Publication: Molecular modeling and assessment of cytotoxic and apoptotic potentials of imatinib analogues featuring (thio)urea motifs in human leukemia and lymphoma cells
No Thumbnail Available
Date
2020
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
MARMARA UNIV
Abstract
Imatinib is a well-known anticancer drug. In this study, cytotoxic properties of thirty-two imatinib analogues featuring (thio)urea motifs have been evaluated against chronic myeloid leukemia (K562), Burkitt lymphoma (Raji) and mouse embryonic fibroblast (NIH 3T3) cells. IC50 values of selected eleven compounds were calculated against K562 and NIH 3T3 cells. Apoptotic properties of the most active three compounds were evaluated on K652 cells subsequently. Favorably, compounds 19, 31 and 32 induced early apoptotic changes on K562 cells. Loss of membrane potential as well as caspase-3 and caspase-9 activation was determined in the present study. Levels of anti-apoptotic proteins, Bcl-XL and Bcl-2 decreased after the implementation of compounds 19, 31 and 32 at 10 mu M and 50 mu M concentrations. To reveal further molecular insight into the anticancer activity of the compounds, compounds 19, 31 and 32 were docked into ABL kinase protein as imatinib shows anticancer activity by inhibiting this enzyme. Modeling studies demonstrated significant molecular interactions between compounds 19, 31 and 32 and ABL protein. Compounds 19, 31 and 32 showed excellent superposition with imatinib in the binding site of ABL. These findings suggest that compounds 19, 31 and 32 have potential to show anticancer activity against chronic myeloid leukemia.
Description
Keywords
Imatinib analogues, ABL kinase, chronic myeloid leukemia, lymphoma, molecular modeling, docking, ABL TYROSINE KINASE, SORAFENIB, INHIBITION, DISCOVERY