Wang Xuebao, Chen Di, Yu Shufang, Zhang Zaikui, Wang Yu, Qi Xiaolu, Fu Weitao, Xie Zixin, Ye Faqing
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
Yichang Humanwell Pharmaceutical Co., Ltd, Yichang, 443005, China.
Chem Biol Drug Des. 2016 Apr;87(4):499-507. doi: 10.1111/cbdd.12687. Epub 2016 Feb 1.
A series of tetrahydrobenzothieno[2,3-d]pyrimidine derivatives were designed, synthesized, and evaluated as inhibitors of FGFR1. These analogs were synthesized via Gewald's reaction under mild conditions. The structures of the synthesized compounds were characterized by spectroscopic data (IR, (1) H NMR and MS). Their antitumor activities were evaluated against H460, A549 and U251 cell lines in vitro. Results revealed that the tested compounds showed moderate antitumor activities. Structure-activity relationship analyses indicated that compounds with an aromatic ring substituted in the C-2 position or with larger molecules such as 3g, 4c, and 7 were more effective than others. The compound, 3g (78.8% FGFR1 inhibition at 10 μm), was identified to have the most potent antitumor activities, with IC50 values of 7.7, 18.9, and 13.3 μm against the H460, A549, and U251 cell lines, respectively. Together, the results suggested that tetrahydrobenzothieno[2,3-d]pyrimidine derivatives may serve as a potential agent for the treatment of FGFR1-mediated cancers.
设计、合成了一系列四氢苯并噻吩并[2,3-d]嘧啶衍生物，并将其作为成纤维细胞生长因子受体1（FGFR1）抑制剂进行评估。这些类似物通过格瓦尔德反应在温和条件下合成。通过光谱数据（红外光谱、核磁共振氢谱和质谱）对合成化合物的结构进行了表征。在体外评估了它们对H460、A549和U251细胞系的抗肿瘤活性。结果表明，所测试的化合物显示出中等程度的抗肿瘤活性。构效关系分析表明，在C-2位有芳环取代的化合物或如3g、4c和7等较大分子的化合物比其他化合物更有效。化合物3g（在10μm时对FGFR1的抑制率为78.8%）被确定具有最有效的抗肿瘤活性，对H460、A549和U251细胞系的半数抑制浓度（IC50）值分别为7.7、18.9和13.3μm。总之，结果表明四氢苯并噻吩并[2,3-d]嘧啶衍生物可能作为治疗FGFR1介导的癌症的潜在药物。
