Design, synthesis and activity of novel sorafenib analogues bearing chalcone unit
Design, synthesis and activity of novel sorafenib analogues bearing chalcone unit
复制标题
含查耳酮单元的新型索拉非尼类似物的设计、合成及活性
DOI：
10.1016/j.bmcl.2016.10.029
复制
发表时间：
2016-11-15
影响因子：
2.7
通讯作者：
Zhu, Wufu
中科院分区：
文献类型：
--
作者：
Wang, Min;Xu, Shan;Zhu, Wufu
合成了两个系列的索拉非尼衍生物（N-甲基吡啶酰胺-4-氧基）查尔酮（5a-o，7a-e），并通过NMR和MS进行了表征。评估了所有目标化合物针对 A549、HepG2、MCF-7 和 PC-3 癌细胞系的细胞毒性，并进一步评估了一些选定化合物针对 VEGFR-2/KDR 和 BRAF 激酶的活性。结果表明，所有化合物均显示出中等至良好的抗肿瘤活性，其中化合物5c对HepG2、MCF-7和PC-3细胞系显示出良好的细胞毒活性，IC50值为0.56±0.83μM、3.88±1.03μM和3.15±0.81μM，比索拉非尼活性高1.03～6.14倍。分别为(3.44+/-1.50μM、3.18+/-1.43μM、3.24+/-0.45μM)。化合物5b对VEGFR-2/KDR激酶表现出良好的活性，其IC50值为0.72μM。构效关系（SAR）和对接研究表明，查尔酮酮取代索拉非尼的脲基团可提高细胞毒活性，结果表明卤素[3-Br,4-F]和甲氧基（C-3,4,5或C-2,3,4位取代）取代有利于活动。 (C) 2016 Elsevier Ltd. 保留所有权利。
Two series of sorafenib derivatives (N-methylpicolinamide-4-oxy) chalcones (5a-o, 7a-e) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR and BRAF kinases. The results indicated that all the compounds showed moderate to good antitumor activity, and the compound 5c showed well cytotoxic activity against HepG2, MCF-7 and PC-3 cell lines with IC50 values of 0.56 +/- 0.83 mu M, 3.88 +/- 1.03 mu M and 3.15 +/- 0.81 mu M, which were 1.03-6.14-fold more active than sorafenib (3.44 +/- 1.50 mu M, 3.18 +/- 1.43 mu M, 3.24 +/- 0.45 mu M), respectively. The compound 5b showed good activity on VEGFR-2/KDR kinase, and its IC50 value was 0.72 mu M. Structure-activity relationships (SARs) and docking studies indicated that replacement of urea group of sorafenib by chalcone ketones improved the cytotoxic activity, and the results suggested that halogen [3-Br, 4-F] and methoxy (substituted on C-3,4,5 or C-2,3,4 position) substitution was benefit for the activity. (C) 2016 Elsevier Ltd. All rights reserved.