title: Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs.
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.
authors.affiliation: Department of Chemistry, Rice University, 6100 Main Street, Houston, TX, 77005, USA. kcn@rice.edu.
authors.forename: Kyriacos C
authors.initials: KC
authors.lastname: Nicolaou
authors.affiliation: Department of Chemistry, Rice University, 6100 Main Street, Houston, TX, 77005, USA. dionysios.vourloumis@rice.edu, d.vourloumis@inn.demokritos.gr.|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.
authors.forename: Dionisios
authors.initials: D
authors.lastname: Vourloumis
authors.affiliation: Department of Chemistry, Rice University, 6100 Main Street, Houston, TX, 77005, USA.
authors.forename: Sotirios
authors.initials: S
authors.lastname: Totokotsopoulos
authors.affiliation: Laboratory of Chemical Biology of Natural Products & Designed Molecules, National Centre of Scientific Research (NCSR) "Demokritos", Agia Paraskevi, Athens, 15310, Greece.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Papakyriakou
authors.affiliation: Stemcentrx, Inc., 450 East Jamie Court, San Francisco, CA, 94080, USA.
authors.forename: Holger
authors.initials: H
authors.lastname: Karsunky
authors.affiliation: Stemcentrx, Inc., 450 East Jamie Court, San Francisco, CA, 94080, USA.
authors.forename: Hanan
authors.initials: H
authors.lastname: Fernando
authors.affiliation: Stemcentrx, Inc., 450 East Jamie Court, San Francisco, CA, 94080, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Gavrilyuk
authors.affiliation: Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: Damien
authors.initials: D
authors.lastname: Webb
authors.affiliation: Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, MA, 02139, USA. Antonia.Stepan@pfizer.com.
authors.forename: Antonia F
authors.initials: AF
authors.lastname: Stepan
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C581634:BCR-ABL1 fusion protein, human; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: anticancer agents; biopharmaceuticals; cubane and bicyclo[1.1.1]pentanes; gleevec; imatinib analogues