Novel Bioactive Hybrid Compound Dual Targeting Estrogen Receptor and Histone Deacetylase for the Treatment of Breast Cancer

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• 作者：Chu Tang ; Changhao Li ; Silong Zhang ; Zhiye Hu ; Jun Wu ; Chune Dong ; Jian Huang ; Hai-Bing Zhou
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：June 11, 2015
• 年：2015
• 卷：58
• 期：11
• 页码：4550-4572
• 全文大小：1300K
• ISSN：1520-4804

文摘

A strategy to develop chemotherapeutic agents by combining several active groups into a single molecule as a conjugate that can modulate multiple cellular pathways may produce compounds having higher efficacy compared to that of single-target drugs. In this article, we describe the synthesis and evaluation of an array of dual-acting ER and histone deacetylase inhibitors. These novel hybrid compounds combine an indirect antagonism structure motif of ER (OBHS, oxabicycloheptene sulfonate) with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). These OBHS鈥揌DACi conjugates exhibited good ER binding affinity and excellent ER伪 antagonistic activity, and they also exhibited potent inhibitory activities against HDACs. Compared with the approved drug tamoxifen, these conjugates exhibited higher antitumor potency in ER伪-positive breast cancer cells (MCF-7). Moreover, these conjugates not only showed selective anticancer activity that was more potent against MCF-7 cells than DU 145 (prostate cancer), but they had no toxicity toward normal cells.