Zaki Waheed A, El-Sayed Selwan M, Alswah Mohamed, El-Morsy Ahmed, Bayoumi Ashraf H, Mayhoub Abrahman S, Moustafa Walaa H, Awaji Aeshah A, Roh Eun Joo, Hassan Ahmed H E, Mahmoud Kazem
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Pharmaceuticals (Basel). 2023 Nov 11;16(11):1593. doi: 10.3390/ph16111593.
CDK2 is a key player in cell cycle processes. It has a crucial role in the progression of various cancers. Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are two common cancers that affect humans worldwide. The available therapeutic options suffer from many drawbacks including high toxicity and decreased specificity. Therefore, there is a need for more effective and safer therapeutic agents. A series of new pyrazolo[3,4-]pyrimidine analogs was designed, synthesized, and evaluated as anticancer agents against the CRC and HCC cells, HCT116, and HepG2, respectively. Pyrazolo[3,4-]pyrimidinone derivatives bearing -2-(4-halophenyl) acetamide substituents were identified as the most potent amongst evaluated compounds. Further evaluation of CDK2 kinase inhibition of two potential cytotoxic compounds and confirmed their CDK2 inhibitory activity. Compound was more potent than the reference roscovitine regarding the CDK2 inhibitory activity (IC values: 0.21 and 0.25 µM, respectively). In silico molecular docking provided insights into the molecular interactions of compounds and with important amino acids within the ATP-binding site of CDK2 (Ile10, Leu83, and Leu134). Overall, compounds and were identified as interesting CDK2 inhibitors eliciting antiproliferative activity against the CRC and HCC cells, HCT116 and HepG2, respectively, for future further investigations and development.
细胞周期蛋白依赖性激酶2（CDK2）是细胞周期进程中的关键因子。它在多种癌症的发展过程中起着至关重要的作用。肝细胞癌（HCC）和结直肠癌（CRC）是全球范围内影响人类的两种常见癌症。现有的治疗方案存在许多缺点，包括高毒性和特异性降低。因此，需要更有效、更安全的治疗药物。设计、合成了一系列新型吡唑并[3,4 - ]嘧啶类似物，并分别作为抗CRC和HCC细胞（HCT116和HepG2）的抗癌药物进行了评估。带有 - 2 -（4 - 卤苯基）乙酰胺取代基的吡唑并[3,4 - ]嘧啶酮衍生物被确定为评估化合物中最有效的。对两种潜在细胞毒性化合物对CDK2激酶抑制作用的进一步评估证实了它们的CDK2抑制活性。就CDK2抑制活性而言，化合物比参考药物罗可辛更有效（IC值分别为0.21和0.25μM）。计算机模拟分子对接提供了化合物与CDK2（Ile10、Leu83和Leu134）ATP结合位点内重要氨基酸分子相互作用的见解。总体而言，化合物被确定为有趣的CDK2抑制剂，分别对CRC和HCC细胞HCT116和HepG2具有抗增殖活性，以供未来进一步研究和开发。
