二氢月桂酸脱氢酶
化学
拉吉细胞
二苯甲酮
IC50型
药理学
细胞周期
嘧啶代谢
细胞生长
嘧啶
尿苷
细胞周期检查点
生物化学
细胞凋亡
体外
酶
生物
基因
核糖核酸
光化学
嘌呤
作者
Chungen Li,Yue Zhou,Jing Xu,Xia Zhou,Song Liu,Zongkai Huang,Zhiqiang Qiu,Ting Zeng,Kun Gou,Lei Tao,Xi Zhong,Xiaowei Yang,Yang Zhou,Naichuan Su,Qiang Chen,Yinglan Zhao,Youfu Luo
标识
DOI:10.1016/j.ejmech.2022.114737
摘要
Blocking the de novo biosynthesis of pyrimidine by inhibiting human dihydroorotate dehydrogenase (hDHODH) is an effective way to suppress the proliferation of cancer cells and activated lymphocytes. Herein, eighteen teriflunomide derivatives and four ASLAN003 derivatives were designed and synthesized as novel hDHODH inhibitors based on a benzophenone scaffold. The optimal compound 7d showed a potent hDHODH inhibitory activity with an IC50 value of 10.9 nM, and displayed promising antiproliferative activities against multiple human cancer cells with IC50 values of 0.1-0.8 μM. Supplementation of exogenous uridine rescued the cell viability of 7d-treated Raji and HCT116 cells. Meanwhile, 7d significantly induced cell cycle S-phase arrest in Raji and HCT116 cells. Furthermore, 7d exhibited favorable safety profiles in mice and displayed effective antitumor activities with tumor growth inhibition (TGI) rates of 58.3% and 42.1% at an oral dosage of 30 mg/kg in Raji and HCT116 cells xenograft models, respectively. Taken together, these findings provide a promising hDHODH inhibitor 7d with potential activities against some tumors.
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