Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 23, Issue 10, Pages 2951-2954Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.03.048
Keywords
DNA-modifying agent; Acute myeloid leukemia; 2 '-Deoxyguanosine; Reactive oxygen species; Structure-activity
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Funding
- University of Cincinnati
- University Research Council
- Institutional Clinical and Translational Science Award, NIH/NCRR [1UL1RR026314-01]
- Center of Excellence in Molecular Hematology P30 award [DK090971]
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This study explores the possible use of reactive oxygen-activated DNA modifying agents against acute myeloid leukemia (AML). A key amine on the lead agent was investigated via cytotoxicity assays and was found necessary for potency. The two best compounds were screened via the NCI-60 cell panel. These two compounds had potency between 200 and 800 nM against many of the leukemia cancer cell types. Subsequent experiments explored activity against a transformed AML model that mimics the molecular signatures identified in primary AML patient samples. A lead compound had an IC50 of 760 nM against this AML cell line as well as a therapeutic index of 7.7 +/- 3 between the transformed AML model cell line and non-cancerous human CD34+ blood stem/progenitor cells (UCB). The selectivity was much greater than the mainstays of AML treatment: doxorubicin and cytarabine. This manuscript demonstrates that this novel type of agent may be useful against AML. (C) 2013 Elsevier Ltd. All rights reserved.
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