Egyptian Drug Authority, Cairo, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Arch Pharm (Weinheim). 2022 Feb;355(2):e2100302. doi: 10.1002/ardp.202100302. Epub 2021 Nov 18.
Novel series of pyrazolo[3,4-b]pyridines 9a-j and 14a-f were prepared via a one-pot three-component reaction. Compounds 9a-j were synthesized by the reaction of 3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-5-amine (4) with benzoyl acetonitriles 3a,b and aldehydes 5a-e, whereas the spiro derivatives 14a-f were synthesized by the reaction of pyrazole derivative 4 with 3a-c and indoline-2,3-diones 10a,b. Screening of the antiproliferative activity of 9a-j and 14a-f revealed that 14a and 14d were the most potent analogues against HepG2 and HeLa cells, with IC = 4.2 and 5.9 μM, respectively. Moreover, compounds 9c and 14a could promote cell cycle disturbance and apoptosis in HepG2 cells, as evidenced by DNA flow cytometry and Annexin V-FITC/PI assays. Cell cycle analysis of 9c and 14a indicated a reduction in HepG2 cells in the G1 phase, with arrest in the S phase and the G2/M phase, respectively. Also, 9c and 14a are good apoptotic inducers in the HepG2 cell line. Furthermore, compounds 9h and 14d stood out as the most efficient antiproliferative agents in the NCI 60-cell line panel screening, with mean GI % equal to 60.3% and 55.4%, respectively. Additionally, 9c, 9h, 14a, and 14d showed good inhibitory action against the cellular pathway regulator p38α kinase, with IC = 0.42, 0.41, 0.13, and 0.64 μM, respectively. A docking study was carried out on the p38α kinase active site, showing a binding mode comparable to that of reported p38 mitogen-activated protein kinase inhibitors. These newly discovered pyrazolo[3,4-b]pyridines could be considered as potential candidates for the development of newly targeted anticancer agents.
通过一锅法三组分反应，制备了一系列新型吡唑并[3,4-b]吡啶 9a-j 和 14a-f。化合物 9a-j 是由 3-(4-氯苯基)-1-苯基-1H-吡唑-5-胺（4）与苯甲酰乙腈 3a,b 和醛 5a-e 反应合成的，而螺环衍生物 14a-f 则是由吡唑衍生物 4 与 3a-c 和吲哚啉-2,3-二酮 10a,b 反应合成的。对 9a-j 和 14a-f 的抗增殖活性进行筛选，结果表明 14a 和 14d 对 HepG2 和 HeLa 细胞的活性最强，IC 50 值分别为 4.2 和 5.9 μM。此外，化合物 9c 和 14a 可通过 DNA 流式细胞术和 Annexin V-FITC/PI 检测，在 HepG2 细胞中诱导细胞周期紊乱和细胞凋亡。9c 和 14a 的细胞周期分析表明，G1 期的 HepG2 细胞减少，S 期和 G2/M 期分别被阻滞。此外，9c 和 14a 是 HepG2 细胞系中良好的凋亡诱导剂。此外，化合物 9h 和 14d 在 NCI 60 细胞系筛选中作为最有效的增殖抑制剂脱颖而出，其平均 GI%分别为 60.3%和 55.4%。此外，9c、9h、14a 和 14d 对细胞通路调节剂 p38α 激酶表现出良好的抑制作用，IC 50 值分别为 0.42、0.41、0.13 和 0.64 μM。在 p38α 激酶活性位点进行对接研究，结果表明其结合模式与已报道的 p38 丝裂原活化蛋白激酶抑制剂相似。这些新发现的吡唑并[3,4-b]吡啶类化合物可被视为开发新型靶向抗癌药物的潜在候选药物。
