New imidazole-2-thiones linked to acenaphythylenone as dual DNA intercalators and topoisomerase II inhibitors: structural optimization, docking, and apoptosis studies.

IF 5.6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Asmaa H Mohamed, Mohammed B Alshammari, Ashraf A Aly, Kamal U Sadek, Akil Ahmad, Eman A Aziz, Amira F El-Yazbi, Eman J El-Agroudy, Marwa E Abdelaziz
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引用次数: 0

Abstract

In this article, a new series of 2-((3,5-disubstituted-2-thioxo-imidazol-1-yl)imino)acenaphthylen-1(2H)-ones were synthesized. Imidazole-2-thione with acenaphthylen-one gave a hybrid scaffold that integrated key structural elements essential for DNA damage via direct DNA intercalation and inhibition of the topoisomerase II enzyme. All the synthesized compounds were screened to detect their DNA damage using a terbium fluorescent probe. Results demonstrated that 4-phenyl-imidazoles 5b and 5e in addition to 4-(4-chlorophenyl)imidazoles 5h and 5j would induce detectable potent damage in ctDNA. The four most potent compounds as DNA intercalators were further evaluated for their antiproliferative activity against HepG2, MCF-7 and HCT-116 utilizing the MTT assay. The highest anticancer activity was recorded with compounds 5b and 5h against the breast cancer cell line MCF-7 which were 1.5- and 3- folds more active than doxorubicin, respectively. Therefore, imidazole-2-thione tethered acenaphthylenone derivatives can be considered as promising scaffold for the development of effective dual DNA intercalators and topoisomerase II inhibitors.

与苊烯酮相连的新型咪唑-2-硫酮作为双重 DNA 中间体和拓扑异构酶 II 抑制剂:结构优化、对接和细胞凋亡研究。
本文合成了一系列新的 2-((3,5-二取代-2-硫酮-咪唑-1-基)亚氨基)苊烯-1(2H)-酮。咪唑-2-硫酮与苊烯-1-酮形成了一个混合支架,通过直接插入 DNA 和抑制拓扑异构酶 II 酶,整合了 DNA 损伤所必需的关键结构元素。利用铽荧光探针对所有合成的化合物进行了筛选,以检测它们对 DNA 的损伤。结果表明,除了 4-(4-氯苯基)咪唑 5h 和 5j 外,4-苯基咪唑 5b 和 5e 也能在 ctDNA 中诱导出可检测到的强效损伤。利用 MTT 试验进一步评估了这四种最有效的 DNA 中间体化合物对 HepG2、MCF-7 和 HCT-116 的抗增殖活性。化合物 5b 和 5h 对乳腺癌细胞株 MCF-7 的抗癌活性最高,分别是多柔比星活性的 1.5 倍和 3 倍。因此,咪唑-2-硫酮系苊烯酮衍生物可被视为开发有效的 DNA 中间体和拓扑异构酶 II 双重抑制剂的前景广阔的支架。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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