关键词: Apoptosis Cancer therapy Cell cycle regulation Epithelial-mesenchymal transition Novel HDAC inhibitors

Mesh : Histone Deacetylase Inhibitors / pharmacology chemistry chemical synthesis Humans Apoptosis / drug effects Antineoplastic Agents / pharmacology chemistry chemical synthesis Epithelial-Mesenchymal Transition / drug effects Animals Zebrafish Cell Cycle / drug effects Structure-Activity Relationship Drug Screening Assays, Antitumor Cell Proliferation / drug effects Molecular Structure Dose-Response Relationship, Drug Cell Line, Tumor Histone Deacetylases / metabolism

来  源:   DOI:10.1016/j.bmc.2024.117792

Abstract:
Cancer has been a leading cause of death over the last few decades in western countries as well as in Taiwan. However, traditional therapies are limited by the adverse effects of chemotherapy and radiotherapy, and tumor recurrence may occur. Therefore, it is critical to develop novel therapeutic drugs. In the field of HDAC inhibitor development, apart from the hydroxamic acid moiety, 2-aminobenzamide also functions as a zinc-binding domain, which is shown in well-known HDAC inhibitors such as Entinostat and Chidamide. With recent successful experiences in synthesizing 1-(phenylsulfonyl)indole-based compounds, in this study, we further combined two features of the above chemical compounds and generated indolyl benzamides. Compounds were screened in different cancer cell lines, and enzyme activity was examined to demonstrate their potential for anti-HDAC activity. Various biological functional assays evidenced that two of these compounds could suppress cancer growth and migration capacity, through regulating epithelial-mesenchymal transition (EMT), cell cycle, and apoptosis mechanisms. Data from 3D cancer cells and the in vivo zebrafish model suggested the potential of these compounds in cancer therapy in the future.
摘要:
在过去的几十年中,癌症一直是西方国家和台湾的主要死亡原因。然而,传统疗法受到化疗和放疗副作用的限制,和肿瘤复发可能发生。因此,开发新的治疗药物至关重要。在HDAC抑制剂开发领域,除了异羟肟酸部分,2-氨基苯甲酰胺还可以作为锌结合域,这在众所周知的HDAC抑制剂如Entinostat和Chidamide中显示。结合近年来合成1-(苯磺酰基)吲哚类化合物的成功经验,在这项研究中,我们进一步结合了上述化合物的两个特征,并产生了吲哚基苯甲酰胺。在不同的癌细胞系中筛选化合物,并检查酶活性以证明其抗HDAC活性的潜力。各种生物功能分析证明,这些化合物中的两种可以抑制癌症的生长和迁移能力,通过调节上皮-间质转化(EMT),细胞周期,和凋亡机制。来自3D癌细胞和体内斑马鱼模型的数据表明这些化合物在未来癌症治疗中的潜力。
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