title: Novel sulfonanilide analogs decrease aromatase activity in breast cancer cells: synthesis, biological evaluation, and ligand-based pharmacophore identification.
abstract: Aromatase converts androgens to estrogens and is a particularly attractive target in the treatment of estrogen receptor positive breast cancer. Previously, the COX-2 selective inhibitor nimesulide and analogs decreased aromatase expression and enzyme activity independent of COX-2 inhibition. In this manuscript, a combinatorial approach was used to generate diversely substituted novel sulfonanilides by parallel synthesis. Their pharmacological evaluation as agents for suppression of aromatase activity in SK-BR-3 breast cancer cells was extensively explored. A ligand-based pharmacophore model was elaborated for selective aromatase modulation (SAM) using the Catalyst HipHop algorithms. The best qualitative model consisted of four features: one aromatic ring, two hydrogen bond acceptors, and one hydrophobic function. Several lead compounds have also been tested in aromatase transfected MCF-7 cells, and they significantly suppressed cellular aromatase activity. The results suggest that both genomic and nongenomic mechanisms of these compounds are involved within the aromatase suppression effect.
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Su
authors.forename: Ran
authors.initials: R
authors.lastname: Tian
authors.forename: Michael V
authors.initials: MV
authors.lastname: Darby
authors.forename: Robert W
authors.initials: RW
authors.lastname: Brueggemeier
mesh_terms: D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014162:Transfection
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D008024:Ligands; D013449:Sulfonamides; D001141:Aromatase; C012655:nimesulide