Synthesis and anticancer activity of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety
Synthesis and anticancer activity of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety
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带有色酮部分的新型4-吗啉代-7,8-二氢-5H-噻喃并[4,3-d]嘧啶衍生物的合成和抗癌活性
DOI：
10.1016/j.bmc.2016.06.032
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发表时间：
2016-08-15
影响因子：
3.5
通讯作者：
Zhu, Wufu
中科院分区：
文献类型：
--
作者：
Sun, Chengyu;Chen, Chen;Zhu, Wufu
在此，我们设计并合成了一系列带有色酮部分的新型7,8-二氢-5H-硫代吡喃并[4,3-d]嘧啶衍生物（10a-j，13a-j）。评估了所有化合物针对五种癌细胞系（A549、PC-3、MCF-7、Hela 和 HepG2）的 IC50 值。七种目标化合物表现出中等至优异的细胞毒性。对于这些化合物，我们测试了它们对mTOR激酶的抑制活性，并进一步测试了其中四种化合物对PI3K α激酶的抑制活性。结果表明，优化后的化合物10j对mTOR激酶、PI3Ka激酶和5种癌细胞系均表现出优异的抑制活性和细胞毒性，IC50值分别为1.1μM、0.92μM和8.77-14.3μM。构效关系（SAR）和对接研究表明，硫代吡喃并[4,3-d]嘧啶支架对目标化合物的抗肿瘤活性影响不大。 C-6位色酮部分被羧基取代有利于抗肿瘤活性。 (C) 2016 Elsevier Ltd. 保留所有权利。
Herein, we designed and synthesized of a novel series of 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety (10a-j, 13a-j). All the compounds were evaluated for the IC50 values against five cancer cell lines (A549, PC-3, MCF-7, Hela and HepG2). Seven of the target compounds exhibited moderate to excellent cytotoxicity. For these compounds, we tested their inhibitory activities against mTOR kinase, and four of them were tested their inhibitory activities against PI3K alpha kinase in further. The results indicated that the optimized compound 10j showed excellent inhibitory activity and cytotoxicity against mTOR kinase, PI3Ka kinase and five cancer cell lines with IC50 values of 1.1 mu M, 0.92 mu M and 8.77-14.3 mu M. 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 chromone moiety at C-6 position with carboxyl were benefit to the antitumor activities. (C) 2016 Elsevier Ltd. All rights reserved.