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

Abstract

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 (GI₅₀ of 0.35-0.60 µM), MCF7 breast cancer cell line (GI₅₀ of 0.34-0.59 µM), and MDA-MB-468 breast cancer cell line (GI₅₀ of 0.23-0.40 µM). Compound 2b was the most potent against all leukemia and prostate cancer cell lines with GI₅₀ values (0.29-0.60 µM). 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 µM, respectively. These findings indicate that these synthesized compounds may represent potential drug candidates to inhibit the proliferation of different types of cancer cells.

Keywords: Apoptosis; Cancer; Chromene derivatives; Cytotoxic activity; Three-component domino reaction.