Synthesis and biological evaluation of benzo[4,5]imidazo[1,2-c]pyrimidine and benzo[4,5]imidazo[1,2-a]pyrazine derivatives as anaplastic lymphoma kinase inhibitors

Sébastien Tardy; Alexandre Orsato; Luca Mologni; William H Bisson; Carla Donadoni; Carlo Gambacorti-Passerini; Leonardo Scapozza; David Gueyrard; Peter G Goekjian

doi:10.1016/j.bmc.2014.01.007

Synthesis and biological evaluation of benzo[4,5]imidazo[1,2-c]pyrimidine and benzo[4,5]imidazo[1,2-a]pyrazine derivatives as anaplastic lymphoma kinase inhibitors

Bioorg Med Chem. 2014 Feb 15;22(4):1303-12. doi: 10.1016/j.bmc.2014.01.007. Epub 2014 Jan 10.

Authors

Sébastien Tardy¹, Alexandre Orsato¹, Luca Mologni², William H Bisson³, Carla Donadoni², Carlo Gambacorti-Passerini², Leonardo Scapozza³, David Gueyrard¹, Peter G Goekjian⁴

Affiliations

¹ Université de Lyon, Laboratoire Chimie Organique 2-Glycochimie, ICBMS, UMR-5246, CNRS-Université Claude Bernard Lyon 1, Bât. 308 CPE Lyon, 43 Bd du 11 Novembre 1918, F-69622 Villeurbanne, France.
² University of Milano-Bicocca, Department of Health Sciences, Via Cadore 48, 20052 Monza, Italy.
³ University of Geneva, School of Pharmaceutical Sciences, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland.
⁴ Université de Lyon, Laboratoire Chimie Organique 2-Glycochimie, ICBMS, UMR-5246, CNRS-Université Claude Bernard Lyon 1, Bât. 308 CPE Lyon, 43 Bd du 11 Novembre 1918, F-69622 Villeurbanne, France. Electronic address: goekjian@univ-lyon1.fr.

PMID: 24468632
DOI: 10.1016/j.bmc.2014.01.007

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anaplastic Lymphoma Kinase
Animals
Binding Sites
Catalysis
Catalytic Domain
Cell Line
Enzyme Activation / drug effects
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry*
Imidazoles / metabolism
Mice
Molecular Docking Simulation
Palladium
Protein Binding
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Pyrazines / chemical synthesis
Pyrazines / chemistry*
Pyrazines / metabolism
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / metabolism
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / genetics
Receptor Protein-Tyrosine Kinases / metabolism
Stereoisomerism

Substances

Imidazoles
Protein Kinase Inhibitors
Pyrazines
Pyrimidines
imidazo(1,2-a)pyrazine
imidazo(1,2-c)pyrimidine
Palladium
ALK protein, human
Alk protein, mouse
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases