-ylmethyl meta to the biphenyl bridge and para to a nitrile. At 1 mg/kg po, 20 and 23 reduced plasma estradiol levels strongly and inhibited liver STS activity potently in vivo. 23 is nonestrogenic and potently inhibits carbonic anhydrase II (IC50 86 nM). A complex was crystallized and its Structure Was solved by X-ray crystallography. This class of DASI should encourage further development toward multitargeted therapeutic intervention in HDBC.

Details

Item Type Articles
CreatorsWoo, L. .W. L., Jackson, T., Putey, A., Cozier, G., Leonard, P., Acharya, K. R., Chander, S. K., Purohit, A., Reed, M. J. and Potter, B. V. L.
DOI10.1021/jm901705h
DepartmentsFaculty of Science > Pharmacy & Pharmacology
Faculty of Science > Biology & Biochemistry
RefereedYes
StatusPublished
ID Code18330

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