Novel Sulfonanilide Analogs Decrease Aromatase Activity in Breast Cancer Cells: Synthesis, Biological Evaluation, and Ligand-Based Pharmacophore Identification
Document Type
Article
Publication Date
3-1-2008
Publication Title
Journal of Medicinal Chemistry
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.
Recommended Citation
Su, Bin; Tian, Ran; Darby, Michael V.; and Brueggemeier, Robert W., "Novel Sulfonanilide Analogs Decrease Aromatase Activity in Breast Cancer Cells: Synthesis, Biological Evaluation, and Ligand-Based Pharmacophore Identification" (2008). Chemistry Faculty Publications. 438.
https://engagedscholarship.csuohio.edu/scichem_facpub/438
DOI
10.1021/jm701107h
Volume
51
Issue
5
Comments
This work was supported by the National Institutes of Health (NIH) Grant R01 CA73698 (R.W.B.), the USAMRMC Breast Cancer Program Grant W81XWH-08-1-0521, and The Ohio State University Comprehensive Cancer Center Breast Cancer Research Fund.