title: Synthesis and Molecular-cellular Mechanistic Study of Pyridine Derivative of Dacarbazine.
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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Marzieh
authors.initials: M
authors.lastname: Amirmostofian
authors.forename: Jalal
authors.initials: J
authors.lastname: Pourahmad Jaktaji
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Soleimani
authors.forename: Kimia
authors.initials: K
authors.lastname: Tabib
authors.forename: Farahnaz
authors.initials: F
authors.lastname: Tanbakosazan
authors.forename: Mirdavood
authors.initials: M
authors.lastname: Omrani
authors.forename: Farzad
authors.initials: F
authors.lastname: Kobarfard
keywords: Cytotoxicity; Dacarbazine; Lysosome; Mitochondrial Membrane potential; Oxidative stress; Pyridine