Anticancer activity of pyrimidodiazepines based on 2-chloro-4-anilinoquinazoline: synthesis, DNA binding and molecular docking

Abstract

Multidrug resistance to chemotherapy is a critical health problem associated with mutation of the therapeutic target. Therefore, the development of anticancer agents remains a challenge to overcome cancer cell resistance. Herein, a new series of quinazoline-based pyrimidodiazepines16a-gwere synthesized by the cyclocondensation reaction of 2-chloro-4-anilinoquinazoline-chalcones14a-gwith 2,4,5,6-tetraaminopyrimidine. All quinazoline derivatives14a-gand16a-gwere selected by the U.S. National Cancer Institute (NCI) for testing their anticancer activity against 60 cancer cell lines of different panels of human tumors. Among the tested compounds, quinazoline-chalcone14gdisplayed high antiproliferative activity with GI50values between 0.622-1.81 μM against K-562 (leukemia), RPMI-8226 (leukemia), HCT-116 (colon cancer) LOX IMVI (melanoma), and MCF7 (breast cancer) cancer cell lines. Additionally, the pyrimidodiazepines16aand16cexhibited high cytostatic (TGI) and cytotoxic activity (LC50), where16cshowed high cytotoxic activity, which was 10.0-fold higher than the standard anticancer agent adriamycin/doxorubicin against ten cancer cell lines. COMPARE analysis revealed that16cmay possess a mechanism of action through DNA binding that is similar to that of CCNU (lomustine). DNA binding studies indicated that14gand16cinteract with the calf thymus DNA by intercalation and groove binding, respectively. Compounds14g,16cand16adisplayed strong binding affinities to DNA, EGFR and VEGFR-2 receptors. None of the active compounds showed cytotoxicity against human red blood cells.