Design, synthesis, anticancer activity and docking studies of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d] pyrimidine derivatives as mTOR inhibitors
Design, synthesis, anticancer activity and docking studies of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d] pyrimidine derivatives as mTOR inhibitors
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新型4-吗啉代-7,8-二氢-5H-噻喃并[4,3-d]嘧啶衍生物作为mTOR抑制剂的设计、合成、抗癌活性和对接研究
DOI：
10.1016/j.bmc.2014.11.003
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发表时间：
2014-12-15
影响因子：
3.5
通讯作者：
Zheng, Pengwu
中科院分区：
文献类型：
--
作者：
Zhu, Wufu;Sun, Chengyu;Zheng, Pengwu
设计、合成了一系列7，8-二氢-5H-噻喃并[4，3-d]嘧啶衍生物（7a-q，10a-q），其结构经H-1 NMR，C-13 NMR，MS和HRMS确证。评价所有化合物在10 μ M水平下对mTOR激酶的抑制活性。进一步评价了5种选定化合物（7 b、7 e、7 h、10 b和10 e）在10 μ M水平下对PI 3 K α的抑制活性，以及对mTOR激酶和两种癌细胞系的IC 50值。12个目标化合物显示出中等的抗肿瘤活性。最有希望的化合物7 e显示出对mTOR激酶、H460和PC-3细胞系的强抗肿瘤活性，其IC 50值为0.80 +/- 0.15 μ M、7.43 +/- 1.45 μ M和11.90 +/- 0.94 μ M，其活性分别比BMCL-200908069-1（1.37 +/- 0.07 μ M，9.52 +/- 0.29 μ M，16.27 +/- 0.54 μ M）高1.28至1.71倍。构效关系（SAR）和对接研究表明，噻喃并[4，3-d]嘧啶骨架对目标化合物的抗肿瘤活性影响不大。4位芳基的取代对化合物的抗肿瘤活性有显著影响，其中4-OH取代效果最好。(C)2014爱思唯尔有限公司版权所有。
A series of 7,8-dihydro-5H-thiopyrano[4,3-d] pyrimidine derivatives (7a-q, 10a-q) were designed, synthesized and their chemical structures were confirmed by H-1 NMR, C-13 NMR, MS and HRMS spectrum. All the compounds were evaluated for the inhibitory activity against mTOR kinase at 10 mu M level. Five selected compounds (7b, 7e, 7h, 10b and 10e) were further evaluated for the inhibitory activity against PI3K alpha at 10 mu M level, and the IC50 values against mTOR kinase and two cancer cell lines. Twelve of the target compounds exhibited moderate antitumor activities. The most promising compound 7e showed strong antitumor activities against mTOR kinase, H460 and PC-3 cell lines with IC50 values of 0.80 +/- 0.15 mu M, 7.43 +/- 1.45 mu M and 11.90 +/- 0.94 mu M, which were 1.28 to 1.71-fold more active than BMCL-200908069-1 (1.37 +/- 0.07 mu M, 9.52 +/- 0.29 mu M, 16.27 +/- 0.54 mu M), respectively. Structure-activity relationships (SARs) and docking studies indicated that the thiopyrano[4,3-d] pyrimidine scaffolds exerted little effect on antitumor activities of target compounds. Substitutions of aryl group at C-4 position had a significant impact on the antitumor activities, and 4-OH substitution produced the best potency. (C) 2014 Elsevier Ltd. All rights reserved.