Novel ROS-activated agents utilize a tethered amine to selectively target acute myeloid leukemia

被引：15

作者：

Bell-Horwath, Tiffany R. ^{[1
]}

Vadukoot, Anish K. ^{[1
]}

Thowfeik, Fathima Shazna ^{[1
]}

Li, Guorui ^{[1
]}

Wunderlich, Mark ^{[2
]}

Mulloy, James C. ^{[2
]}

Merino, Edward J. ^{[1
]}

机构：

[1] Univ Cincinnati, Dept Chem, Cincinnati, OH 45221 USA

[2] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 10期

关键词：

DNA-modifying agent; Acute myeloid leukemia; 2 '-Deoxyguanosine; Reactive oxygen species; Structure-activity; THERAPEUTIC TARGET; DNA; MUTATIONS; PRODRUGS; CELLS;

D O I：

10.1016/j.bmcl.2013.03.048

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：2951 / 2954

页数：4

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