Synthesis and evaluation of debromohymenialdisine-derived Chk2 inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 4; pp. 1475 - 1481
• Main Authors: Saleem, Rahman Shah Zaib, Lansdell, Theresa A., Tepe, Jetze J.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.02.2012; Elsevier
• Subjects: Animals; antagonists & inhibitors; Azepines; Azepines - chemical synthesis; Azepines - chemistry; Azepines - pharmacology; Binding Sites; Biological and medical sciences; Checkpoint Kinase 1; Checkpoint Kinase 2; Checkpoint kinases; chemical synthesis; chemistry; Chk2; Crystallography, X-Ray; Debromohymenialdisine; drug effects; drugs; Enzyme Activation; Enzyme Activation - drug effects; Hymenialdisine; Inhibitory Concentration 50; Medical sciences; metabolism; metabolites; Molecular Structure; Natural products; pharmacology; Pharmacology. Drug treatments; Porifera; Porifera - chemistry; Protein Kinase Inhibitors; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacology; Protein Kinases; Protein Kinases - metabolism; Protein Serine-Threonine Kinases; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Pyrroles; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Radioprotection; Substrate Specificity; Hymenialdisine; Debromohymenialdisine; Checkpoint kinases; Chk2; Natural products; Radioprotection; Evaluation; Enzyme; Transferases; Non-specific serine/threonine protein kinase; Chemical structure; Natural compound; Signal transduction; Alkaloid; Kinase; Inhibitor; Chemical synthesis
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2011.12.054

Natural products have been the subject of interest for drug discovery and as tools for understanding the underlying cellular pathways in various diseases. We present herein the synthesis and evaluation of new analogs of the marine sponge metabolite, debromohymenialdisine, as checkpoint kinase 2 (Chk2) inhibitors. We illustrate herein that slight modifications to the natural product scaffold can induce strong selectivity for Chk2 over Chk1. These Chk2 inhibitors can serve as drug templates or molecular tools to gain insight in Chk2 mediated radioprotection.