Cui Hangrui, Zhang Ruifeng, Xiong Xin, Cui Zhiwen, Min Zhijian, Liu Jinglong, Li Xunping, Min Zhenli
Institute of Advanced Pharmaceutical Technology, Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, 430081, China.
The First Clinical College, Lanzhou University, Lanzhou, 730099, China.
Curr Comput Aided Drug Des. 2024 Mar 12. doi: 10.2174/0115734099285448240304072649.
Cancer poses a great threat to human health, and effective drugs to treat it are always needed. Several compounds containing a 2-aminopyrazine framework have been identified as antitumor agents with SHP2 inhibition activities. This current work aimed to search for more potent novel compounds possessing a 2-aminopyrazine moiety with antitumor activities.
A series of 12 novel 2-aminopyrazine derivatives was synthesized, and their structures were confirmed by spectroscopic techniques. The inhibitory activities of all the synthesized compounds against MDA-MB-231 and H1975 cancer cell lines were evaluated by an MTT assay. The most potent compound 3e was analyzed by flow cytometry. Subsequently, computational studies were performed to investigate the possible antitumor mechanisms of compound 3e.
The results indicated that compound 3e exhibited potent antitumor activities with IC50 values of 11.84±0.83μM against H1975 cells and 5.66±2.39μM against MDA-MB-231 cells, which were more potent than the SHP2 inhibitor GS493 (IC50 = 19.08±1.01 μM against H1975 cells and IC50 = 25.02±1.47 μM against MDA-MB-231 cells). Further analysis by flow cytometry demonstrated that compound 3e induced cell apoptosis in H1975 cells. The results of the molecular docking and MD simulations, including RMSD, RMSF, PCA, DCCM and binding energy and decomposition analyses, revealed that compound 3e probably selectively inhibited SHP2.
A new compound having a 2-aminopyrazine substructure with potent inhibitory activities against the H1975 and MDA-MB-231 cancer cells was obtained, meriting further investigation as an antitumor drug.
癌症对人类健康构成巨大威胁，始终需要有效的治疗药物。几种含有2-氨基吡嗪骨架的化合物已被鉴定为具有SHP2抑制活性的抗肿瘤剂。本研究旨在寻找更具活性的含2-氨基吡嗪部分的新型抗肿瘤化合物。
合成了一系列12种新型2-氨基吡嗪衍生物，并用光谱技术确证了其结构。通过MTT法评估所有合成化合物对MDA-MB-231和H1975癌细胞系的抑制活性。用流式细胞术分析最具活性的化合物3e。随后，进行了计算研究以探究化合物3e可能的抗肿瘤机制。
结果表明，化合物3e表现出强效抗肿瘤活性，对H1975细胞的IC50值为11.84±0.83μM，对MDA-MB-231细胞的IC50值为5.66±2.39μM，比SHP2抑制剂GS493更具活性（对H1975细胞的IC50 = 19.08±1.01 μM，对MDA-MB-231细胞的IC50 = 25.02±1.47 μM）。流式细胞术进一步分析表明，化合物3e诱导H1975细胞凋亡。分子对接和分子动力学模拟结果，包括均方根偏差、均方根波动、主成分分析、动态聚类相关矩阵和结合能及分解分析，表明化合物3e可能选择性抑制SHP2。
获得了一种具有2-氨基吡嗪亚结构且对H1975和MDA-MB-231癌细胞具有强效抑制活性的新化合物，作为一种抗肿瘤药物值得进一步研究。
