Design, synthesis, biological evaluation and docking studies of novel 2-substituted-4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d] pyrimidine derivatives as dual PI3Kα/mTOR inhibitors
Design, synthesis, biological evaluation and docking studies of novel 2-substituted-4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d] pyrimidine derivatives as dual PI3Kα/mTOR inhibitors
复制标题
作为双重 PI3K α/mTOR 抑制剂的新型 2-取代-4-吗啉代-7,8-二氢-5H-噻喃并[4,3-d]嘧啶衍生物的设计、合成、生物学评价和对接研究
DOI：
10.1016/j.ejmech.2016.03.033
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发表时间：
2016-06-30
影响因子：
6.7
通讯作者：
Zhu, Wufu
中科院分区：
文献类型：
--
作者：
Lei, Fei;Sun, Chengyu;Zhu, Wufu
设计、合成了4个系列的2-取代-4-吗啉代-7，8-二氢-5H-噻喃并[4，3-d]嘧啶衍生物（9-28），其结构经H-1 NMR、C-13 NMR和MS确证。评价所有化合物对三种癌细胞系（A549、PC-3和MCF-7）的IC 50值。进一步评价了四种选定化合物（10、11、24、27）对PI 3 K α和mTOR激酶的IC 50值。其中7个目标化合物对这3种癌细胞系表现出中等至优异的抗肿瘤活性。化合物11对A549、PC-3和MCF-7细胞系显示出良好的抗肿瘤活性，其IC 50值分别为0.52 ± 0.10 μ M、1.41 ± 0.10 μ M，4.82 +/- 0.24 μ M，对PI 3 K α/mTOR具有中等抗肿瘤活性，IC 50值为6.72 +/- 0.30 μ M和0.94 +/- 0.10 μ M。构效关系（SAR）和对接研究表明，芳基脲类支架对化合物的抗肿瘤活性有显著影响，其中芳基吡啶脲类支架的抗肿瘤活性最好。芳基取代基的变化对活性有显著影响，并且3-Cl-4-F或3-CF 3 -4-Cl取代更优选。(C)2016 Elsevier Masson SAS。All rights reserved.
Four series of 2-substituted-4-morpholino- 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives (9-28) were designed, synthesized and their structures were confirmed by H-1 NMR, C-13 NMR and MS spectrum. All compounds were evaluated for the IC50 values against three cancer cell lines (A549, PC-3 and MCF-7). And four selected compounds (10, 11, 24, 27) were further evaluated for the IC50 values against PI3K alpha and mTOR kinases. Seven of the target compounds exhibited moderate to excellent antitumor activities against these three cancer cell lines. The most promising compound 11 showed good antitumor potency for A549, PC-3 and MCF-7 cell lines with IC50 values of 0.52 +/- 0.10 mu M,1.41 +/- 0.10 mu M, 4.82 +/- 0.24 mu M and moderate antitumor activities against PI3K alpha/mTOR with IC50 values of 6.72 +/- 0.30 mu M and 0.94 +/- 0.10 mu M. Structure-activity relationships (SARs) and docking studies indicated that aryl urea scaffolds had a significant impact on the antitumor activities, and aryl pyridine urea scaffolds produced the best potency. Variations in substitutions of the aryl group had a significant impact on the activity and 3-Cl-4-F or 3-CF3-4-Cl substitution was more preferred. (C) 2016 Elsevier Masson SAS. All rights reserved.