Synthesis and biological evaluation of 2-aryl-benzimidazole derivatives of dehydroabietic acid as novel tubulin polymerization inhibitors.
Ting-Ting MiaoXu-Bing TaoDong-Dong LiHao ChenXiao-Yan JinYi GengShi-Fa WangZi-Hui YangPublished in: RSC advances (2018)
A series of novel 2-aryl-benzimidazole derivatives of dehydroabietic acid were synthesized and characterized by IR, 1 H NMR, 13 C 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 IC 50 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.
Keyphrases
- cell cycle arrest
- cell death
- pi k akt
- molecular docking
- induced apoptosis
- cell cycle
- oxidative stress
- cell proliferation
- magnetic resonance
- endoplasmic reticulum stress
- cell migration
- high resolution
- signaling pathway
- computed tomography
- mass spectrometry
- dna damage
- magnetic resonance imaging
- multiple sclerosis
- squamous cell carcinoma
- molecular dynamics simulations
- drug delivery
- positron emission tomography
- solid state
- single cell
- contrast enhanced
- transcription factor