Synthesis of a 3,7-Disubstituted Isothiazolo[4,3-<i>b</i>]pyridine as a Potential Inhibitor of Cyclin G-Associated Kinase
Tom Grisez,
Nitha Panikkassery Ravi,
Mathy Froeyen,
Dominique Schols,
Luc Van Meervelt,
Steven De Jonghe,
Wim Dehaen
Affiliations
Tom Grisez
Department of Chemistry, Sustainable Chemistry for Metals and Molecules, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Nitha Panikkassery Ravi
Department of Chemistry, Sustainable Chemistry for Metals and Molecules, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Mathy Froeyen
Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49, P.O. Box 1041, B-3000 Leuven, Belgium
Dominique Schols
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, Herestraat 49, P.O. Box 1043, B-3000 Leuven, Belgium
Luc Van Meervelt
Department of Chemistry, Biomolecular Architecture, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Steven De Jonghe
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, Herestraat 49, P.O. Box 1043, B-3000 Leuven, Belgium
Wim Dehaen
Department of Chemistry, Sustainable Chemistry for Metals and Molecules, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Disubstituted isothiazolo[4,3-b]pyridines are known inhibitors of cyclin G-associated kinase. Since 3-substituted-7-aryl-isothiazolo[4,3-b]pyridines remain elusive, a strategy was established to prepare this chemotype, starting from 2,4-dichloro-3-nitropyridine. Selective C-4 arylation using ligand-free Suzuki-Miyaura coupling and palladium-catalyzed aminocarbonylation functioned as key steps in the synthesis. The 3-N-morpholinyl-7-(3,4-dimethoxyphenyl)-isothiazolo[4,3-b]pyridine was completely devoid of GAK affinity, in contrast to its 3,5- and 3,6-disubstituted congeners. Molecular modeling was applied to rationalize its inactivity as a GAK ligand.
