Design and discovery of novel pyrazole‐pyrrolopyrimidine derivatives as anti‐glioma agents via promoting apoptosis, inhibiting cell cycle and EGFR‐TK

胶质瘤 细胞凋亡 细胞周期 埃罗替尼 化学 表皮生长因子受体 癌细胞 U87型 细胞周期检查点 癌症研究 IC50型 激酶 药理学 癌症 生物 生物化学 受体 体外 遗传学
作者
Yufu Zhang,Li Gao
出处
期刊:Chemical Biology & Drug Design [Wiley]
卷期号:102 (5): 1248-1256
标识
DOI:10.1111/cbdd.14320
摘要

Glioma is an aggressive type of brain malignancy responsible for significant morbidity and mortality. In the current scenario, epidermal growth factor receptor (EGFR) kinases targeted therapy showed significant benefits in glioma patients. Therefore, in the present study, we intend to investigate the anti-glioma potential of a novel class of pyrazole-pyrrolopyrimidine derivatives and their mechanism of action. The compounds will be synthesized in a straight-forward synthetic route in excellent yields and subsequently tested for EGFR kinase inhibition. The compounds showed a diverse range of inhibitory activity against EGFR (IC50 = 3.4-873.2 nM). With an IC50 of 1.5 nM, compound 4i was determined to be the most effective EGFR inhibitor, even superior to the standard erlotinib (IC50 2.3 nM). Among them, the three most potent compounds (4i, 4j, and 4k) were further subjected to the anticancer activity against the panel of various cancer cell lines MCF-7 (breast cancer), A549 (lung cancer), U87 (glioblastoma cell)-EGFR-Wild Type, U87 (mutant glioblastoma cells) EGFR-mutant cell, MCF-12A (normal cells). The compound 4i showed the most potent activity against glioblastoma cells as compared to other cancer cells. The effect of compound 4i was also studied on the apoptosis of U87 cells, where it showed induction of apoptosis in a concentration-dependent manner. It also showed inhibition of the G2/M cell cycle phase of U87 cells. Our study demonstrated the development of novel pyrazole-pyrrolopyrimidine derivatives as a novel class of anti-glioma agents.
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