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.
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.
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.
Sébastien
S
Tardy
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.
Alexandre
A
Orsato
University of Milano-Bicocca, Department of Health Sciences, Via Cadore 48, 20052 Monza, Italy.
Luca
L
Mologni
University of Geneva, School of Pharmaceutical Sciences, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland.
William H
WH
Bisson
University of Milano-Bicocca, Department of Health Sciences, Via Cadore 48, 20052 Monza, Italy.
Carla
C
Donadoni
University of Milano-Bicocca, Department of Health Sciences, Via Cadore 48, 20052 Monza, Italy.
Carlo
C
Gambacorti-Passerini
University of Geneva, School of Pharmaceutical Sciences, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland.
Leonardo
L
Scapozza
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.
David
D
Gueyrard
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.
Peter G
PG
Goekjian
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D020134:Catalytic Domain; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D010165:Palladium; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism
D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011743:Pyrimidines; C556838:imidazo(1,2-a)pyrazine; C584266:imidazo(1,2-c)pyrimidine; D010165:Palladium; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
Anaplastic lymphoma kinase; Aza-Graebe–Ullman; Kinase inhibitors; Palladium catalyzed coupling; Regioselective cross coupling