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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Discovery of a chiral fluorinated azetidin-2-one as a tubulin polymerisation inhibitor with potent antitumour efficacy
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Discovery of a chiral fluorinated azetidin-2-one as a tubulin polymerisation inhibitor with potent antitumour efficacy

机译：发现手性氟化氮丁胺蛋白-2-on作为管蛋白聚合抑制剂，具有有效的抗肿瘤疗效

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Inhibition of tubulin polymerisation with small molecules has been clinically validated as a promising therapy for multiple solid tumours. Herein, a series of chiral azetidin-2-ones were asymmetrically synthesised and biologically evaluated for antitumour activities. Among them, a chiral fluorinated azetidin-2-one, 18, was found to exhibit the most potent activities against five cancer cell lines, including a drug-resistant cell line, with IC50 values ranging from 1.0 to 3.6 nM. Further mechanistic studies revealed that the compound 18 worked by disrupting tubulin polymerisation, blocking the cell cycle in the G(2)/M phase, inducing cellular apoptosis, and suppressing angiogenesis. Additionally, 18 exhibited higher human-microsomal metabolic stability and aqueous solubility compared to those of combretastatin A-4. Finally, 18 was also found to effectively inhibit tumour growth in a xenograft mice model with low toxicity and thus might be a promising lead for further clinical development. (C) 2020 Elsevier Masson SAS. All rights reserved.
机译：用小分子抑制小分子的抑制已被临床验证为多种实体肿瘤的有望疗法。在此，一系列手性氮酸丁胺蛋白-2-含有在抗肿瘤活动中具有不对称合成和生物学评价的。其中，发现手性氟化氮腺苷酸-2-1，18，含有针对五种癌细胞系的最有效的活性，包括耐药细胞系，IC50值范围为1.0至3.6nm。进一步的机械研究表明，化合物18通过破坏小管蛋白聚合而工作，阻断G（2）/ m相中的细胞周期，诱导细胞凋亡和抑制血管生成。另外，与组合A-4相比，18表现出更高的人微粒体代谢稳定性和含水溶解度。最后，还发现18有效地抑制了低毒性的异种移植小鼠模型中的肿瘤生长，因此可能是进一步临床发育的有前途的铅。 （c）2020 Elsevier Masson SAS。版权所有。

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