European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2022-06-23 , DOI: 10.1016/j.ejmech.2022.114560 Xiaoling Hu 1 , Junfang Li 1 , Honghua Zhang 1 , Quanwei Yu 2 , Yuying Wang 3 , Xuelin Li 4 , Lin Long 4 , Weifan Jiang 4 , Zhen Wang 5
Novel tolfenamic acid derivatives based on the structure of I-1 were designed and synthesized to improve its poor target inhibition and solubility. Among them, W10 was identified as a potent dual-target inhibitor of Topo I (IC50 = 0.90 ± 0.17 μM) and COX-2 (IC50 = 2.31 ± 0.07 μM) with improved water solubility (32.33 μg/mL). Moreover, W10 also exhibited fairly potent anti-proliferative and pro-apoptosis activity via the mitochondrial pathway, as well as suppressed aberrant NF-κB/IκB activation in colon cancer cells in vitro. Additionally, W10 possessed favorable pharmacokinetic properties and excellent antitumor effects in vivo. In general, our study has demonstrated the potency of a novel Topo I/COX-2 dual inhibitor, which can potentially be developed into a chemotherapeutic candidate for colon cancer.
中文翻译:
发现用于结肠癌治疗的拓扑异构酶 I 和环氧合酶 2 双重抑制剂
设计并合成了基于I-1结构的新型托芬那酸衍生物,以改善其较差的靶向抑制和溶解性。其中,W10被鉴定为 Topo I (IC 50 = 0.90 ± 0.17 μM) 和 COX-2 (IC 50 = 2.31 ± 0.07 μM)的有效双靶点抑制剂, 具有改善的水溶性 (32.33 μg/mL)。此外,W10还通过线粒体途径表现出相当有效的抗增殖和促凋亡活性,并在体外抑制结肠癌细胞中的异常 NF-κB/IκB 活化。此外,W10在体内具有良好的药代动力学特性和优异的抗肿瘤作用。总的来说,我们的研究已经证明了一种新型 Topo I/COX-2 双重抑制剂的效力,它有可能被开发为结肠癌的化疗候选药物。