Discovery of 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol Derivatives as Glutathione Transferase Inhibitors with Favorable Selectivity and Tolerated Toxicity,Journal of Medicinal Chemistry

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Discovery of 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol Derivatives as Glutathione Transferase Inhibitors with Favorable Selectivity and Tolerated Toxicity
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-02-02 , DOI: 10.1021/acs.jmedchem.0c02048
Qingqing Liu ₁ , Zhikun Liu ₁ , Wuyang Hua ₁ , Shaohua Gou _{1,

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Affiliation

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, 4n 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 4n toward 143b cells revealed that 4n could arrest the cell cycle at the G2 phase and induced cell apoptosis in a dose-dependent manner. Like NBDHEX, 4n displayed good pharmacokinetic characteristics. An in vivo study on 143b xenograft models demonstrated that 4n could significantly reduce tumor growth in a dose-dependent manner, showing stronger antitumor activity than NBDHEX. Thus, 4n deserves to be further investigated as a potential antitumor agent for cancer therapy.

中文翻译：

发现6-（7-硝基-2,1,3-苯并恶二唑-4-基硫基）己醇衍生物作为谷胱甘肽转移酶抑制剂具有良好的选择性和耐受性

谷胱甘肽转移酶（GST P1-1）是抗癌药物的潜在靶标。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-基硫基）己醇（NBDHEX）衍生物作为GST P1-1抑制剂，并对其生物学活性进行了评估。在目标化合物中，4n对其母体分子表现出对GST P1-1和GST M2-2的更多选择性抑制，更好的水溶性和对所有测试癌细胞（除了HOS）更有效的抗癌活性。关于4n对143b细胞的作用的详细生物学研究表明，4n可以将细胞周期阻滞在G2期，并以剂量依赖的方式诱导细胞凋亡。像NBDHEX，4n显示出良好的药代动力学特征。的体内上143B异种移植模型的研究表明，4N可以显著降低肿瘤生长以剂量依赖的方式，显示出比NBDHEX更强的抗肿瘤活性。因此，4n作为一种潜在的抗癌药物值得进一步研究。

更新日期：2021-02-11

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