Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, 52727, Republic of Korea.
KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea; Center for Neuroscience and Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
Eur J Med Chem. 2018 May 10;151:186-198. doi: 10.1016/j.ejmech.2018.03.055. Epub 2018 Mar 23.
Repositioning of the antipsychotic drug trifluoperazine for treatment of glioblastoma, an aggressive brain tumor, has been previously suggested. However, trifluoperazine did not increase the survival time in mice models of glioblastoma. In attempt to identify an effective trifluoperazine analog, fourteen compounds have been synthesized and biologically in vitro and in vivo assessed. Using MTT assay, compounds 3dc and 3dd elicited 4-5 times more potent inhibitory activity than trifluoperazine with IC = 2.3 and 2.2 μM against U87MG glioblastoma cells, as well as, IC = 2.2 and 2.1 μM against GBL28 human glioblastoma patient derived primary cells, respectively. Furthermore, they have shown a reasonable selectivity for glioblastoma cells over NSC normal neural cell. In vivo evaluation of analog 3dc confirmed its advantageous effect on reduction of tumor size and increasing the survival time in brain xenograft mouse model of glioblastoma. Molecular modeling simulation provided a reasonable explanation for the observed variation in the capability of the synthesized analogs to increase the intracellular Ca levels. In summary, this study presents compound 3dc as a proposed new tool for the adjuvant chemotherapy of glioblastoma.
先前有研究建议将抗精神病药物三氟拉嗪重新定位用于治疗胶质母细胞瘤，这是一种侵袭性脑肿瘤。然而，三氟拉嗪并未延长胶质母细胞瘤小鼠模型的生存时间。为了寻找有效的三氟拉嗪类似物，我们已经合成了 14 种化合物，并在体外和体内进行了生物学评估。通过 MTT 测定，化合物 3dc 和 3dd 对 U87MG 胶质母细胞瘤细胞的抑制活性比三氟拉嗪分别高出 4-5 倍，IC50 值分别为 2.3 和 2.2 μM，对 GBL28 人胶质母细胞瘤患者来源的原代细胞的抑制活性分别为 2.2 和 2.1 μM。此外，它们对神经干细胞（NSC）正常神经细胞的选择性也较高。体内实验评估表明，3dc 类似物可有效减小肿瘤体积并延长脑异种移植胶质母细胞瘤小鼠模型的生存时间。分子模拟模拟为观察到的合成类似物增加细胞内 Ca 水平的能力的差异提供了合理的解释。总之，本研究提出化合物 3dc 可作为胶质母细胞瘤辅助化疗的新工具。
