Abstract
Chromosomal translocations involving anaplastic lymphoma kinase (ALK) are the driving mutations for a range of cancers and ALK is thus considered an attractive therapeutic target. We synthesized a series of functionalized benzo[4,5]imidazo[1,2-c]pyrimidines and benzo[4,5]imidazo[1,2-a]pyrazines by an aza-Graebe-Ullman reaction, followed by palladium-catalyzed cross-coupling reactions. A sequential regioselective cross-coupling route is reported for the synthesis of unsymmetrically disubstituted benzo[4,5]imidazo[1,2-a]pyrazines. The inhibition of ALK was evaluated and compound 19 in particular showed good activity against both the wild type and crizotinib-resistant L1196M mutant in vitro and in ALK-transfected BaF3 cells.
Keywords:
Anaplastic lymphoma kinase; Aza-Graebe–Ullman; Kinase inhibitors; Palladium catalyzed coupling; Regioselective cross coupling.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anaplastic Lymphoma Kinase
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Animals
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Binding Sites
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Catalysis
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Catalytic Domain
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Cell Line
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Enzyme Activation / drug effects
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Humans
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Imidazoles / chemical synthesis
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Imidazoles / chemistry*
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Imidazoles / metabolism
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Mice
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Molecular Docking Simulation
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Palladium
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Pyrazines / chemical synthesis
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Pyrazines / chemistry*
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Pyrazines / metabolism
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / metabolism
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism
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Stereoisomerism
Substances
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Imidazoles
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Protein Kinase Inhibitors
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Pyrazines
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Pyrimidines
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imidazo(1,2-a)pyrazine
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imidazo(1,2-c)pyrimidine
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Palladium
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ALK protein, human
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Alk protein, mouse
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Anaplastic Lymphoma Kinase
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Receptor Protein-Tyrosine Kinases