我们报告了新型化合物（E）-1-甲基-9-（3-甲基苯基亚甲基）-6,7,8,9-四氢嘧唑[3,4- d]吡啶[1,2- a]嘧啶-4（1H）-酮（PP562）的合成、分子对接和抗癌特性。PP562被筛选对16种人类癌细胞系，并表现出优异的抗增殖活性，IC50值在0.016至5.667μM之间。在一个包含100种不同酶的激酶面板上，使用目标PP562的单剂量1.0μM进行实验。使用分子动力学分析确定了PP562抑制DDR2的可能结合机制。还在具有DDR2基因高低表达的癌细胞模型中检查了PP562对细胞增殖的影响；PP562对高表达细胞的抑制作用比低表达细胞的更为突出。PP562对HGC-27胃癌细胞系也表现出优异的抗癌潜力。此外，PP562抑制了克隆形成、细胞迁移和粘附，导致细胞周期在G2 / M期停滞，并影响ROS产生和细胞凋亡。DDR2基因沉默后，PP562对肿瘤细胞的抗肿瘤效果明显受损。这些结果表明，PP562可能通过DDR2靶标对HCG-27增殖施加其抑制作用。Copyright © 2023. Published by Elsevier Inc.

We report the synthesis, molecular docking and anticancer properties of the novel compound (E)-1-methyl-9-(3-methylbenzylidene)-6,7,8,9-tetrahydropyrazolo[3,4-d]pyrido[1,2-a]pyrimidin-4(1H)-one (PP562). PP562 was screened against sixteen human cancer cell lines and exhibited excellent antiproliferative activity with IC50 values ranging from 0.016 to 5.667 μM. Experiments were carried out using the target PP562 at a single dose of 1.0 μM against a kinase panel comprising 100 different enzymes. A plausible binding mechanism for PP562 inhibition of DDR2 was determined using molecular dynamic analysis. The effect of PP562 on cell proliferation was also examined in cancer cell models with both high and low expression of the DDR2 gene; PP562 inhibition of high-expressing cells was more prominent than that for low expressing cells. PP562 also exhibits excellent anticancer potency toward the HGC-27 gastric cancer cell line. In addition, PP562 inhibits colony formation, cell migration, and adhesion, induces cell cycle arrest at the G2/M phase, and affects ROS generation and cell apoptosis. After DDR2 gene knockdown, the antitumor effects of PP562 on tumor cells were significantly impaired. These results suggested that PP562 might exert its inhibitory effect on HCG-27 proliferation through the DDR2 target.Copyright © 2023. Published by Elsevier Inc.