부산대학교 도서관

Graphical abstract Highlights • Novel pyrrolopyrimidine derivatives were synthesized and evaluated for anticancer activity against A549, PC3 and MCF-7 cells. • Compounds 6b , 8a , 9a and 7a , 8b displayed the significant cytotoxic activities against A549 and PC3 cells with IC 50 values ranging from 0.35 to 1.89 µM. • Compounds 6b , 8a and 9a induced apoptosis in A549 cells by intrinsic pathway. • Also, compounds 6b , 8a and 9a induced apoptosis in HCT116 wt cells. Bax/Bak KO cells were found resistance to 6b , 8a and 9a treatment. Abstract 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 50 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. [ABSTRACT FROM AUTHOR]