Title

Synthesis and Biological Evaluation of Selective Aromatase Expression Regulators in Breast Cancer Cells

Document Type

Article

Publication Date

4-1-2007

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. The enzyme is encoded by the CYP19 gene, which is expressed in a tissue-specific manner. Prostaglandin E2 (PGE2), 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 μM 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.

Comments

This work was supported by the National Institutes of Health (NIH) Grant R01 CA73698 (R.W.B.), and The Ohio State University Comprehensive Cancer Center Breast Cancer Research Fund.

DOI

10.1021/jm061133j

Volume

50

Issue

7