Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China.
College of Service, Naval Logistics Academy of PLA, Tianjin 300450, China.
Molecules. 2017 Oct 31;22(11):1870. doi: 10.3390/molecules22111870.
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-5-thiopyrano[4,3-]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 (IC) 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.
磷脂酰肌醇 3-激酶/蛋白激酶 B/雷帕霉素靶蛋白（PI3K/Akt/mTOR）信号通路在癌细胞的生长和增殖中异常活跃。PI3K 激酶的抑制可以有效地阻断信号通路的传导，是药物设计的理想靶点。在本文中；合成了两个系列含有吡唑啉部分的 4-吗啉基-7,8-二氢-5-噻吩并[4,3-d]嘧啶衍生物（7a-l；8a-l），并通过 3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑溴盐（MTT）法评估了它们对四种人癌细胞系（A549、PC-3、MCF-7 和 HepG2 细胞系）的体外细胞毒性。进一步评价了最有希望的化合物 8d 对 PI3Kα 激酶的活性。结果表明，大多数目标化合物表现出中度至优异的细胞毒性，最有希望的化合物 8d 对四种癌细胞系表现出优异的细胞毒性，半数最大抑制浓度（IC）值为 6.02-10.27μM。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；苯环在 C-4 位置的取代基为吸电子基团（如取代基（Cl；F；Br）的化合物比含有供电子基团（OCH₃；H）的化合物具有更好的活性。然而；目前确切的作用机制尚不清楚。我们将在不久的将来进行进一步的研究，以确定确切的靶标。
