Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 23, Issue 7, Pages 2056-2060Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.02.007
Keywords
Cdc7 inhibitors; Azaindole; Cell division cycle; Conformational analysis
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Cdc7 kinase is responsible for the initiation and regulation of DNA replication and has been proposed as a target for cancer therapy. We have identified a class of Cdc7 inhibitors based on a substituted indole core. Synthesis of focused indole and azaindole analogs yielded potent and selective 5-azaindole Cdc7 inhibitors with improved intrinsic metabolic stability (ie 36). In parallel, quantum mechanical conformational analysis helped to rationalize SAR observations, led to a proposal of the preferred binding conformation in the absence of co-crystallography data, and allowed the design of 7-azaindole 37 as a second lead in this series. (C) 2013 Elsevier Ltd. All rights reserved.
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