Author/Authors :
Amirmostofian, Marzieh Department of Medicinal Chemistry - School of Pharmacy - Shahid Beheshti University of Medical Sciences, Tehran , Pourahmad Jaktaji, Jalal Department of Pharmacology and Toxicology - School of Pharmacy - Shahid Beheshti University of Medical Sciences, Tehran , Soleimani, Zohreh Department of Medicinal Chemistry - School of Pharmacy - Shahid Beheshti University of Medical Sciences, Tehran , Tabib, Kimia Department of Medicinal Chemistry - School of Pharmacy - Shahid Beheshti University of Medical Sciences, Tehran , Tanbakosazan, Farahnaz Department of Pharmacology and Toxicology - School of Pharmacy - Shahid Beheshti University of Medical Sciences, Tehran , Omrani, Mirdavood Department of Genetics - School of Medicine - Shahid Beheshti University of Medical Sciences, Tehran , Kobarfard, Farzad Department of Medicinal Chemistry - School of Pharmacy and Phytochemistry Research Center Shahid Beheshti University of Medical Sciences, Tehran
Abstract :
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 μM and 33 μM 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 causedlysosomal membrane rupture. Cytotoxicity was prevented by ROS scavengers and antioxidants. Cytotoxicity wasalso prevented by CYP450 inhibitors, lysosomalinactivators and MPT (Mitochondrial Permeability Transition Pore) blockers.
Keywords :
Dacarbazine , Pyridine , Cytotoxicity , Oxidative stress , Lysosome , Mitochondrial Membrane potential
