School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, PR China.
School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, PR China.
Eur J Med Chem. 2019 May 15;170:99-111. doi: 10.1016/j.ejmech.2019.03.011. Epub 2019 Mar 10.
Nannocystin A is a novel 21-membered macrocyclic lactam that targets eukaryotic translation elongation factor 1α (eEF1A) and displays potent antiproliferative activities. Herein, a series of nannocystin A analogues were synthesized and their structure-activity relationship (SAR) were established based on the MTT assay and western blotting analysis. The SAR enabled us to identify a structurally simplified nannocystin A analogue LQ18, which exhibited potent antiproliferative activities with IC values ranging from 4.3 to 48 nM against the tested cell lines, and inhibited eEF1A1 expression in A549 cell line. LQ18 arrested cell cycle at G2 phase and induced A549 cell apoptosis via up-regulation of caspase-3, caspase-9 and bax protein expressions in a dose-dependent manner, while it significantly decreased the bcl-2 expression. Collectively, these data demonstrated that LQ18 could be a promising lead for the development of structurally novel eEF1A1 inhibitor for cancer treatment.
南极菌素 A 是一种新型的 21 元大环内酰胺，靶向真核翻译延伸因子 1α（eEF1A），并表现出强大的抗增殖活性。在此，我们合成了一系列南极菌素 A 类似物，并通过 MTT 分析和 Western blot 分析确定了它们的构效关系（SAR）。SAR 使我们能够识别出结构简化的南极菌素 A 类似物 LQ18，它对测试的细胞系具有强大的抗增殖活性，IC 值范围为 4.3 至 48 nM，并且抑制 A549 细胞系中 eEF1A1 的表达。LQ18 通过上调 caspase-3、caspase-9 和 bax 蛋白的表达，以剂量依赖的方式将细胞周期阻滞在 G2 期，并诱导 A549 细胞凋亡，同时显著降低 bcl-2 的表达。总的来说，这些数据表明 LQ18 可能是一种有前途的先导化合物，可用于开发新型的 eEF1A1 抑制剂，用于癌症治疗。
