Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs |
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| Authors: | Prof Kyriacos C Nicolaou Dr Dionisios Vourloumis Dr Sotirios Totokotsopoulos Dr Athanasios Papakyriakou Dr Holger Karsunky Hanan Fernando Dr Julia Gavrilyuk Dr Damien Webb Dr Antonia F Stepan |
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| Affiliation: | 1. Department of Chemistry, Rice University, Houston, TX, USA;2. Laboratory of Chemical Biology of Natural Products & Designed Molecules, National Centre of Scientific Research (NCSR) “Demokritos”, Athens, Greece;3. Stemcentrx, Inc., San Francisco, CA, USA;4. Pfizer Worldwide Research & Development, Cambridge, MA, USA |
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| Abstract: | 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 bicyclo1.1.1]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. |
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| Keywords: | anticancer agents biopharmaceuticals cubane and bicyclo[1 1 1]pentanes gleevec imatinib analogues |
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