Abstract
A series of novel 2-aryl-benzimidazole derivatives of dehydroabietic acid were synthesized and characterized by IR, 1H NMR, 13C NMR, MS and elemental analyses. All the target compounds were evaluated for their in vitro cytotoxic activity against SMMC-7721, MDA-MB-231, HeLa and CT-26 cancer cell lines and the normal hepatocyte cell line QSG-7701 through MTT assays. Among them, compound 6j displayed the most potent cytotoxic activity with IC50 values of 0.08 ± 0.01, 0.19 ± 0.04, 0.23 ± 0.05 and 0.42 ± 0.07 μM, respectively, and substantially reduced cytotoxicity against QSG-7701 cells (5.82 ± 0.38 μM). The treatment of SMMC-7721 cells with compound 6j led to considerable inhibition of cell migration ability. The influence of compound 6j on cell cycle distribution was assessed on SMMC-7721 cells, exhibiting a cell cycle arrest at the G2/M phase. Moreover, tubulin polymerization assays and immunofluorescence assays elucidated that compound 6j could significantly inhibit tubulin polymerization and disrupt the intracellular microtubule network. A molecular docking study provided insight into the binding mode of compound 6j in the colchicine site of tubulin. In addition, compound 6j was found to induce apoptosis of SMMC-7721 cells, an increase of intracellular ROS level and a loss of mitochondrial membrane potential in a dose-dependent manner. These findings provided new molecular scaffolds for the further development of novel antitumor agents targeting tubulin polymerization.
Highlights
Microtubules, as key components of the cytoskeleton, are dynamic polymers of a, b-tubulin and involved in a series of important cellular processes including regulation of motility, cell signaling, maintenance of cell shape, cell proliferation and intracellular transport.[1,2,3,4] Due to the multiple functions of microtubules in the cell cycle, tubulin has become an attractive target for the development of novel antimitotic agents for cancer therapy.[5,6] Antimitotic agents are generally divided into two types: microtubule stabilizing agents and tubulin polymerization inhibitors
Two nitro groups of compound 4 were reduced by Fe powder to afford the diamino derivatives 5 in 57% yield, which was reacted with different substituted arylaldehyde to get a series of 20-aryl-12-bromobenzimidazole derivatives (6a–k) in 60–83% yield
Compound 6j exhibited the most potent anticancer activity against all test cancer cell lines and it was found to be comparatively safe towards human normal hepatocyte cell line QSG-7701
Summary
Microtubules, as key components of the cytoskeleton, are dynamic polymers of a, b-tubulin and involved in a series of important cellular processes including regulation of motility, cell signaling, maintenance of cell shape, cell proliferation and intracellular transport.[1,2,3,4] Due to the multiple functions of microtubules in the cell cycle, tubulin has become an attractive target for the development of novel antimitotic agents for cancer therapy.[5,6] Antimitotic agents are generally divided into two types: microtubule stabilizing agents (e.g., paclitaxel, epothilones) and tubulin polymerization inhibitors (e.g., vinca alkaloids, colchicine). DAA and its derivatives has been found to exhibit a broad spectrum of biological activities, such as antimicrobial, antiprotozoal, antiviral, antiulcer, anti-aging and radical scavenging activities.[32,33,34,35,36,37] Especially, a lot of DAA derivatives have been reported exhibiting prominent anticancer activity through various mechanisms including DNA binding,[38] induction of apoptosis[39] or oncosis[40] and inhibition of cancer cell migration.[41] These results suggest that dehydroabietic acid is a promising lead compound for the investigation of new anticancer agents, and the incorporation of benzimidazole and TMP moieties to the structure of DAA may result in novel hybrid molecules with improved antimitotic properties. The possible anticancer mechanisms of these derivatives as tubulin polymerization inhibitor and apoptosis inducer were preliminarily explored
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