Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt; Pharmaceutical Chemistry Department,School of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, 11777, Egypt.
Eur J Med Chem. 2021 Jun 5;218:113389. doi: 10.1016/j.ejmech.2021.113389. Epub 2021 Mar 18.
Novel series of diphenyl-1H-pyrazoles (4a-g) and pyrazolo[3,4-b]pyridines (5a-g and 7a-i) were synthesized and evaluated for their antiproliferative activity against breast cancer cell line (MCF7) and Hepatocellular carcinoma cell line (HepG2). The highest MCF7 growth inhibition activity was attained via compounds 4f and 7e (IC = 1.29 and 0.93 μM, respectively), while compounds 5b and 7f were the most active ones against HepG2 (IC = 1.57 and 1.33 μM, respectively) compared to doxorubicin (IC = 1.88 and 7.30 μM, respectively). Cell cycle analysis showed arrest at S and G2-M phases in MCF7 cells treated with 4f and 7e, and at G2-M and G1/S phases in HepG2 cells treated with 5b and 7f, respectively. Apoptotic effect of compounds 4f, 5b, 7e, and 7f was indicated via their pre-G1 early and late apoptotic effects and augmented levels of caspase-9/MCF7 and caspase-3/HepG2. A worthy safety profile was assessed for compounds 4f and 7e on MCF10A and compounds 5b and 7f on THLE2 treated normal cells. Furthermore, compounds 4f, 5b and 7f displayed a promising selective profile for CDK2 inhibition vs. CDK1, CDK4, and CDK7 isoforms as proved from their selectivity index. Docking in CDK2 ATP binding site, co-crystallized with R-Roscovitine, demonstrated analogous interactions and comparable binding energy with the native ligand. 2D QSAR sighted the possible structural features governing the CDK2 inhibition activity elicited by the studied pyrazolo[3,4-b]pyridines. These findings present compounds 4f, 5b, and 7f as selective CDK2 inhibitors with promising antiproliferative activity against MCF7 and HepG2 cancer cells.
新型系列二苯基-1H-吡唑（4a-g）和吡唑并[3,4-b]吡啶（5a-g 和 7a-i）被合成并评估其对乳腺癌细胞系（MCF7）和肝癌细胞系（HepG2）的抗增殖活性。化合物 4f 和 7e 对 MCF7 的生长抑制活性最高（IC=1.29 和 0.93 μM），而化合物 5b 和 7f 对 HepG2 的活性最强（IC=1.57 和 1.33 μM），与阿霉素（IC=1.88 和 7.30 μM）相比。细胞周期分析显示，用 4f 和 7e 处理 MCF7 细胞时，细胞在 S 和 G2-M 期停滞，用 5b 和 7f 处理 HepG2 细胞时，细胞在 G2-M 和 G1/S 期停滞。化合物 4f、5b、7e 和 7f 通过其 Pre-G1 早期和晚期凋亡作用以及 caspase-9/MCF7 和 caspase-3/HepG2 水平的升高，显示出凋亡作用。在 MCF10A 上评估化合物 4f 和 7e 的良好安全性概况，在 THLE2 上评估化合物 5b 和 7f 的正常细胞的安全性概况。此外，化合物 4f、5b 和 7f 对 CDK2 的抑制作用表现出有希望的选择性，对 CDK1、CDK4 和 CDK7 同工型的选择性指数证明了这一点。在与 R-Roscovitine 共结晶的 CDK2 ATP 结合位点进行对接，证明了类似的相互作用和与天然配体相当的结合能。2D-QSAR 指出了可能的结构特征，这些特征决定了所研究的吡唑并[3,4-b]吡啶对 CDK2 抑制活性的影响。这些发现表明化合物 4f、5b 和 7f 是选择性 CDK2 抑制剂，对 MCF7 和 HepG2 癌细胞具有有希望的抗增殖活性。
