N-2-(Phenylamino) Benzamide Derivatives as Dual Inhibitors of COX-2 and Topo I Deter Gastrointestinal Cancers via Targeting Inflammation and Tumor Progression,Journal of Medicinal Chemistry

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N-2-(Phenylamino) Benzamide Derivatives as Dual Inhibitors of COX-2 and Topo I Deter Gastrointestinal Cancers via Targeting Inflammation and Tumor Progression
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-07-22 , DOI: 10.1021/acs.jmedchem.2c00635
Junfang Li _{1,

2} , Xiaoling Hu _{1,

2} , Honghua Zhang _{1,

2} , Yan Peng ₃ , Shuang Li ₃ , Yongxia Xiong ₃ , Weifan Jiang ₃ , Zhen Wang _{1,

2,

3}

Affiliation

Given the close association between inflammation and cancer, combining anti-inflammation therapy is prominent to improve the anticancer effect. Based on I-1, a series of agents targeting COX-2 and Topo I were designed by combining fenamates and phenols. The optimal compound 1H-30 displayed an enhanced inhibitory effect on COX-2 compared to tolfenamic acid and I-1 and showed better inhibition of Topo I than I-1. Importantly, 1H-30 showed potential anticancer effects and suppressed the activation of the NF-κB pathway in cancer cells. 1H-30 inhibited the nuclear translocation of NF-κB and suppressed the production of NO, COX-2, and IL-1β in RAW264.7. In vivo, 1H-30 showed acceptable pharmacokinetic parameters, decreased the tumor growth without affecting the body weight, down-regulated COX-2 and MMP-9, and induced apoptosis in the CT26.WT tumor-bearing mice. Accordingly, 1H-30 as a potential Topo I/COX-2 inhibitor which possessed anti-inflammatory and anticancer effects, with inhibition of the NF-κB pathway, is promising for gastrointestinal cancer therapy.

中文翻译：

N-2-（苯氨基）苯甲酰胺衍生物作为 COX-2 和 Topo I 的双重抑制剂通过靶向炎症和肿瘤进展来阻止胃肠道癌症

鉴于炎症与癌症之间的密切联系，结合抗炎治疗对于提高抗癌效果是突出的。在I-1的基础上，结合fenamates和酚类设计了一系列靶向COX-2和Topo I的药物。与托芬那酸和I-1相比，最佳化合物1H-30对COX-2的抑制作用增强，对Topo I的抑制作用优于I-1。重要的是，1H-30显示出潜在的抗癌作用并抑制癌细胞中 NF-κB 通路的激活。1H-30抑制 NF-κB 的核转位并抑制 RAW264.7 中 NO、COX-2 和 IL-1β 的产生。体内，1H-30显示可接受的药代动力学参数，在不影响体重的情况下降低肿瘤生长，下调 COX-2 和 MMP-9，并在 CT26.WT 荷瘤小鼠中诱导细胞凋亡。因此，1H-30作为一种潜在的 Topo I/COX-2 抑制剂，具有抗炎和抗癌作用，可抑制 NF-κB 通路，有望用于胃肠道癌症治疗。

更新日期：2022-07-22

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