title: First dual aromatase-steroid sulfatase inhibitors.
abstract: Aromatase inhibitors in clinical use block the biosynthesis of estrogens. Hydrolysis of estrone 3-sulfate by steroid sulfatase is an important additional source of tumor estrogen, and blockade of both enzymes should provide a more effective endocrine therapy. Sulfamoylated derivatives of the aromatase inhibitor YM511 inhibited sulfatase and aromatase in JEG-3 cells with respective IC(50) values of 20-227 and 0.82-100 nM (cf. letrozole, 0.89 nM). One dual inhibitor was potent against both enzymes in vivo, validating the concept.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd., University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: L W Lawrence
authors.initials: LW
authors.lastname: Woo
authors.forename: Oliver B
authors.initials: OB
authors.lastname: Sutcliffe
authors.forename: Christian
authors.initials: C
authors.lastname: Bubert
authors.forename: Anna
authors.initials: A
authors.lastname: Grasso
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Chander
authors.forename: Atul
authors.initials: A
authors.lastname: Purohit
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reed
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047072:Aromatase Inhibitors; D001192:Arylsulfatases / Q000037:antagonists & inhibitors*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004958:Estradiol / Q000032:analysis / Q000097:blood; D004965:Estrogen Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D008099:Liver / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D043266:Steryl-Sulfatase
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D004958:Estradiol; D001192:Arylsulfatases; D043266:Steryl-Sulfatase