Novel artesunate-pyrimidine-based hybrids with anticancer potential against multidrug-resistant cancer cells

The synthesis of 17 hybrid molecules, consisting of artesunate, a derivative of naturally occurring artemisinin, and synthetic 4-aryl-2-aminopyrimidines, is described. New compounds were designed to improve the parent compounds' cytotoxic properties, activity, and selectivity. The synthesized hybrid molecules (15a-f with ethylenediamine linker and 16a-k with piperazine linker), as well as their precursors - pyrimidine derivatives (13a-f and 14a-k), artemisinin, and artesunate, were tested on sensitive and multidrug-resistant (MDR) human non-small cell lung carcinoma (NSCLC) cells. All hybrid compounds with piperazine linker 16a-k were selective toward NSCLC cells and displayed IC50 values below 5 mu M. Although they showed similar anticancer potency as artesunate, their selectivity against cancer cells was considerably improved. Importantly, 16h-k hybrid compounds were able to evade MDR phenotype, inhibit P-glycoprotein (P-gp) activity, and increase the sensitivity of MDR NSCLC cells to doxorubicin (DOX). The inhibition of P-gp activity induced by 16h-j was stronger than the one obtained with artesunate. Among these four hybrid compounds, 16k was the most potent anticancer agent with similar IC50 values of around 1.5 mu M (for comparison - over 3.1 mu M for artesunate) in sensitive and MDR NSCLC cells.