State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China; School of Pharmacy, Lanzhou University, Lanzhou, Gansu 730000, China; College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China; College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
Eur J Med Chem. 2017 Nov 10;140:435-447. doi: 10.1016/j.ejmech.2017.09.027. Epub 2017 Sep 19.
Mammalian thioredoxin reductase (TrxR) enzymes play a crucial role in regulating multiple redox-based signaling pathways and have attracted increasing attention as promising anticancer drug targets. We report here the synthesis of a panel of naphthazarin derivatives and discovery of 2-methyl-5,8-dihydroxy-1,4-naphthoquinone (3, 2-methylnaphthazarin) as a potent cytotoxic agent with a submicromolar half maximal inhibitory concentration to the human promyelocytic leukemia HL-60 cells. Mechanism studies reveal that the compound selectively inhibits TrxR to induce oxidative stress-mediated apoptosis of HL-60 cells. Knockdown of TrxR sensitizes the cells to 3 insults, while overexpression of the functional enzyme confers resistance to the compound treatment, underpinning the physiological significance of targeting TrxR by 3. Clarification of the interaction of compound 3 with TrxR unveils a mechanism underlying the cellular action of the compound, and sheds light in considering development of the compound as a potential cancer chemotherapeutic agent.
哺乳动物硫氧还蛋白还原酶（TrxR）在调节多种基于氧化还原的信号通路中起着至关重要的作用，作为有前途的抗癌药物靶点引起了越来越多的关注。我们在此报告了一组萘并恶嗪衍生物的合成，并发现 2-甲基-5,8-二羟基-1,4-萘醌（3，2-甲基萘并恶嗪）是一种有效的细胞毒性剂，对人早幼粒细胞白血病 HL-60 细胞的半数最大抑制浓度为亚微摩尔级。机制研究表明，该化合物选择性抑制 TrxR 以诱导 HL-60 细胞氧化应激介导的细胞凋亡。TrxR 的敲低使细胞对 3 种损伤敏感，而功能性酶的过表达赋予细胞对该化合物处理的抗性，为 3 靶向 TrxR 的生理意义提供了依据。阐明化合物 3 与 TrxR 的相互作用揭示了该化合物的细胞作用机制，并为考虑将该化合物开发为潜在的癌症化疗药物提供了思路。
