Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey.
Department of Biochemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey.
Bioorg Chem. 2019 Mar;83:511-519. doi: 10.1016/j.bioorg.2018.10.060. Epub 2018 Oct 30.
In this work we described the synthesis and evaluation of cytotoxic and apoptotic activity of novel pyrrolopyrimidine derivatives against A549, PC3 and MCF-7 cells. Among the synthesized compounds, 6b, 8a, 9a and 7a, 8b displayed the significant cytotoxic activities against A549 and PC3 cells with IC value of 0.35, 1.48, 1.56 and 1.04, 1.89 µM, respectively. It was found that A549 cells were more sensitive to synthesized compounds than PC3 and MCF-7 cells. In order to evaluate the mechanism of cytotoxic activity in A549, compounds 6b, 8a and 9a were selected for further studies. Annexin V binding assay and western blot analysis results revealed that 6b, 8a and 9a induced apoptosis in A549 cells by intrinsic apoptotic pathway through the activation pro-apoptotic proteins such as Bim, Bax, Bak, Puma and deactivation of anti-apoptotic proteins including Bcl-2, Mcl-1 and Bcl-XL accompanied by the activation of caspase-3, caspase-9 and cleavage of PARP. Also, compounds 6b, 8a and 9a triggered apoptosis in HCT116 wt cells via activation of caspase-3 and caspase-9, but not in HCT116 Bax/Bak KO cells, indicating resistance to 6b, 8a and 9a treatment.
在这项工作中，我们描述了新型吡咯嘧啶衍生物的合成及其对 A549、PC3 和 MCF-7 细胞的细胞毒性和细胞凋亡活性的评价。在所合成的化合物中，6b、8a、9a 和 7a、8b 对 A549 和 PC3 细胞表现出显著的细胞毒性活性，IC 值分别为 0.35、1.48、1.56 和 1.04、1.89µM。结果发现，与 PC3 和 MCF-7 细胞相比，A549 细胞对合成的化合物更为敏感。为了评估化合物在 A549 中的细胞毒性作用机制，选择了 6b、8a 和 9a 进行进一步研究。Annexin V 结合实验和 Western blot 分析结果表明，化合物 6b、8a 和 9a 通过内在凋亡途径诱导 A549 细胞凋亡，通过激活促凋亡蛋白如 Bim、Bax、Bak、Puma 和失活抗凋亡蛋白，包括 Bcl-2、Mcl-1 和 Bcl-XL，同时激活 caspase-3、caspase-9 和 PARP 的裂解。此外，化合物 6b、8a 和 9a 通过激活 caspase-3 和 caspase-9 引发 HCT116 wt 细胞的凋亡，但在 HCT116 Bax/Bak KO 细胞中没有，表明对 6b、8a 和 9a 治疗有抗性。
