Abstract：
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.
摘要：
胶质瘤是一种侵袭性的脑恶性肿瘤，可导致大量的发病率和死亡率。在当前场景中,表皮生长因子受体(EGFR)激酶靶向治疗在胶质瘤患者中显示出显著的获益.因此,在本研究中，我们打算研究一类新型吡唑-吡咯并嘧啶衍生物的抗神经胶质瘤潜力及其作用机制。所述化合物将以优异的产率以直接的合成途径合成,随后测试EGFR激酶抑制。这些化合物对EGFR显示出不同范围的抑制活性(IC50=3.4-873.2nM)。IC50为1.5nM,化合物4i被确定为最有效的EGFR抑制剂，甚至优于标准厄洛替尼（IC502.3nM）。其中,三种最有效的化合物(4i，4j,和4k）进一步对各种癌细胞系MCF-7（乳腺癌）的组进行抗癌活性，A549（肺癌），U87（胶质母细胞瘤细胞）-EGFR-野生型，U87（突变胶质母细胞瘤细胞）EGFR突变细胞，MCF-12A(正常细胞)。与其他癌细胞相比,化合物4i对胶质母细胞瘤细胞显示出最有效的活性。还研究了化合物4i对U87细胞凋亡的影响，它显示以浓度依赖性方式诱导细胞凋亡。它还显示了对U87细胞的G2/M细胞周期期的抑制。我们的研究证明了新型吡唑-吡咯并嘧啶衍生物作为新型抗神经胶质瘤药物的开发。
