Discovery of Nonquinone Substrates for NAD(P)H: Quinone Oxidoreductase 1 (NQO1) as Effective Intracellular ROS Generators for the Treatment of Drug-Resistant Non-Small-Cell Lung Cancer,Journal of Medicinal Chemistry

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Discovery of Nonquinone Substrates for NAD(P)H: Quinone Oxidoreductase 1 (NQO1) as Effective Intracellular ROS Generators for the Treatment of Drug-Resistant Non-Small-Cell Lung Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-12-03 00:00:00 , DOI: 10.1021/acs.jmedchem.8b01424
Xingsen Wu _{1,

2} , Xiang Li _{1,

3} , Zhihong Li _{1,

2} , Yancheng Yu _{1,

2} , Qidong You ₁ , Xiaojin Zhang _{1,

2}

Affiliation

The elevation of oxidative stress preferentially in cancer cells by efficient NQO1 substrates, which promote ROS generation through redox cycling, has emerged as an effective strategy for cancer therapy, even for treating drug-resistant cancers. Here, we described the identification and structural optimization studies of the hit compound 1, a new chemotype of nonquinone substrate for NQO1 as an efficient ROS generator. Further structure–activity relationship studies resulted in the most active compound 20k, a tricyclic 2,3-dicyano indenopyrazinone, which selectively inhibited the proliferation of NQO1-overexpressing A549 and A549/Taxol cancer cells. Furthermore, 20k dramatically elevated the intracellular ROS levels through NQO1-catalyzed redox cycling and induced PARP-1-mediated cell apoptosis in A549/Taxol cells. In addition, 20k significantly suppressed the growth of A549/Taxol xenograft tumors in mice with no apparent toxicity observed in vivo. Together, 20k acts as an efficient NQO1 substrate and may be a new option for the treatment of NQO1-overexpresssing drug-resistant NSCLC.

中文翻译：

NAD（P）H的非醌底物的发现：醌氧化还原酶1（NQO1）作为有效的细胞内ROS产生剂，用于治疗抗药性非小细胞肺癌

有效的NQO1底物优先提高癌细胞的氧化应激水平，这种底物通过氧化还原循环促进ROS的产生，已成为癌症治疗，甚至用于治疗耐药性癌症的有效策略。在这里，我们描述了命中化合物1的鉴定和结构优化研究，命中化合物1是NQO1作为有效ROS产生剂的一种新的非醌底物化学型。进一步的结构-活性关系研究产生了活性最高的化合物20k，即三环2,3-二氰基茚并吡嗪酮，该化合物选择性抑制过表达NQO1的A549和A549 / Taxol癌细胞的增殖。再说20k通过NQO1催化的氧化还原循环显着提高了细胞内ROS水平，并诱导了A549 / Taxol细胞中PARP-1介导的细胞凋亡。此外，20k显着抑制小鼠中A549 / Taxol异种移植肿瘤的生长，而在体内未观察到明显的毒性。总之，20k可作为有效的NQO1底物，可能是治疗过表达NQO1的耐药NSCLC的新选择。

更新日期：2018-12-03

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