Zhang Qiumeng, Hu Zonglong, Shen Qianqian, Chen Yi, Lu Wei
School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Molecules. 2017 May 12;22(5):788. doi: 10.3390/molecules22050788.
Thieno[3,2-]pyrimidine as an effective pharmacophore has been extensively studied. However, its 2,6-substituted derivatives are rarely reported. In the present study, eighteen 2,6-substituted thieno[3,2-]pyrimidine derivatives containing electrophilic warheads were designed based on the first known Fibroblast growth factor receptor-4 (FGFR4) inhibitor Blu9931. Unexpectedly, all of the derivatives exhibited negligible activity against FGFR4. However, most of the target compounds exhibited antiproliferative activities against four human cancer cell lines, including A431, NCI-H1975, Ramos and SNU-16. Compound showed the most potent antiproliferative activities on the above four cell lines with IC values of 1.4 μM, 1.2 μM, 0.6 μM, and 2.6 μM, respectively. Additionally, the antiproliferative activity of against MDA-MB-221 proved that had the selectivity towards certain tumor cell lines. Furthermore, preliminary structure-activity relationship analysis was discussed based on the experimental data.
噻吩并[3,2 - ]嘧啶作为一种有效的药效基团已被广泛研究。然而，其2,6 - 取代衍生物鲜有报道。在本研究中，基于首个已知的成纤维细胞生长因子受体 - 4（FGFR4）抑制剂Blu9931，设计了18种含有亲电弹头的2,6 - 取代噻吩并[3,2 - ]嘧啶衍生物。出乎意料的是，所有衍生物对FGFR4均表现出可忽略不计的活性。然而，大多数目标化合物对四种人类癌细胞系，包括A431、NCI - H1975、Ramos和SNU - 16，表现出抗增殖活性。化合物 在上述四种细胞系上表现出最有效的抗增殖活性，IC值分别为1.4 μM、1.2 μM、0.6 μM和2.6 μM。此外， 对MDA - MB - 221的抗增殖活性证明 对某些肿瘤细胞系具有选择性。此外，基于实验数据讨论了初步的构效关系分析。
