Phosphatidylinositol 3-kinase/Protein kinase B/Mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway is abnormally active in the growth and proliferation of cancer cells. The inhibition of PI3K kinase can effectively block the conduction of signaling pathways and is an ideal target for drug design. In this paper; two series of 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing pyrazoline moiety (7a-l; 8a-l) were synthesized; and their cytotoxicity in vitro were evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method against four human cancer cell lines including A549; PC-3; MCF-7; and HepG2 cell lines. The activity of the most promising compound 8d against PI3Kα kinase was further evaluated. The results indicated that most of the target compounds showed moderate to excellent cytotoxicity and the most promising compound 8d showed excellent cytotoxicity against four cancer cell lines with half maximal inhibitory concentration (IC50) values of 6.02-10.27 μM. In addition; the compound 8d was found to have a moderate inhibitory activity in the PI3Kα enzyme assay. What's more; the compounds of which the substituents of benzene ring at the C-4 position are electron-withdrawing groups such as substituents (Cl; F; Br) have better activity than the compounds containing the electron donating groups (OCH₃; H). However; the exact action mechanism is not quite clear right now. Further study will be carried out to identify the exact target in near future.

中文翻译：

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带有吡唑啉骨架的4-Morpholino-7,8-Dihydro-5H-噻喃并[4,3-d]嘧啶衍生物的合成及构效关系。

磷脂酰肌醇3-激酶/蛋白激酶B /雷帕霉素的哺乳动物靶标（PI3K / Akt / mTOR）信号通路在癌细胞的生长和增殖中异常活跃。PI3K激酶的抑制作用可有效阻断信号传导途径的传导，是药物设计的理想靶标。在本文中; 合成了带有吡唑啉部分（7a-1； 8a-1）的两个系列的4-吗啉代-7，8-二氢-5H-硫代吡喃并[4，3-d]嘧啶衍生物。通过3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四溴化铵（MTT）方法评估了它们的体外细胞毒性对包括A549在内的四种人类癌细胞系的影响。PC-3；MCF-7；和HepG2细胞系。进一步评估了最有希望的化合物8d对PI3Kα激酶的活性。结果表明，大多数目标化合物对中度至优异的细胞毒性均表现出优势，最有希望的化合物8d对四种癌细胞的半数最大抑制浓度（IC50）值为6.02-10.27μM，均具有优异的细胞毒性。此外; 在PI3Kα酶测定中发现化合物8d具有中等抑制活性。更重要的是; 那些在C-4位上的苯环取代基是吸电子基团的化合物，例如取代基（Cl； F； Br），比含有供电子基团的化合物（OCH 3； H）具有更好的活性。然而; 确切的动作机制目前尚不清楚。将在不久的将来进行进一步的研究，以确定确切的目标。