Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs

Kyriacos C Nicolaou; Dionisios Vourloumis; Sotirios Totokotsopoulos; Athanasios Papakyriakou; Holger Karsunky; Hanan Fernando; Julia Gavrilyuk; Damien Webb; Antonia F Stepan

doi:10.1002/cmdc.201500510

Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs

ChemMedChem. 2016 Jan 5;11(1):31-7. doi: 10.1002/cmdc.201500510. Epub 2015 Nov 20.

Authors

Kyriacos C Nicolaou¹, Dionisios Vourloumis^{2

3}, Sotirios Totokotsopoulos⁴, Athanasios Papakyriakou⁵, Holger Karsunky⁶, Hanan Fernando⁶, Julia Gavrilyuk⁶, Damien Webb⁷, Antonia F Stepan⁸

Affiliations

¹ Department of Chemistry, Rice University, 6100 Main Street, Houston, TX, 77005, USA. kcn@rice.edu.
² Department of Chemistry, Rice University, 6100 Main Street, Houston, TX, 77005, USA. dionysios.vourloumis@rice.edu, d.vourloumis@inn.demokritos.gr.
³ Laboratory of Chemical Biology of Natural Products & Designed Molecules, National Centre of Scientific Research (NCSR) "Demokritos", Agia Paraskevi, Athens, 15310, Greece. dionysios.vourloumis@rice.edu, d.vourloumis@inn.demokritos.gr.
⁴ Department of Chemistry, Rice University, 6100 Main Street, Houston, TX, 77005, USA.
⁵ Laboratory of Chemical Biology of Natural Products & Designed Molecules, National Centre of Scientific Research (NCSR) "Demokritos", Agia Paraskevi, Athens, 15310, Greece.
⁶ Stemcentrx, Inc., 450 East Jamie Court, San Francisco, CA, 94080, USA.
⁷ Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, MA, 02139, USA.
⁸ Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, MA, 02139, USA. Antonia.Stepan@pfizer.com.

PMID: 26585829
DOI: 10.1002/cmdc.201500510

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 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.

Keywords: anticancer agents; biopharmaceuticals; cubane and bicyclo[1.1.1]pentanes; gleevec; imatinib analogues.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Fusion Proteins, bcr-abl / antagonists & inhibitors*
Fusion Proteins, bcr-abl / metabolism
Humans
Imatinib Mesylate / analogs & derivatives*
Imatinib Mesylate / chemical synthesis
Imatinib Mesylate / chemistry
Imatinib Mesylate / pharmacology*
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
BCR-ABL1 fusion protein, human
Protein Kinase Inhibitors
Imatinib Mesylate
Fusion Proteins, bcr-abl