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Development of fluorizoline analogues as prohibitin ligands that modulate C-RAF signaling, p21 expression and melanogenesis
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2022-08-04 , DOI: 10.1016/j.ejmech.2022.114635
Nora Chouha 1 , Hussein Abou-Hamdan 2 , Hajime Yurugi 3 , Riku Yoshii 4 , Hiromi Ii 4 , Ahmad Najem 5 , Ghanem E Ghanem 5 , Susumu Nakata 4 , Krishnaraj Rajalingam 3 , Yu Peng 6 , Dong Wang 7 , Canan G Nebigil 2 , Laurent Désaubry 8
Affiliation  

Fluorizoline is a cytotoxic trifluorothiazoline that targets the scaffold proteins prohibitins-1 and -2 (PHB1/2) to inhibit the kinase C-RAF and promote the expression of the cyclin-dependent kinase inhibitor p21 to induce cancer cell death. In melanocytes, fluorizoline also induces the synthesis of melanin. Herein we report the first structural requirement of fluorizoline analogues for these activities. We identified in particular some compounds that display enhanced anti-C-RAF and anti-MEK activities, and a higher cytotoxicity in HeLa cells compared to fluorizoline. These results provide a foundation for further optimization of PHB ligands for the treatment of cancers. We also discovered an analogue of fluorizoline that displays pharmacological effects opposed to those of fluorizoline and that can be used as a chemical tool to explore PHB signaling in cancers and other diseases.



中文翻译:

开发氟唑啉类似物作为调节 C-RAF 信号、p21 表达和黑素生成的抑制素配体

Fluorizo​​line 是一种具有细胞毒性的三氟噻唑啉,靶向支架蛋白禁止素-1 和 -2 (PHB1/2) 以抑制激酶 C-RAF 并促进细胞周期蛋白依赖性激酶抑制剂 p21 的表达以诱导癌细胞死亡。在黑色素细胞中,氟唑啉还诱导黑色素的合成。在这里,我们报告了氟唑啉类似物对这些活动的第一个结构要求。我们特别鉴定了一些显示增强的-C-RAF 和-MEK 活性,与氟唑啉相比,在 HeLa 细胞中的细胞毒性更高。这些结果为进一步优化PHB配体治疗癌症提供了基础。我们还发现了一种氟唑啉类似物,它显示出与氟唑啉相反的药理作用,可用作探索癌症和其他疾病中 PHB 信号传导的化学工具。

更新日期:2022-08-04
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