Development of potential anticancer agents and apoptotic inducers based on 4-aryl-4H chromene scaffold: Design, synthesis, biological evaluation and insight on their proliferation inhibition mechanism

An array of 4-aryl-2-amino-4H chromene derivatives were designed, synthesized, and evaluated for cytotoxic activity against four cancer cell lines and two non-cancerous cell lines. The most active candidates were further screened for their in vitro anticancer activity on NCI panel of 60 human cancer cell lines where compounds 2a, 2b, 4a-2, and 2e showed promising activity against various leukemia, non-small lung, renal, prostate, and breast cancer cell lines, particularly against NCI-H522 non-small lung cancer cell line (GI(50) of 0.35-0.60 mu M), MCF7 breast cancer cell line (GI(50) of 0.34-0.59 mu M), and MDA-MB-468 breast cancer cell line (GI(50) of 0.23-0.40 mu M). Compound 2b was the most potent against all leukemia and prostate cancer cell lines with GI(50) values (0.29-0.60 mu M). Compound 2b inhibited the proliferation of MCF-7 and HepG2 cells by inducing cell cycle arrest and apopotosis. 2b downregulated the mRNA abundance of BAX, Apaf-1 and caspase-3 and upregulated BCL-2. The activities of caspase-3 and caspase-9 were declined in MCF-7 and HepG2 cells treated with compound 2b. Compounds 2b and 4a-2 inhibited tubulin polymerization, with an IC50 values of 0.92 and 1.13 mu M, respectively. These findings indicate that these synthesized compounds may represent potential drug candidates to inhibit the proliferation of different types of cancer cells.