莫那可尔N-1芳基化对胶质瘤细胞系中驱动蛋白Eg5抑制作用的影响。
Effect of N-1 arylation of monastrol on kinesin Eg5 inhibition in glioma cell lines.
作者信息
Gonçalves Itamar Luís, Rockenbach Liliana, das Neves Gustavo Machado, Göethel Gabriela, Nascimento Fabiana, Porto Kagami Luciano, Figueiró Fabrício, Oliveira de Azambuja Gabriel, de Fraga Dias Amanda, Amaro Andressa, de Souza Lauro Mera, da Rocha Pitta Ivan, Avila Daiana Silva, Kawano Daniel Fábio, Garcia Solange Cristina, Battastini Ana Maria Oliveira, Eifler-Lima Vera Lucia
机构信息
Laboratório de Síntese Orgânica Medicinal/LaSOM , Faculdade de Farmácia , Universidade Federal do Rio Grande do Sul , Avenida Ipiranga , 2752 , Porto Alegre/RS , Brazil . Email:
Laboratório de Toxicologia - LATOX , Faculdade de Farmácia , Universidade Federal do Rio Grande do Sul , Porto Alegre/RS , Brazil.
出版信息
Medchemcomm. 2018 Apr 17;9(6):995-1010. doi: 10.1039/c8md00095f. eCollection 2018 Jun 1.
An original and focused library of two sets of dihydropyrimidin-2-thiones (DHPMs) substituted with N-1 aryl groups derived from monastrol was designed and synthesized in order to discover a more effective Eg5 ligand than the template. Based on molecular docking studies, four ligands were selected to perform pharmacological investigations against two glioma cell lines. The results led to the discovery of two original compounds, called and , with an anti-proliferative effects, achieving IC values of about half that of the IC of monastrol in both cell lines. As with monastrol, flow cytometry analyses showed that the and compounds induced cell cycle arrest in the G/M phase, and immunocytochemistry essays revealed the formation of monopolar spindles due to Eg5 inhibition without any toxicity to .
设计并合成了一个原创且聚焦的两组二氢嘧啶-2-硫酮（DHPMs）文库，其被源自莫那可林的N-1芳基取代，目的是发现一种比模板更有效的Eg5配体。基于分子对接研究，选择了四种配体对两种胶质瘤细胞系进行药理学研究。结果发现了两种原创化合物，分别称为 和 ，它们具有抗增殖作用，在两种细胞系中的IC值约为莫那可林IC值的一半。与莫那可林一样，流式细胞术分析表明 和 化合物诱导细胞周期停滞在G/M期，免疫细胞化学分析显示由于Eg5抑制形成了单极纺锤体，且对 无任何毒性。
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