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

• Published in: New journal of chemistry 2023-04, Vol.47 (14), p.6844-6855
• Main Authors: Kora ak, Ljiljana, Lupši, Ema, Jovanovi, Nataša Terzi, Jovanovi, Mirna, Novakovic, Miroslav, Nedialkov, Paraskev, Trendafilova, Antoaneta, Zlatovi, Mario, Peši, Milica, Opsenica, Igor M
• Format: Article
• Language: English
• Subjects: Anticancer properties; Cancer; Chemical synthesis; Doxorubicin; Ethylenediamine; Glycoproteins; Selectivity
• ISSN: 1144-0546; 1369-9261
• DOI: 10.1039/d3nj00427a

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 IC 50 values below 5 μM. 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 IC 50 values of around 1.5 μM (for comparison - over 3.1 μM for artesunate) in sensitive and MDR NSCLC cells. Approach based on hybrid compounds of artesunate and pyrimidine provided novel and promising anticancer agents.