Synthesis and biological evaluation of 3-aminoisoquinolin-1(2H)-one based inhibitors of the dual-specificity phosphatase Cdc25B
| Autor: | John S. Lazo, William D. Paquette, Ahmet Bakan, Andreas Vogt, Paul A. Johnston, Peter Wipf, Kara M. George Rosenker, Elizabeth R. Sharlow |
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| Rok vydání: | 2014 |
| Předmět: |
DNA damage
Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Biochemistry Cyclin-dependent kinase Cell Line Tumor Neoplasms Drug Discovery Dual-specificity phosphatase Humans cdc25 Phosphatases Enzyme Inhibitors Molecular Biology Mitosis Biological evaluation Cell Proliferation biology Cell growth Chemistry Kinase Organic Chemistry Isoquinolines Molecular Docking Simulation biology.protein Molecular Medicine Pharmacophore |
| Zdroj: | Bioorganicmedicinal chemistry. 23(12) |
| ISSN: | 1464-3391 |
| Popis: | The cell division cycle 25B dual specificity phosphatase (Cdc25B) regulates the normal progression of the mammalian cell cycle by dephosphorylating and activating cyclin-dependent kinase (Cdk) complexes, particularly in response to DNA damage. Elevated Cdc25B levels enable a bypass of normal cell cycle checkpoints, and the overexpression of Cdc25B has been linked to a variety of human cancers. Thus, Cdc25B is an attractive target for the development of anticancer therapeutics. Herein we describe the synthesis and biological evaluation of a series of non-quinoid inhibitors of Cdc25B containing the 3-aminoisoquinolin-1(2H)-one pharmacophore. In addition to several strategies that address specific substitution patterns on isoquinolines, we have applied a regioselective Pd-catalyzed cross-coupling methodology to synthesize a new lead structure, 6-(3-aminophenyl)-3-(phenylamino)isoquinolin-1(2H)-one (13), which proved to be a reversible, competitive Cdc25B inhibitor with a Ki of 1.9 μM. Compound 13 prevented human cancer cell growth and blocked Cdc25B-mediated mitotic checkpoint bypass. Molecular docking studies support binding near the catalytic site. |
| Databáze: | OpenAIRE |
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