Title

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.

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.

DOI

10.1021/jm701107h

Volume

51

Issue

5