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Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs
Author(s) -
Nicolaou Kyriacos C.,
Vourloumis Dionisios,
Totokotsopoulos Sotirios,
Papakyriakou Athanasios,
Karsunky Holger,
Fernando Hanan,
Gavrilyuk Julia,
Webb Damien,
Stepan Antonia F.
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500510
Subject(s) - cytotoxicity , chemistry , moiety , imatinib , stereochemistry , structure–activity relationship , kinase , molecular model , imatinib mesylate , combinatorial chemistry , biopharmaceutical , biochemistry , in vitro , biology , cancer research , myeloid leukemia , genetics
A convenient synthesis of imatinib, a potent inhibitor of ABL1 kinase and widely prescribed drug for the treatment of a variety of leukemias, was devised and applied to the construction of a series of novel imatinib analogues featuring a number of non‐aromatic structural motifs in place of the parent molecule's phenyl moiety. These analogues were subsequently evaluated for their biopharmaceutical properties (e.g., ABL1 kinase inhibitory activity, cytotoxicity). The bicyclo[1.1.1]pentane‐ and cubane‐containing analogues were found to possess higher themodynamic solubility, whereas cubane‐ and cyclohexyl‐containing analogues exhibited the highest inhibitory activity against ABL1 kinase and the most potent cytotoxicity values against cancer cell lines K562 and SUP‐B15. Molecular modeling was employed to rationalize the weak activity of the compounds against ABL1 kinase, and it is likely that the observed cytotoxicity of these agents arises through off‐target effects.