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| 两面针碱简化骨架四唑硫醚衍生物的设计合成与抗肿瘤活性研究 |
| Rational Design and Antitumor Activity Optimization of Nitidine Chloride Simplified Skeleton Tetrazole-Thioether Derivatives |
| 投稿时间：2025-04-24 修订日期：2025-05-28 |
| DOI： |
| 中文关键词: 氯化两面针碱 巯基四唑 抗肿瘤活性 分子对接 |
| 英文关键词:Nitidine Chloride, Thicaptetrazole, Antitumor activities, Molecular docking |
| 基金项目:广西研究生教育创新计划项目(YCSW2024425)；国家自然科学基金项目（ 22067001）；广西自然科学基金项目(2023GXNSFAA026476) |
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| 中文摘要: |
| [1]本研究以间甲基苯甲酰氯、对甲基苯甲酰氯等四种芳香酰氯为起始原料,通过酰化、钯催化环化及脱保护基的多步反应成功构建了菲啶酮母核(4a-4d)。随后,基于药效团拼接原理,选用1,4-二溴丁烷与1,6-二溴己烷作为连接子,通过亲核取代反应将巯基四唑结构单元引入菲啶酮母核,从而设计并合成了40个结构新颖的两面针碱-四唑硫醚杂合体(8a-8t、9a-9t)。目标化合物的结构通过1H NMR、13C NMR、HR-MS及X-单晶衍射等多种现代波谱技术进行了系统表征。采用CCK-8法对目标化合物进行了体外抗增殖活性测试,结果显示大部分化合物对人肝癌细胞HepG2、人肺癌细胞H460以及人宫颈癌细胞HeLa表现出良好的抑制作用。其中,化合物8p和8r对H460细胞株显示出较强的抑制活性,其抑制率分别为77.46%±7.64%和76.47%±1.71%,优于阳性对照药物5-氟尿嘧啶(45.08%±2.85%)。此外,这些化合物对正常肝细胞LO2表现出较低的细胞毒性,显示出良好的选择性。分子对接研究表明,化合物8p、8r、9a和9f能够与DNA拓扑异构酶I形成较为稳定的相互作用,提示其抗肿瘤活性可能与其对DNA拓扑异构酶I的作用机制相关。 |
| 英文摘要: |
| In this study, four aromatic acyl chlorides, including 3-methylbenzoyl chloride and 4-methylbenzoyl chloride, were used as starting materials to successfully construct the pholidineone skeleton (4a-4d) through a series of reactions including acylation, palladium-catalyzed cyclization and deprotection. Subsequently, based on the principle of pharmacophore splicing, 1,4-dibromobutane and 1,6-dibromohexane were selected as linkers, and the thiazole structure unit was introduced into the pholidineone skeleton through nucleophilic substitution reactions, thereby designing and synthesizing 40 novel two-faced needle alkaloid-thiazole sulfide hybrids (8a-8t, 9a-9t). The structures of the target compounds were systematically characterized by various modern spectroscopic techniques such as 1H NMR, 13C NMR, HR-MS and X-ray single crystal diffraction. The in vitro antiproliferative activities of the target compounds were tested by the CCK-8 method. The results showed that most of the compounds exhibited significant inhibitory effects on human hepatoma cells HepG2, human lung cancer cells H460 and human cervical cancer cells HeLa. Among them, compounds 8p and 8r showed strong inhibitory activity against the H460 cell line, with inhibition rates of 77.46% ± 7.64% and 76.47% ± 1.71%, respectively, which were superior to the positive control drug 5-fluorouracil (45.08% ± 2.85%). In addition, these compounds showed low cytotoxicity to normal liver cells LO2, indicating good selectivity. Molecular docking studies indicated that compounds 8p, 8r, 9a and 9f could form relatively stable interactions with DNA topoisomerase I, suggesting that their antitumor activity might be related to their mechanism of action on DNA topoisomerase I. |
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