Synthesis of a 3,7-Disubstituted Isothiazolo[4,3-<i>b</i>]pyridine as a Potential Inhibitor of Cyclin G-Associated Kinase
Disubstituted isothiazolo[4,3-<i>b</i>]pyridines are known inhibitors of cyclin G-associated kinase. Since 3-substituted-7-aryl-isothiazolo[4,3-<i>b</i>]pyridines remain elusive, a strategy was established to prepare this chemotype, starting from 2,4-dichloro-3-nitropyridine....
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MDPI AG
2024-02-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/29/5/954 |
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| author | Tom Grisez Nitha Panikkassery Ravi Mathy Froeyen Dominique Schols Luc Van Meervelt Steven De Jonghe Wim Dehaen |
| author_facet | Tom Grisez Nitha Panikkassery Ravi Mathy Froeyen Dominique Schols Luc Van Meervelt Steven De Jonghe Wim Dehaen |
| author_sort | Tom Grisez |
| collection | DOAJ |
| description | Disubstituted isothiazolo[4,3-<i>b</i>]pyridines are known inhibitors of cyclin G-associated kinase. Since 3-substituted-7-aryl-isothiazolo[4,3-<i>b</i>]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-<i>N</i>-morpholinyl-7-(3,4-dimethoxyphenyl)-isothiazolo[4,3-<i>b</i>]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. |
| first_indexed | 2024-04-25T00:24:23Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-25T00:24:23Z |
| publishDate | 2024-02-01 |
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| spelling | doaj.art-6adfaa32270c44a1bcf40a26f955d7cb2024-03-12T16:50:32ZengMDPI AGMolecules1420-30492024-02-0129595410.3390/molecules29050954Synthesis of a 3,7-Disubstituted Isothiazolo[4,3-<i>b</i>]pyridine as a Potential Inhibitor of Cyclin G-Associated KinaseTom Grisez0Nitha Panikkassery Ravi1Mathy Froeyen2Dominique Schols3Luc Van Meervelt4Steven De Jonghe5Wim Dehaen6Department of Chemistry, Sustainable Chemistry for Metals and Molecules, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, BelgiumDepartment of Chemistry, Sustainable Chemistry for Metals and Molecules, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, BelgiumLaboratory 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, BelgiumLaboratory 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, BelgiumDepartment of Chemistry, Biomolecular Architecture, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, BelgiumLaboratory 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, BelgiumDepartment of Chemistry, Sustainable Chemistry for Metals and Molecules, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, BelgiumDisubstituted isothiazolo[4,3-<i>b</i>]pyridines are known inhibitors of cyclin G-associated kinase. Since 3-substituted-7-aryl-isothiazolo[4,3-<i>b</i>]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-<i>N</i>-morpholinyl-7-(3,4-dimethoxyphenyl)-isothiazolo[4,3-<i>b</i>]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.https://www.mdpi.com/1420-3049/29/5/954GAKisothiazolo[4,3-<i>b</i>]pyridinekinaseinhibitor |
| spellingShingle | Tom Grisez Nitha Panikkassery Ravi Mathy Froeyen Dominique Schols Luc Van Meervelt Steven De Jonghe Wim Dehaen Synthesis of a 3,7-Disubstituted Isothiazolo[4,3-<i>b</i>]pyridine as a Potential Inhibitor of Cyclin G-Associated Kinase Molecules GAK isothiazolo[4,3-<i>b</i>]pyridine kinase inhibitor |
| title | Synthesis of a 3,7-Disubstituted Isothiazolo[4,3-<i>b</i>]pyridine as a Potential Inhibitor of Cyclin G-Associated Kinase |
| title_full | Synthesis of a 3,7-Disubstituted Isothiazolo[4,3-<i>b</i>]pyridine as a Potential Inhibitor of Cyclin G-Associated Kinase |
| title_fullStr | Synthesis of a 3,7-Disubstituted Isothiazolo[4,3-<i>b</i>]pyridine as a Potential Inhibitor of Cyclin G-Associated Kinase |
| title_full_unstemmed | Synthesis of a 3,7-Disubstituted Isothiazolo[4,3-<i>b</i>]pyridine as a Potential Inhibitor of Cyclin G-Associated Kinase |
| title_short | Synthesis of a 3,7-Disubstituted Isothiazolo[4,3-<i>b</i>]pyridine as a Potential Inhibitor of Cyclin G-Associated Kinase |
| title_sort | synthesis of a 3 7 disubstituted isothiazolo 4 3 i b i pyridine as a potential inhibitor of cyclin g associated kinase |
| topic | GAK isothiazolo[4,3-<i>b</i>]pyridine kinase inhibitor |
| url | https://www.mdpi.com/1420-3049/29/5/954 |
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