title: Structure-activity relationship for the first-in-class clinical steroid sulfatase inhibitor Irosustat (STX64, BN83495).
abstract: Structure-activity relationship studies were conducted on Irosustat (STX64, BN83495), the first steroid sulfatase (STS) inhibitor to enter diverse clinical trials for patients with advanced hormone-dependent cancer. The size of its aliphatic ring was expanded; its sulfamate group was N,N-dimethylated, relocated to another position and flanked by an adjacent methoxy group; and series of quinolin-2(1H)-one and quinoline derivatives of Irosustat were explored. The STS inhibitory activities of the synthesised compounds were assessed in a preparation of JEG-3 cells. Stepwise enlargement of the aliphatic ring from 7 to 11 members increases potency, although a further increase in ring size is detrimental. The best STS inhibitors in vitro had IC50 values between 0.015 and 0.025 nM. Other modifications made to Irosustat were found to either abolish or significantly weaken its activity. An azomethine adduct of Irosustat with N,N-dimethylformamide (DMF) was isolated, and crystal structures of Irosustat and this adduct were determined. Docking studies were conducted to explore the potential interactions between compounds and the active site of STS, and suggest a sulfamoyl group transfer to formylglycine 75 during the inactivation mechanism.
authors: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY (UK), Fax:(+44) 1225-386-114.
authors: L W Lawrence
authors: LW
authors: Woo
authors: Dharshini
authors: D
authors: Ganeshapillai
authors: Mark P
authors: MP
authors: Thomas
authors: Oliver B
authors: OB
authors: Sutcliffe
authors: Bindu
authors: B
authors: Malini
authors: Mary F
authors: MF
authors: Mahon
authors: Atul
authors: A
authors: Purohit
authors: Barry V L
authors: BV
authors: Potter
mesh_terms: D001391:Azo Compounds / Q000737:chemistry; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004126:Dimethylformamide; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005559:Formamides / Q000737:chemistry; D006801:Humans; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000737:chemistry* / Q000494:pharmacology*; D013882:Thiosemicarbazones / Q000737:chemistry
chemical_list: D001391:Azo Compounds; D004791:Enzyme Inhibitors; D005559:Formamides; D013451:Sulfonic Acids; D013882:Thiosemicarbazones; C512188:azomethine; C520511:irosustat; D004126:Dimethylformamide; D043266:Steryl-Sulfatase