New quinazolynyl-flavone derivatives: Synthesis, structure analysis, and investigation of bromodomain inhibitory activities

Bromodomains (BRDs) are key transcriptional regulators that control expression of genes. The inhibition of BRD is a critical therapeutic strategy in cancer treatment. Flavones can act as a potent anticancer agent. In this paper, a novel series of dihydroquinazolinylsulfonylflavone compounds (7a-x) was synthesized and their cytotoxicity was investigated in human A549 lung carcinoma, MCF-7 breast carcinoma and K562 myeloid leukemia cell lines. The most cytotoxic compounds 7f, 7 h, 7i, 7 m, 7q, 7r, 7 u, 7 w and 7x were tested for their bromodomain containing 2 protein (BRD2), bromodomain containing 3 protein (BRD3) and bromodomain containing 4 protein (BRD4) inhibitor activities. The results showed that there is a significant inhibition on BRD2 by compound 7f, 7 h, 7 m, 7q, 7r and BRD3 by both compounds 7f, 7 h, 7i, 7 m, 7q, 7r, 7 u, 7 w, 7x. None of the tested compounds showed significant BRD4 inhibition. We suggest that dihydroquinazolinylsulfonylflavone compounds have the potential to inhibit BRD2 and BRD3 activity in various cancer cells, thus may be pharmacologically of interest for further investigations.