Novel sulfonanilide analogs decrease aromatase activity in breast cancer cells: synthesis, biological evaluation, and ligand-based pharmacophore identification

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.