Benzothiophene derivatives as selective estrogen receptor covalent antagonists: Design, synthesis and anti-ERα activities

• Published in: Bioorganic & medicinal chemistry 2021-10, Vol.47, p.116395-116395, Article 116395
• Main Authors: Bai, Chengfeng, Wu, Shuangjie, Ren, Shengnan, Zhu, Meiqi, Luo, Guoshun, Xiang, Hua
• Format: Article
• Language: English
• Subjects: Breast cancer; Covalent antagonist; Dose-Response Relationship, Drug; Drug Design; Estrogen Antagonists - chemical synthesis; Estrogen Antagonists - chemistry; Estrogen Antagonists - pharmacology; Estrogen receptor; Estrogen Receptor alpha - antagonists & inhibitors; Estrogen Receptor alpha - metabolism; Humans; Molecular Structure; Resistance; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2021.116395

[Display omitted] •Compound 19d exhibited potent antiproliferative effect in MCF-7 and Ishikawa cell lines in vitro.•19d could attenuate the expression of TFF-1, GREB-1 gene and downregulate the levels of cellular ERα protein.•19d was confirmed as a covalent antagonist, while without inducing effect on proliferation of Ishikawa cells.•Mechanism research revealed the anti-ERα activity of 19d was tightly associated with its electrophile moiety.•19d could induce cell cycle G0/G1 phase arrest and apoptosis in MCF-7 cells. Estrogen receptor α emerged as a well validated therapeutic target of breast cancer for decades. However, approximately 50% of patients who initially responding to standard-of-care (SoC), such as undergo therapy of Tamoxifen, generally inevitably progress to an endocrine-resistance ER+ phenotype. Recently, selective estrogen receptor covalent antagonists (SERCAs) targeted to ERα have been demonstrated as a therapeutic alternative. In the present study, series of novel 6-OH-benzothiophene (BT) derivatives targeting ERα and deriving from Raloxifene were designed, synthesized, and biologically evaluated as covalent antagonists. Driven by the antiproliferative efficacy in ER+ breast cancer cells, our chemical optimization finally led to compound 19d that with potent antagonistic activity in ER+ tumor cells while without agonistic activity in endometrial cells. Moreover, the docking simulation was carried out to elucidate the binding mode, revealing 19d as an antagonist and covalently binding to the cysteine residue at the 530 position of ER helix H11.