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首页> 外文期刊>European journal of pharmaceutical sciences >Synthesis and anti-cancer activity of ND-646 and its derivatives as acetyl-CoA carboxylase 1 inhibitors
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Synthesis and anti-cancer activity of ND-646 and its derivatives as acetyl-CoA carboxylase 1 inhibitors

机译：ND-646的合成和抗癌活性及其衍生物作为乙酰-CoA羧化酶1抑制剂

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摘要

Acetyl-coA carboxylase 1 (ACC1) is the first and rate-limiting enzyme in the de novo fatty acid synthesis (FASyn) pathway. In this study, through public database analysis and clinic sample test, we for the first time verified that ACC1 mRNA is overexpressed in non-small-cell lung cancer (NSCLC), which is accompanied by reduced DNA methylation at CpG island S shore of ACC1. Our study further demonstrated that higher ACC1 levels are associated with poor prognosis in NSCLC patients. Besides, we developed a novel synthetic route for preparation of a known ACC inhibitor ND-646, synthesized a series of its derivatives and evaluated their activity against the enzyme ACC1 and the A549 cell. As results, most of the tested compounds showed potent ACC1 inhibitory activity with IC50 values 3-10 nM. Among them, compounds A2, A7 and A9 displayed strong cancer inhibitory activity with IC50 values 9-17 nM by impairing cell growth and inducing cell death. Preliminary SAR analysis clearly suggested that (R)-configuration and amide group were vital to ACC1 and A549 inhibition, since compound (S)-A1 (the enantiomer of ND-646) had poor activity of ACC1 inhibition and the carboxylic acid ND-630 almost lost anticancer effect on A549 cells. Collectively, these findings indicate that ACC1 is a potential biomarker and target for non-small-cell lung cancer, and ND-646 and its derivatives as ACC1 inhibitors deserve further study for treatment of NSCLC.
机译：乙酰-CoA羧化酶1（ACC1）是DE Novo脂肪酸合成（Fasyn）途径中的第一和速率限制酶。在本研究中，通过公共数据库分析和临床样本测试，我们首次核实ACC1 mRNA在非小细胞肺癌（NSCLC）中过表达，其伴随着CPG岛S岸的DNA甲基化伴随着ACC1 。我们的研究进一步证明，较高的ACC1水平与NSCLC患者的预后不良有关。此外，我们开发了一种用于制备已知的ACC抑制剂ND-646的新型合成途径，合成一系列衍生物并评估它们对酶ACC1和A549细胞的活性。结果，大多数测试化合物显示出效率的ACC1抑制活性，IC50值3-10nm。其中，通过损害细胞生长和诱导细胞死亡，化合物A2，A7和A9与IC50值9-17nm显示出强烈的癌症抑制活性。初步SAR分析清楚地表明，（R）联合和酰胺组对ACC1和A549抑制至关重要，因为化合物-A1（ND-646的对映体）的ACC1抑制活性差和羧酸ND-630几乎失去了对A549细胞的抗癌影响。总的来说，这些发现表明ACC1是潜在的生物标志物和非小细胞肺癌的靶标，ND-646及其衍生物作为ACC1抑制剂应该得到进一步研究NSCLC的研究。

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    Li En-Qin; Zhao Wei; Zhang Chenxi; Qin Lu-Zhe; Liu Sheng-Jie; Feng Zhi-Qi; Wen Xiaoan; Chen Cai-Ping;

  • 作者单位

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis 24 Tongjia Xiang Nanjing 210009;

    Chengdu Med Coll Sch Lab Med Dept Clin Biochem Chengdu 610050 Sichuan Peoples R China;

    Southeast Univ Med Sch Nanjing Chest Hosp Cent Lab Nanjing 210029 Jiangsu Peoples R China;

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis 24 Tongjia Xiang Nanjing 210009;

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis 24 Tongjia Xiang Nanjing 210009;

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis 24 Tongjia Xiang Nanjing 210009;

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis 24 Tongjia Xiang Nanjing 210009;

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis 24 Tongjia Xiang Nanjing 210009;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药学;
  • 关键词

    Acetyl-CoA carboxylase; De novo fatty acid synthesis; Lung cancer;

    机译：乙酰基 - 用羧化酶;再次脂肪酸合成;肺癌;

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