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新型联苯胺类化合物抑制雌激素受体阳性乳腺癌细胞中的雌激素受体-α。

Novel Biphenyl Amines Inhibit Oestrogen Receptor (ER)-α in ER-Positive Mammary Carcinoma Cells.

机构信息

Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.

Department of Chemistry, Bangalore University, Bangalore 560001, India.

出版信息

Molecules. 2021 Feb 3;26(4):783. doi: 10.3390/molecules26040783.

DOI:10.3390/molecules26040783
PMID:33546391
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7913524/
Abstract

Herein, the activity of adamantanyl-tethered-biphenyl amines (ATBAs) as oestrogen receptor alpha (ERα) modulating ligands is reported. Using an ERα competitor assay it was demonstrated that ATBA compound 3-(adamantan-1-yl)-4-methoxy-N-(4-(trifluoromethyl) phenyl) aniline (AMTA) exhibited an inhibitory concentration 50% (IC) value of 62.84 nM and demonstrated better binding affinity compared to tamoxifen (IC 79.48 nM). Treatment of ERα positive (ER+) mammary carcinoma (MC) cells (Michigan Cancer Foundation-7 (MCF7)) with AMTA significantly decreased cell viability at an IC value of 6.4 μM. AMTA treatment of MC cell-generated three-dimensional (3D) spheroids resulted in significantly decreased cell viability. AMTA demonstrated a superior inhibitory effect compared to tamoxifen-treated MC cell spheroids. Subsequently, by use of an oestrogen response element (ERE) luciferase reporter construct, it was demonstrated that AMTA treatment significantly deceased ERE transcriptional activity in MC cells. Concordantly, AMTA treatment of MC cells also significantly decreased protein levels of oestrogen-regulated CCND1 in a dose-dependent manner. In silico molecular docking analysis suggested that AMTA compounds interact with the ligand-binding domain of ERα compared to the co-crystal ligand, 5-(4-hydroxyphenoxy)-6-(3-hydroxyphenyl)-7- methylnaphthalen-2-ol. Therefore, an analogue of AMTA may provide a structural basis to develop a newer class of ERα partial agonists.

摘要

本文报道了金刚烷基连接的联苯胺（ATBAs）作为雌激素受体α（ERα）调节剂的活性。通过 ERα 竞争测定法，证明 ATBA 化合物 3-（金刚烷-1-基）-4-甲氧基-N-（4-（三氟甲基）苯基）苯胺（AMTA）的抑制浓度 50%（IC）值为 62.84 nM，与他莫昔芬（IC 79.48 nM）相比具有更好的结合亲和力。用 AMTA 处理 ERα 阳性（ER+）乳腺癌细胞（密歇根癌症基金会-7（MCF7））时，在 6.4 μM 的 IC 值时细胞活力明显降低。AMTA 处理 MC 细胞生成的三维（3D）球体导致细胞活力明显降低。与他莫昔芬处理的 MC 细胞球体相比，AMTA 表现出优越的抑制作用。随后，通过使用雌激素反应元件（ERE）荧光素酶报告基因构建体，证明 AMTA 处理显著降低了 MC 细胞中的 ERE 转录活性。一致地，AMTA 处理 MC 细胞还显著降低了雌激素调节的 CCND1 蛋白水平，呈剂量依赖性。计算机分子对接分析表明，与共晶配体 5-（4-羟基苯氧基）-6-（3-羟基苯基）-7-甲基萘-2-醇相比，AMTA 化合物与 ERα 的配体结合域相互作用。因此，AMTA 的类似物可能为开发新型 ERα 部分激动剂提供结构基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48ec/7913524/994bd83d5e39/molecules-26-00783-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48ec/7913524/2a06c80994c1/molecules-26-00783-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48ec/7913524/f51125d0d945/molecules-26-00783-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48ec/7913524/19f85d0a0a0b/molecules-26-00783-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48ec/7913524/1d2b4529d96c/molecules-26-00783-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48ec/7913524/1e2729ca7977/molecules-26-00783-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48ec/7913524/994bd83d5e39/molecules-26-00783-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48ec/7913524/2a06c80994c1/molecules-26-00783-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48ec/7913524/f51125d0d945/molecules-26-00783-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48ec/7913524/19f85d0a0a0b/molecules-26-00783-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48ec/7913524/1d2b4529d96c/molecules-26-00783-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48ec/7913524/1e2729ca7977/molecules-26-00783-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48ec/7913524/994bd83d5e39/molecules-26-00783-g005.jpg

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