title: Novel oxazolidinone based compounds as inhibitors of aromatase and the use of the substrate-heme complex approach in the rationalisation of these compounds.
abstract: The synthesis, biochemical evaluation and molecular modelling of a series of N-alkylated 4-(4(')-aminobenzyl)-2-oxazolidinones is described involving the derivatisation of the starting R- or S-enantiomer of 4-benzyl-2-oxazolidinones. The compounds were tested for human placental aromatase (AR) inhibition in vitro and were found, in general, to be more potent than the standard compound, aminoglutethimide (AG). The inhibitory activity of the compounds was rationalised through the use of the novel substrate-heme complex (SHC) approach and suggests that the S-enantiomer based compounds protrude beyond the C(13), C(17), and C(16) area of the steroid backbone, resulting in steric hindrance with the active site of AR and thus reduced inhibitory activity. The R-enantiomer based compounds do not protrude in the same area and as such are not thought to undergo any steric hindrance and in comparison to the S-enantiomer, possess greater inhibitory activity.
authors.affiliation: School of Chemical and Pharmaceutical Sciences, Kingston University, Penrhyn Road, Kingston, Surrey, UK. s.ahmed@kingston.ac.uk
authors.forename: Sabbir
authors.initials: S
authors.lastname: Ahmed
authors.forename: Shaheen
authors.initials: S
authors.lastname: Adat
authors.forename: Annabel
authors.initials: A
authors.lastname: Murrells
authors.forename: Caroline P
authors.initials: CP
authors.lastname: Owen
mesh_terms: D047072:Aromatase Inhibitors; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D006418:Heme / Q000737:chemistry*; D006801:Humans; D046911:Macromolecular Substances; D008958:Models, Molecular; D023303:Oxazolidinones / Q000737:chemistry* / Q000494:pharmacology*; D010920:Placenta / Q000201:enzymology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D047072:Aromatase Inhibitors; D046911:Macromolecular Substances; D023303:Oxazolidinones; D006418:Heme