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Bifunctional Naphtho[2,3-d][1,2,3]triazole-4,9-dione Compounds Exhibit Antitumor Effects In Vitro and In Vivo by Inhibiting Dihydroorotate Dehydrogenase and Inducing Reactive Oxygen Species Production.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-04 , DOI: 10.1021/acs.jmedchem.0c00512 Zeping Zuo 1 , Xiaocong Liu 1 , Xinying Qian 1 , Ting Zeng 1 , Na Sang 1 , Huan Liu 1 , Yue Zhou 1 , Lei Tao 1 , Xia Zhou 1 , Na Su 2 , Yamei Yu 1 , Qiang Chen 1 , Youfu Luo 1 , Yinglan Zhao 1, 3
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-04 , DOI: 10.1021/acs.jmedchem.0c00512 Zeping Zuo 1 , Xiaocong Liu 1 , Xinying Qian 1 , Ting Zeng 1 , Na Sang 1 , Huan Liu 1 , Yue Zhou 1 , Lei Tao 1 , Xia Zhou 1 , Na Su 2 , Yamei Yu 1 , Qiang Chen 1 , Youfu Luo 1 , Yinglan Zhao 1, 3
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Human dihydroorotate dehydrogenase (hDHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound 3s with a naphtho[2,3-d][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against hDHODH. Further optimization led to compounds 11k and 11l, which inhibited hDHODH activity with IC50 values of 9 and 4.5 nM, respectively. Protein–ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of 11k and 11l with hDHODH. Compounds 11k and 11l significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound 11l displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound 11l with hDHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration.
中文翻译：
双功能萘[2,3-d] [1,2,3]三唑-4,9-二酮化合物通过抑制二氢乳清酸脱氢酶和诱导活性氧的产生，在体内和体外表现出抗肿瘤作用。
人二氢乳清酸酯脱氢酶（h DHODH）是癌症治疗的诱人靶标。基于其晶体结构，我们设计并合成了包含1，4-苯醌结构部分的聚焦化合物文库，该化合物具有活性氧（ROS）诱导能力。具有萘[2,3- d ] [1,2,3]三唑-4,9-二酮骨架的化合物3s表现出对h DHODH的抑制活性。进一步优化导致化合物11k和11l抑制h DHODH活性，IC 50值分别为9和4.5 nM。蛋白质-配体共晶体结构清楚地描述了氢键和疏水相互作用11K和11升与ħ DHODH。化合物11k和11l显着抑制白血病细胞和实体瘤细胞增殖并诱导ROS产生，线粒体功能障碍，细胞凋亡和细胞周期停滞。化合物11l的纳米结晶在Raji异种移植模型中显示出显着的体内抗肿瘤作用。总的来说，该研究提供了具有h DHODH抑制和ROS诱导功效的新型双功能化合物11l，其代表了有希望的抗癌药物，值得进一步探索。
更新日期：2020-07-23
中文翻译：
双功能萘[2,3-d] [1,2,3]三唑-4,9-二酮化合物通过抑制二氢乳清酸脱氢酶和诱导活性氧的产生，在体内和体外表现出抗肿瘤作用。
人二氢乳清酸酯脱氢酶（h DHODH）是癌症治疗的诱人靶标。基于其晶体结构，我们设计并合成了包含1，4-苯醌结构部分的聚焦化合物文库，该化合物具有活性氧（ROS）诱导能力。具有萘[2,3- d ] [1,2,3]三唑-4,9-二酮骨架的化合物3s表现出对h DHODH的抑制活性。进一步优化导致化合物11k和11l抑制h DHODH活性，IC 50值分别为9和4.5 nM。蛋白质-配体共晶体结构清楚地描述了氢键和疏水相互作用11K和11升与ħ DHODH。化合物11k和11l显着抑制白血病细胞和实体瘤细胞增殖并诱导ROS产生，线粒体功能障碍，细胞凋亡和细胞周期停滞。化合物11l的纳米结晶在Raji异种移植模型中显示出显着的体内抗肿瘤作用。总的来说，该研究提供了具有h DHODH抑制和ROS诱导功效的新型双功能化合物11l，其代表了有希望的抗癌药物，值得进一步探索。
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