Synthesis of Aromatase Inhibitors and Dual Aromatase Steroid Sulfatase Inhibitors by Linking an Arylsulfamate Motif to 4-(4H-1,2,4-triazol-4-ylamino)benzonitrile: SAR, Crystal Structures, in vitro and in vivo Activities
| Autor: | Oliver B. Sutcliffe, L. W. Lawrence Woo, Mary F. Mahon, Atul Purohit, Barry V. L. Potter, Christian Bubert, Surinder K. Chander, Michael J. Reed |
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| Rok vydání: | 2008 |
| Předmět: |
Stereochemistry
medicine.drug_class Chemistry Pharmaceutical Amino Acid Motifs Molecular Conformation In Vitro Techniques Crystallography X-Ray Biochemistry Sulfone Inhibitory Concentration 50 Structure-Activity Relationship chemistry.chemical_compound Aromatase In vivo Cell Line Tumor Nitriles Drug Discovery Steroid sulfatase medicine Humans Structure–activity relationship General Pharmacology Toxicology and Pharmaceutics Pharmacology Sulfonamides Aromatase inhibitor Estradiol biology Aromatase Inhibitors Chemistry Organic Chemistry Triazoles In vitro Drug Design biology.protein Molecular Medicine Steryl-Sulfatase Linker |
| Zdroj: | ChemMedChem. 3:1708-1730 |
| ISSN: | 1860-7187 1860-7179 |
| Popis: | 4-(((4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)phenyl sulfamate (6 a) was the first dual aromatase-sulfatase inhibitor (DASI) reported. Several series of its derivatives with various linker systems between the steroid sulfatase (STS) and the aromatase inhibitory pharmacophores were synthesised and evaluated in JEG-3 cells. The X-ray crystal structures of the aromatase inhibitors, DASI precursors 42 d and 60, and DASI 43 h were determined. Nearly all derivatives show improved in vitro aromatase inhibition over 6 a but decreased STS inhibition. The best aromatase inhibitor is 42 e (IC(50)=0.26 nM) and the best DASI is 43 e (IC(50 aromatase)=0.45 nM, IC(50 STS)=1200 nM). SAR for aromatase inhibition shows that compounds containing an alkylene- and thioether-based linker system are more potent than those that are ether-, sulfone-, or sulfonamide-based, and that the length of the linker has a limited effect on aromatase inhibition beyond two methylene units. Compounds 43 d-f were studied in vivo (10 mg kg(-1), single, p.o.). The most potent DASI is 43 e, which inhibited PMSG-induced plasma estradiol levels by 92 % and liver STS activity by 98 % 3 h after dosing. These results further strengthen the concept of designing and developing DASIs for potential treatment of hormone-related cancers. |
| Databáze: | OpenAIRE |
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