Journal
CHEMMEDCHEM
Volume 11, Issue 1, Pages 31-37Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201500510
Keywords
anticancer agents; biopharmaceuticals; cubane and bicyclo[1; 1; 1]pentanes; gleevec; imatinib analogues
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Funding
- Cancer Prevention & Research Institute of Texas (CPRIT), USA
- Welch Foundation, Houston, USA [C-1819]
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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.
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