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

L .W. Lawrence Woo, Tobey Jackson, Aurelien Putey, Gyles Cozier, Philip Leonard, K. Ravi Acharya, Surinder K. Chander, Atul Purohit, Michael J. Reed, Barry V. L. Potter

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81 Citations (SciVal)


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.
Original languageEnglish
Pages (from-to)2155-2170
JournalJournal of Medicinal Chemistry
Issue number5
Early online date11 Feb 2010
Publication statusPublished - 11 Mar 2010


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