| 储著飞,李苗苗,张俊娜,李佳佳,王海波,邓晓军.化学通报,2026,89(4):416-423. |
| 马拉巴酮A类似物的设计合成、结构表征及体外抗肿瘤活性评价 |
| Synthesis, Structural Characterization and in vitro Anti-tumor Activity Evaluation of Malabaricone A Analogues |
| 投稿时间：2025-11-14 修订日期：2026-01-16 |
| DOI： |
| 中文关键词: 马拉巴酮A类似物 二芳基壬烷 合成 铁死亡 抗肿瘤活性 A549细胞 |
| 英文关键词:Malabaricone analogues Diarylnonane Synthesis Ferroptosis Anti-tumor activity A549 cells |
| 基金项目:国家自然科学基金项目(82104246,81973236)和空军军医大学基金项目(2024JC-054)资助 |
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| 中文摘要: |
| 肺癌是我国发病率和死亡率最高的恶性肿瘤,防治形势严峻,其巨大的疾病负担对社会经济和公共卫生系统构成了沉重压力。马拉巴酮A(Malabaricone A)是一种源自肉豆蔻科植物的二芳基壬烷类天然产物,具有广泛的生物活性。本研究以其为先导化合物,基于官能团修饰策略,以壬溴酸为起始原料,在Fe(acac)?/HMTA/TMEDA催化体系下高效构建碳骨架,经四步反应首次合成了11个结构新颖的马拉巴酮A类似物(5-1 ~ 5-11),所有化合物均通过NMR、HRMS和HPLC进行结构确证,且纯度良好。活性评价结果表明,部分类似物对人肺腺癌A549细胞表现出优异的浓度依赖性增殖抑制活性。其中,化合物5-10和5-11表现尤为突出,它们在高效抑制A549细胞增殖的同时,对正常肺上皮MLE-12细胞毒性显著较低,展现出良好的选择性。进一步的机制研究表明,先导化合物5-10能够显著抑制A549细胞的克隆形成能力。同时,它可诱导细胞内Fe2?水平和脂质过氧化产物(MDA)显著升高,并耗竭还原型谷胱甘肽(GSH)、抑制GPX4酶活性,从而证实其通过激活铁死亡通路发挥抗肿瘤作用。分子对接结果显示,化合物5-10能够以较高的亲和力与Keap1和GPX4结合,预测结合自由能分别为S-7.0 kcal/mol和-6.9 kcal/mol,为其在细胞中有效抑制细胞抗氧化防御、促进脂质过氧化并最终引发铁死亡,提供了合理的分子机制解释。本研究为开发基于马拉巴酮A骨架的高选择性抗肺癌先导化合物提供了重要的物质基础和理论依据。 |
| 英文摘要: |
| Lung cancer is the malignant tumor with the highest incidence and mortality in China. The situation of prevention and treatment is grim, and its huge disease burden poses a heavy pressure on the social economy and public health system. Malabaricone A is a natural product of diaryl nonanes derived from Myristicaceae plants, which has a wide range of biological activities. In this study, 11 novel analogues of malabarone a (5-1~5-11) were synthesized for the first time in four steps with nonabromic acid as the starting material and Fe (ACAC)3/hmta/tmeda catalytic system based on the functional group modification strategy. All compounds were confirmed by NMR, HRMS and HPLC, and the purity was good. The results of activity evaluation showed that some analogues exhibited excellent concentration dependent proliferation inhibitory activity on human lung adenocarcinoma A549 cells. Among them, compounds 5-10 and 5-11 are particularly prominent. They not only effectively inhibit the proliferation of A549 cells, but also have significantly lower toxicity to normal lung epithelial mle-12 cells, showing good selectivity. Further mechanism studies showed that lead compounds 5-10 could significantly inhibit the clonogenic ability of A549 cells. At the same time, it can induce a significant increase in intracellular Fe2+ level and lipid peroxidation products (MDA), deplete reduced glutathione (GSH), and inhibit GPx4 enzyme activity, thus confirming its anti-tumor effect by activating the iron death pathway. Molecular docking results showed that compounds 5-10 could bind with high affinity to Keap1 and GPx4, and the predicted binding free energies were -9.24 kcal/mol and -7.56 kcal/mol, respectively, which provided a reasonable molecular mechanism explanation for their effective inhibition of cellular antioxidant defense, promotion of lipid peroxidation, and ultimately triggered iron death in cells. This study provides an important material basis and theoretical basis for the development of highly selective anti lung cancer lead compounds based on malabarone a skeleton. |
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