title: Chiral aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole template: synthesis, absolute configuration, and in vitro activity.
abstract: To explore aromatase inhibition and to broaden the structural diversity of dual aromatase-sulfatase inhibitors (DASIs), we introduced the steroid sulfatase (STS) inhibitory pharmacophore to letrozole. Letrozole derivatives were prepared bearing bis-sulfamates or mono-sulfamates with or without adjacent substituents. The most potent of the achiral and racemic aromatase inhibitor was 40 (IC 50 = 3.0 nM). Its phenolic precursor 39 was separated by chiral HPLC, and the absolute configuration of each enantiomer was determined using vibrational and electronic circular dichroism in tandem with calculations of the predicted spectra. Of the two enantiomers, ( R)-phenol ( 39a) was the most potent aromatase inhibitor (IC 50 = 0.6 nM, comparable to letrozole), whereas the ( S)-sulfamate, ( 40b) inhibited STS most potently (IC 50 = 553 nM). These results suggest that a new structural class of DASI for potential treatment of hormone-dependent breast cancer has been identified, and this is the first report of STS inhibition by an enantiopure nonsteroidal compound.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd., University of Bath, Claverton Down, UK.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Wood
authors.forename: L W Lawrence
authors.initials: LW
authors.lastname: Woo
authors.forename: Jean-Robert
authors.initials: JR
authors.lastname: Labrosse
authors.forename: Melanie N
authors.initials: MN
authors.lastname: Trusselle
authors.forename: Sergio
authors.initials: S
authors.lastname: Abbate
authors.forename: Giovanna
authors.initials: G
authors.lastname: Longhi
authors.forename: Ettore
authors.initials: E
authors.lastname: Castiglioni
authors.forename: France
authors.initials: F
authors.lastname: Lebon
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: D001141:Aromatase / Q000187:drug effects*; D047072:Aromatase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D006801:Humans; D000077289:Letrozole; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; D001141:Aromatase; D043266:Steryl-Sulfatase