Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing, Jiangsu Province 211189, China.
J Med Chem. 2021 Feb 11;64(3):1701-1712. doi: 10.1021/acs.jmedchem.0c02048. Epub 2021 Feb 2.
Glutathione transferase (GST P1-1) is a potential target for anticancer drugs. In this work, a series of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) derivatives as GST P1-1 inhibitors were designed, synthesized, and evaluated for their biological activity. Among the target compounds, showed more selective inhibition toward GST P1-1 and GST M2-2, better water solubility, and more potent anticancer activities toward all the tested cancer cells (except for HOS) than its parent molecule. Detailed biological studies on the effect of toward 143b cells revealed that could arrest the cell cycle at the G2 phase and induced cell apoptosis in a dose-dependent manner. Like NBDHEX, displayed good pharmacokinetic characteristics. An study on 143b xenograft models demonstrated that could significantly reduce tumor growth in a dose-dependent manner, showing stronger antitumor activity than NBDHEX. Thus, deserves to be further investigated as a potential antitumor agent for cancer therapy.
谷胱甘肽转移酶（GST P1-1）是一种潜在的抗癌药物靶标。在这项工作中，设计、合成了一系列 6-（7-硝基-2,1,3-苯并恶二唑-4-基硫代）己醇（NBDHEX）衍生物作为 GST P1-1 抑制剂，并评估了它们的生物活性。在目标化合物中，化合物 对 GST P1-1 和 GST M2-2 的抑制作用更具选择性，水溶解度更好，对所有测试的癌细胞（除 HOS 外）的抗癌活性比其母体分子更强。对 化合物 对 143b 细胞的作用的详细生物学研究表明，化合物 能够以剂量依赖的方式将细胞周期阻滞在 G2 期，并诱导细胞凋亡。与 NBDHEX 一样，化合物 表现出良好的药代动力学特征。在 143b 异种移植模型上的 研究表明，化合物 能够以剂量依赖的方式显著抑制肿瘤生长，显示出比 NBDHEX 更强的抗肿瘤活性。因此，化合物 值得进一步研究作为癌症治疗的潜在抗肿瘤药物。
