Ye Faqing, Wang Yuewu, Nian Siyun, Wang Yu, Chen Di, Yu Shufang, Wang Sicen
a School of Pharmacy, Health Science Center Xi'an Jiaotong University , Xi'an , China and.
b School of Pharmaceutical Sciences, Wenzhou Medical University , Wenzhou , China.
J Enzyme Inhib Med Chem. 2015 Dec;30(6):961-6. doi: 10.3109/14756366.2014.1002401. Epub 2015 Feb 16.
A series of 5,7-dimethyl-oxazolo[5,4-d]pyrimidine-4,6(5H,7H)-dione derivatives, N5a-5l, was designed, synthesized and evaluated for their FGFR1-inhibition ability as well as cytotoxicity against three cancer cell lines (H460, B16F10 and A549) in vitro. Several compounds displayed good-to-excellent potency against these cancer cell lines compared to SU5402. Structure-activity relationship analyses indicated that compounds with a rigid structure and more heteroatoms at the side chain of the parent ring were more effective than those without these substitutions. The compound N5g (37.4% FGFR1 inhibition at 1.0 μM) was identified to have the most potent antitumor activities, with IC50 values of 5.472, 4.260 and 5.837 μM against H460, B16F10 and A549 cell lines, respectively. Together, our results suggest that 5,7-dimethyl-oxazolo[5,4-d]pyrimidine-4,6(5H,7H)-dione derivatives may serve as potential agents for the treatment of FGFR1-mediated cancers.
设计、合成了一系列5,7-二甲基-恶唑并[5,4-d]嘧啶-4,6(5H,7H)-二酮衍生物N5a - 5l，并对其体外抑制FGFR1的能力以及对三种癌细胞系（H460、B16F10和A549）的细胞毒性进行了评估。与SU5402相比，几种化合物对这些癌细胞系显示出良好至优异的效力。构效关系分析表明，具有刚性结构且在母环侧链上有更多杂原子的化合物比没有这些取代基的化合物更有效。化合物N5g（在1.0 μM时对FGFR1的抑制率为37.4%）被确定具有最强的抗肿瘤活性，对H460、B16F10和A549细胞系的IC50值分别为5.472、4.260和5.837 μM。总之，我们的结果表明5,7-二甲基-恶唑并[5,4-d]嘧啶-4,6(5H,7H)-二酮衍生物可能作为治疗FGFR1介导的癌症的潜在药物。
