Synthetic 1,2,4-triazole-3-carboxamides Induce Cell Cycle Arrest and Apoptosis in Leukemia Cells.

Abstract

A number of studies demonstrate the efficacy of ribavirin against various cancer types in in vitro and in vivo models. However, ribavirin induces the development of multiple side effects, suggesting a high demand for ribavirin analogues with improved therapeutic indexes. This study was focused on the analysis of ribavirin, its aglycon 1,2,4-triazole-3-carboxamide, and several of its derivatives activities in blood cancer cells in vitro. Four 1,2,4-triazole-3-carboxamide derivatives were designed and synthesized. Antiproliferative effects were evaluated in chronic myeloid leukemia cells К562 and acute lymphoblastic leukemia cells CCRF-SB as well as in the cells of whole blood mononuclear fraction of healthy volunteers by cell counting using the trypan blue exclusion method. Cell cycle distribution and apoptosis under the influence of the compounds were analyzed by flow cytometry with PI staining, and then apoptosis data were confirmed by Western blot analysis for PARP1 and caspase-3 cleavage. We demonstrated the significant antiproliferative effect of 5-(tetrahydropyran-2-yl)-1,2,4-triazole-3- carboxamide and 1-(tetrahydropyran-2-yl)-1,2,4-triazol-3-carboxamide in leukemia cell lines in vitro in comparison to non-transformed monocytes, providing the rationale for further studies of 1,2,4-triazole-3-carboxamide derivatives as anti-leukemia drugs. These results implied that the 1,2,4-triazole-3-carboxamide derivatives exhibited their antiproliferative activities by induction of cell cycle arrest. Consequently, 5-(tetrahydropyran-2-yl)-1,2,4-triazole-3-carboxamide and 1-(tetrahydrofuran-2-yl)-1,2,4-triazol-3-carboxamide may present antimetabolites with potential anticancer efficacy.