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Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template. 2010

L W Lawrence Woo, and Toby Jackson, and Aurélien Putey, and Gyles Cozier, and Philip Leonard, and K Ravi Acharya, and Surinder K Chander, and Atul Purohit, and Michael J Reed, and Barry V L Potter
Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd, University of Bath, Claverton Down, Bath BA2 7AY, UK.

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 (IC(50): aromatase, 2.0 nM; STS, 35 nM) and its chlorinated congener 23 (IC(50): 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 (IC(50) 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.

UI MeSH Term Description Entries
D009682 Magnetic Resonance Spectroscopy Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (MAGNETIC RESONANCE IMAGING). In Vivo NMR Spectroscopy,MR Spectroscopy,Magnetic Resonance,NMR Spectroscopy,NMR Spectroscopy, In Vivo,Nuclear Magnetic Resonance,Spectroscopy, Magnetic Resonance,Spectroscopy, NMR,Spectroscopy, Nuclear Magnetic Resonance,Magnetic Resonance Spectroscopies,Magnetic Resonance, Nuclear,NMR Spectroscopies,Resonance Spectroscopy, Magnetic,Resonance, Magnetic,Resonance, Nuclear Magnetic,Spectroscopies, NMR,Spectroscopy, MR
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001713 Biphenyl Compounds Whitish aromatic crystalline organic compounds made up of two conjoined BENZENE rings. Compounds, Biphenyl
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D014230 Triazoles Heterocyclic compounds containing a five-membered ring with two carbon atoms and three nitrogen atoms with the molecular formula C2H3N3. Triazole
D017208 Rats, Wistar A strain of albino rat developed at the Wistar Institute that has spread widely at other institutions. This has markedly diluted the original strain. Wistar Rat,Rat, Wistar,Wistar Rats
D043266 Steryl-Sulfatase An arylsulfatase with high specificity towards sulfated steroids. Defects in this enzyme are the cause of ICHTHYOSIS, X-LINKED. 3 Beta-Hydroxysteroid Sulfate Sulfatase,Arylsulfatase C,Arylsulphatase C,Cholesterol Sulfatase,Cholesterol Sulfate Sulfatase,DHEA Sulfatase,Dehydroepiandrosterone Sulfate Sulfatase,Estrone Sulfate Sulfatase,Estrone Sulfate Sulfohydrolase,Steroid Sulfatase,Steroid Sulfohydrolase,Steroid Sulphatase,Sterol Sulfatase,Sterylsulfatase,3 Beta Hydroxysteroid Sulfate Sulfatase,Steryl Sulfatase,Sulfatase, Cholesterol,Sulfatase, Cholesterol Sulfate,Sulfatase, DHEA,Sulfatase, Dehydroepiandrosterone Sulfate,Sulfatase, Estrone Sulfate,Sulfatase, Steroid,Sulfatase, Sterol,Sulfate Sulfatase, Cholesterol,Sulfate Sulfatase, Dehydroepiandrosterone,Sulfate Sulfatase, Estrone,Sulfate Sulfohydrolase, Estrone,Sulfohydrolase, Estrone Sulfate,Sulfohydrolase, Steroid,Sulphatase, Steroid
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines

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