title: Synthesis and evaluation of debromohymenialdisine-derived Chk2 inhibitors.
abstract: 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.
authors.affiliation: Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Rahman Shah Zaib
authors.initials: RS
authors.lastname: Saleem
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Lansdell
authors.forename: Jetze J
authors.initials: JJ
authors.lastname: Tepe
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011161:Porifera / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D001381:Azepines; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C097660:debromohymenialdisine; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases