化学
共晶
活性氧
二氢月桂酸脱氢酶
体内
化疗增敏剂
立体化学
体外
生物化学
酶
氢键
细胞毒性
分子
有机化学
生物
生物技术
作者
Zeping Zuo,Xiaocong Liu,Xinying Qian,Ting Zeng,Na Sang,Huan Liu,Yue Zhou,Lei Tao,Xia Zhou,Naichuan Su,Yamei Yu,Qiang Chen,Youfu Luo,Yinglan Zhao
标识
DOI:10.1021/acs.jmedchem.0c00512
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI