Design, synthesis, molecular modelling, and biological evaluation of novel substituted pyrimidine derivatives as potential anticancer agents for hepatocellular carcinoma

Abstract

New anticancer agents are highly needed to overcome cancer cell resistance. A novel series of pyrimidine pyrazoline-anthracene derivatives (PPADs) (<b>4a-t)</b> were designed and synthesised. The anti-liver cancer activity of all compounds was screened <i>in vitro</i> against two hepatocellular carcinoma (HCC) cell lines (HepG2 and Huh-7) as well as normal fibroblast cells by resazurin assay. The designed compounds <b>4a-t</b> showed a broad-spectrum anticancer activity against the two cell lines and their activity was more prominent on cancer compared to normal cells. Compound <b>4e</b> showed high potency against HepG2 and Huh-7 cell lines (<b>(</b>IC₅₀=5.34 and 6.13 μg/mL, respectively) comparable to that of doxorubicin (DOX) activities. A structure activity relationship (SAR) has been investigated and compounds <b>4e</b>, <b>4i</b>, <b>4m,</b> and <b>4q</b> were the most promising anticancer agents against tested cell lines. These compounds induced apoptosis in HepG2 and Huh-7 cells through significant activation of caspase 3/7 at all tested concentrations. In conclusion, <b>4e</b> could be a potent anticancer drug.