Synthesis and evaluation of debromohymenialdisine-derived Chk2 inhibitors

Rahman Shah Zaib Saleem; Theresa A Lansdell; Jetze J Tepe

doi:10.1016/j.bmc.2011.12.054

Synthesis and evaluation of debromohymenialdisine-derived Chk2 inhibitors

Bioorg Med Chem. 2012 Feb 15;20(4):1475-81. doi: 10.1016/j.bmc.2011.12.054. Epub 2012 Jan 11.

Authors

Rahman Shah Zaib Saleem¹, Theresa A Lansdell, Jetze J Tepe

Affiliation

¹ Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA.

PMID: 22285028
DOI: 10.1016/j.bmc.2011.12.054

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Azepines / chemical synthesis
Azepines / chemistry*
Azepines / pharmacology*
Binding Sites
Checkpoint Kinase 1
Checkpoint Kinase 2
Crystallography, X-Ray
Enzyme Activation / drug effects
Inhibitory Concentration 50
Molecular Structure
Porifera / chemistry
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / pharmacology
Protein Kinases / metabolism
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Pyrroles / chemical synthesis
Pyrroles / chemistry*
Pyrroles / pharmacology*
Substrate Specificity

Substances

Azepines
Protein Kinase Inhibitors
Pyrroles
debromohymenialdisine
Protein Kinases
Checkpoint Kinase 2
Checkpoint Kinase 1
Protein Serine-Threonine Kinases