Design, synthesis and cytotoxicity evaluation of new 1,2-diaryl-4, 5, 6, 7-tetrahydro-1H-benzo[d] imidazolesas tubulin inhibitors

A new series of 1,2-diaryl-4,5,6,7-tetrahydro-1H-benzo[d]imidazoles, possessing trimethoxyphenyl pharmacophore, were synthesized to evaluate their biological activities as tubulin inhibitors. Cytotoxic activity of the synthesized compounds 7a-f was assessed against several human cancer cell lines, including MCF-7 [breast cancer cell], HEPG2 [liver hepatocellular cells], A549 [adenocarcinomic human alveolar basal epithelial cells], T47D [Human ductal breast epithelial tumor cell line] and fibroblast. According to our results, HEPG2 seems to be the most sensitive, while MCF7 was the most resistant cell line to the compounds. All the compounds expect 7b, possessed satisfactory activity against HEPG2 with mean IC[50] values ranging from 15.60 to 43.81 micro M

Synthesis and molecular-cellular mechanistic study of pyridine derivative of dacarbazine

Dacarbazine is an antitumor prodrug which is used for the treatment of malignant metastatic melanoma and Hodgkin's disease. It requires initial activation in liver through an N-demethylationreaction. The active metabolite prevents the progress of disease via alkylation of guanine bases in DNA strands. In order to investigate the importance of imidazole ring and its dynamictautomerization in anticancer activity of dacarbazine, a pyridine analog of this drug was synthesized and the cytotoxic activity and cellular-molecular mechanisms of action for this compound were compared with those of dacarbazine. EC50 values for dacarbazine and the pyridine analog were found to be 56 micro M and 33 micro M respectively. Both dacarbazine and the pyridine analog resulted in formation of reactive oxygen species [ROS] upon their addition to the isolated rat hepatocytes. They also decreased the mitochondrial membrane potential and caused lysosomal membrane rupture. Cytotoxicity was prevented by ROS scavengers and antioxidants. Cytotoxicity was also prevented by CYP[450] inhibitors, lysosomalinactivators and MPT [Mitochondrial Permeability Transition Pore] blockers