Synthesis of 3-(1 H-benzimidazol-2-yl)-5-isoquinolin-4-ylpyrazolo[1,2- b]pyridine, a potent cyclin dependent kinase 1 (CDK1) inhibitor

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 5; pp. 1243 - 1245
• Main Authors: Huang, Shenlin, Lin, Ronghui, Yu, Yang, Lu, Yanhua, Connolly, Peter J., Chiu, George, Li, Shengjian, Emanuel, Stuart L., Middleton, Steven A.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.03.2007; Elsevier
• Subjects: Antineoplastic agents; Benzimidazoles; Biological and medical sciences; Catalysis; CDC2 Protein Kinase - antagonists & inhibitors; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclin dependent kinase 1 inhibitor; General aspects; Humans; Isoquinolines - chemical synthesis; Isoquinolines - pharmacology; Medical sciences; Palladium; Pharmacology. Drug treatments; Pyrazolo[1,2- b]pyridine; Pyridines - chemical synthesis; Pyridines - pharmacology; Structure-Activity Relationship; Sulfur; Vascular Endothelial Growth Factor Receptor-2 - drug effects; Cyclin dependent kinase 1 inhibitor; Pyrazolo[1,2- b]pyridine; Cell proliferation; Stille coupling; Isoquinoline derivatives; Angiogenic factor; Enzyme; Transferases; In vitro; Biological activity; Signal transduction; Growth factor receptor; Vascular endothelium growth factor; Pyrazolo[1,2-b]pyridine; Benzimidazole derivatives; Protein kinase; Inhibitor; Chemical synthesis; Cyclin dependent kinase; Protein-tyrosine kinase; Tumor cell
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.12.031

A novel compound 3-(1 H-benzimidazol-2-yl)-5-isoquinolin-4-ylpyrazolo[1,2- b]pyridine was discovered to be a potent CDK1 inhibitor. An efficient chemistry was developed for the synthesis, with key steps including Pd(II) catalyzed Stille coupling reaction and sulfur(0) induced benzimidazole formation. The effects on VEGFR-2 kinase and tumour cell proliferation are also described. The novel compound 3-(1 H-benzimidazol-2-yl)-5-isoquinolin-4-ylpyrazolo[1,2- b]pyridine was discovered to be a potent CDK1 inhibitor. Described here is the chemistry for its synthesis, including Pd(II) catalyzed Stille coupling reaction and sulfur(0) induced benzimidazole formation. Its effects on VEGFR-2 kinase activity and tumour cell proliferation are also described.