In silico and in vitro studies of novel cyanoacrylamides incorporating pyrazole moiety against breast and prostate carcinomas

Abstract

We report novel cyanoacrylamide derivatives bearing the pyrazole moiety. The molecular structures of the prepared cyanoacrylamides were confirmed by the different spectral tools such as NMR, IR, and elemental analyses. The anticancer effect of all the newly prepared cyanoacrylamides was studied against four cancer cell lines (HEPG2, MCF7, PACA2, and PC3) as well as the normal cell line (BJ1). The best cytotoxic effect was shown against PC3, where compounds 5f and 5i revealed promising IC50 values (11.7 and 66.8 µM) respectively compared to doxorubicin (43.8 µM). In addition, the effective compounds were screened against a normal BJ1 cell line, which showed promising selectivity against PC3 and moderate selectivity toward MCF7 cells. The molecular docking study showed the affinities of compounds 5c and 5d toward STAT1 protein and compound 5i toward KRAS with promising energy scores. The subsequent molecular experiments were studied on compounds 5b, 5c, 5d, 5f, and 5i. Quantitative Real-time-PCR revealed that the expression of RBL2 and STAT2 genes were down-regulated in 5c and 5d treated MCF7 cells much lower than the other treated MCF7 samples. Also, the expression level of KRAS and SMAD genes was determined, which revealed the significant down-regulation of them in compounds 5f and 5i treated PC3 cells. The percentages of DNA damage were raised significantly in all treated MCF7 and PC3 samples as compared to the negative control, and the highest percentages were for compounds 5c and 5d treated MCF7 cells.Graphical