Synthesis and biological evaluation of selective aromatase expression regulators in breast cancer cells

Aromatase converts androgens to estrogens and is a particularly attractive target in the treatment of estrogen receptor positive breast cancer. The enzyme is encoded by the CYP19 gene, which is expressed in a tissue-specific manner. Prostaglandin E-2 (PGE(2)), the major product of cyclooxygenase-2 (COX-2), stimulates aromatase gene expression via protein kinase A and C signaling pathways. Our previous study demonstrated that COX-2 selective inhibitor nimesulide decreased aromatase activity from the transcriptional level in breast cancer cells. In this manuscript, the synthesis and biological evaluation of a series of nimesulide analogues as potential selective aromatase expression regulators are described. Several novel sulfonanilide compounds demonstrate IC50 values from 0.33 to 2.68 mu M in suppressing aromatase enzyme activity in SK-BR-3 breast cancer cells and are 10- to 80-fold more active than nimesulide. Also, the sulfonanilide compounds selectively decrease aromatase gene expression in breast cancer cells, without exhibiting cytotoxic or apoptotic effects at low micromole concentrations.