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Synthesis and Antitumor Activity Evaluation of Novel Pyrimidoquinoline Derivatives

Abstract Quinoline-based structures possess various types of biological activities and recently have attracted attention as an antitumor scaffold via different known anti-cancer mechanisms. In this study, a novel series of tetrahydropyrimido[4,5-b]quinoline-4,6(3H,7H)-diones (7a-r) were synthesized and evaluated for their in vitro cytotoxic effects on breast cancer cells (MCF-7 cells), prostate cancer cells (LNCaP cells), and normal human adult dermal fibroblast (HDF) cells. Among them, the compounds (7c), (7d), (7 g), (7j), (7k), (7 l), and (7r) showed high activity against LNCaP and MCF-7 cancer cells with IC50 values ranging from 37.62 to 67.3 µM, compared to etoposide as reference drug. The compound (7 l) was the most active compound against LNCaP cancer cells and was examined for further 4′,6-diamidino-2-phenylindole dihydrochloride (DAPI) staining which confirmed apoptosis and DNA damage in LNCaP cells. The study showed upregulation of Bax and downregulation of Bcl-2 as two potential markers of an intrinsic pathway of apoptosis in LNCaP cell line by using quantitative real-time PCR (qRT-PCR) method. Finally, we found that compound 7I can be considered as a potential agent for induction of apoptosis in cancer cells (LNCaP cells).