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

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 microM 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.

CoMFA, LeapFrog and blind docking studies on sulfonanilide derivatives acting as selective aromatase expression regulators

“…2 none of the N-methylated molecules bind the active site. This result is in line with the finding made by Su et al [15][16][17] who determined that modulation of aromatase expression by NS-398 analogues does not necessarily require the inhibition of COX-2 enzyme activity [29,30]. Interestingly, some of the NH-bearing sulfonanilide derived molecules do not dock the active site either.…”

“…In vitro inhibitory activity data (IC 50 nM) of sulfonanilide analogues on SK-BR-3 breast cancer cell, reported by Su et al [15][16][17] were taken for the study. Out of 66 aromatase gene expression inhibitors which were reported, 55 molecules (Tables 1-3) were selected for developing the model and 11 molecules whose IC 50 values were not quantitatively reported were not considered for the study.…”

“…Besides, it has been shown that COX-1 and COX-2 inhibitors (Nonsteroidal anti-inflammatory drugs) can suppress the aromatase activity in SK-BR-3 breast cancer cells at transcriptional level [12], and consequently, the COX selective inhibitors could serve as the first generation of selective aromatase expression regulators (SAERs). Recently, the derivative analogue series of COX-2 inhibitors Nimesulide [13] and NS-398 [14] has been synthesized and tested in SK-BR-3 breast cancer cells [15][16][17], which suppress aromatase activity in breast cancer cells by suppressing its transcription [12]. Derivatives of NS-398 suppress aromatase activity at similar levels with the compound itself, whereas the N-methyl derivatives of NS-398 exhibit no COX-2 inhibition [15][16][17].…”

“…Recently, the derivative analogue series of COX-2 inhibitors Nimesulide [13] and NS-398 [14] has been synthesized and tested in SK-BR-3 breast cancer cells [15][16][17], which suppress aromatase activity in breast cancer cells by suppressing its transcription [12]. Derivatives of NS-398 suppress aromatase activity at similar levels with the compound itself, whereas the N-methyl derivatives of NS-398 exhibit no COX-2 inhibition [15][16][17].…”

Synthesis and Biological Evaluation of Novel Sulfonanilide Compounds as Antiproliferative Agents for Breast Cancer

“…25 Two targeted libraries of nimesulide analogs have been synthesized in our laboratory, and their pharmacological effect on aromatase has been extensively studied. 25,26 In this publication, their biological effect on breast cancer cell growth was investigated in a panel of breast cancer cell lines. Two analogs significantly inhibited SK-BR-3 breast cancer cell growth, which is a HER2/neu overexpressed breast cancer cell line.…”