通过靶向丙酮酸羧化酶设计、合成和评估抗肝细胞癌的双苄基类似物
Design, Synthesis, and Evaluation of Bibenzyl Analogues against Hepatocellular Carcinoma by Targeting Pyruvate Carboxylase.
摘要(中文译文)
丙酮酸羧化酶（PC）补充三羧酸循环中间产物，驱动癌症代谢重编程。为提高来自Lindl的强效PC抑制剂毛兰素的代谢稳定性，我们设计并合成了55个衍生物，最终鉴定出化合物，其表现出强效的PC抑制作用（IC = 1.74 nM）并抑制HCC细胞活力（IC = 25.18 nM），与毛兰素相当。值得注意的是，该化合物表现出显著改善的稳定性，半衰期（= 1.21 h）远长于毛兰素（约0.1 h）。在机制上，该化合物通过诱导凋亡和铁死亡抑制HCC增殖和转移。此外，它促进线粒体氧化应激并抑制糖酵解，从而使细胞对谷氨酰胺剥夺敏感。该化合物表现出与索拉非尼相当的抗肿瘤疗效但安全性改善。凭借其强效的PC抑制作用和良好的类药性质，该化合物代表了HCC治疗的有前景的治疗候选物。
Abstract
Pyruvate carboxylase (PC) replenishes tricarboxylic acid cycle intermediates, driving cancer metabolic reprogramming. To improve the metabolic stability of erianin, a potent PC inhibitor from Lindl, we designed and synthesized 55 derivatives, culminating in the identification of which exhibited potent PC inhibition (IC = 1.74 nM) and suppressed HCC cell viability (IC = 25.18 nM), comparable to erianin. Notably, demonstrated significantly improved stability, with a half-life ( = 1.21 h) much longer than erianin ( ∼ 0.1 h). Mechanistically, suppressed HCC proliferation and metastasis by inducing apoptosis and ferroptosis. Moreover, it promoted mitochondrial oxidative stress and inhibited glycolysis, thereby sensitizing cells to glutamine deprivation. , exhibited comparable antitumor efficacy but improved safety compared to sorafenib. With its potent PC inhibition and favorable drug-like properties, represented a promising therapeutic candidate for HCC treatment.
如何引用
AMA
Zeen Qiao, Lingyu Li, Yuwen Sheng, Jinlian Yang, Jialing Yu, Fan Wu, et al. Design, Synthesis, and Evaluation of Bibenzyl Analogues against Hepatocellular Carcinoma by Targeting Pyruvate Carboxylase.. Journal of medicinal chemistry. 2026; doi:10.1021/acs.jmedchem.6c00075.
APA
Zeen Qiao, Lingyu Li, Yuwen Sheng, Jinlian Yang, Jialing Yu, Fan Wu, et al (2026). Design, Synthesis, and Evaluation of Bibenzyl Analogues against Hepatocellular Carcinoma by Targeting Pyruvate Carboxylase.. Journal of medicinal chemistry. https://doi.org/10.1021/acs.jmedchem.6c00075
GB/T 7714
Zeen Qiao, Lingyu Li, Yuwen Sheng, Jinlian Yang, Jialing Yu, Fan Wu, et al. Design, Synthesis, and Evaluation of Bibenzyl Analogues against Hepatocellular Carcinoma by Targeting Pyruvate Carboxylase.[J]. Journal of medicinal chemistry, 2026 doi:10.1021/acs.jmedchem.6c00075.
在 PubMed增强版 阅读全文
翻译全文 · AI 文献问答 · PDF 原文下载 · 引用导出