Synthesis, Molecular Docking Analysis, and In Vitro Cytotoxic Evaluation of New Fluorinated...

A series of new fluorinated γ-butyrolactone fused aza-anthraquinone derivatives were synthesized through a two-step procedure involving a three-component reaction followed by dehydro-aromatization. The final compounds were fully characterized by infrared, nuclear magnetic resonance, and high resolution mass spectroscopy. The cytotoxic activity of these compounds was assessed by screening against KB, HepG2, A549, MCF7 cell lines using MTT assay. The result revealed that 10 out of the 13 synthesized derivatives exhibited moderate to high cytotoxicity against all tested cancer cell lines. Among these compounds, compounds 6d (Ar = 2,5-difluoro-4-methoxyphenyl), 6e (Ar = 4-methoxy-2-(trifluoromethyl)phenyl), and 6i (Ar = 4-(trifluoromethyl)phenyl) have exhibited pronounced cytotoxicity for A549 cancer cell line. The interaction of new synthesized compounds with the colchicine-binding site of tubulin was investigated in silico to examine the tubulin inhibition activity of ten cytotoxic compounds. Molecular docking revealed that compounds 6d, 6e, and 6i had relatively strong binding affinity with the colchicine-binding site of tubulin and formed stable chelation with Zn²⁺. Besides that, physicochemical and absorption, distribution, metabolism, excretion, and toxicity (ADMET)-related properties were predicted to evaluate the drug-likeness of the most active compounds.