Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

The design and synthesis of a series of bicyclic ring containing dual aromatase-sulfatase inhibitors (DASIs) based on the aromatase inhibitor (AI) 4-[(4-bromobenzyl)(4H-1,2,4-triazol-4-yl)amino]benzonitrile are reported. Biological evaluation with JEG-3 cells revealed structure-activity relationships. The X-ray crystal structure of sulfamate 23 was determined, and selected compounds were docked into the aromatase and steroid sulfatase (STS) crystal structures. In the sulfamate-containing series, compounds containing a naphthalene ring are both the most potent AI (39, IC(50 AROM)=0.25 nM) and the best STS inhibitor (31, IC(50 STS)=26 nM). The most promising DASI is 39 (IC(50 AROM)=0.25 nM, IC(50 STS)=205 nM), and this was evaluated orally in vivo at 10 mg kg(-1), showing potent inhibition of aromatase (93 %) and STS (93 %) after 3 h. Potent aromatase and STS inhibition can thus be achieved with a DASI containing a bicyclic ring system; development of such a DASI could provide an attractive new option for the treatment of hormone-dependent breast cancer.

Original publication

DOI

10.1002/cmdc.201000203

Type

Journal article

Journal

ChemMedChem

Publication Date

03/09/2010

Volume

5

Pages

1577 - 1593

Keywords

Antineoplastic Agents, Aromatase, Aromatase Inhibitors, Binding Sites, Cell Line, Tumor, Computer Simulation, Crystallography, X-Ray, Humans, Molecular Conformation, Steryl-Sulfatase, Structure-Activity Relationship, Sulfonic Acids, Triazoles