Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 18, Issue 1, Pages 168-174Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2009.11.005
Keywords
Pyrrole-imidazole polyamide; DNA alkylating agent; Histone; Gene Silencing; Anticancer agent
Funding
- International Center for Integrated Research and Advanced Education in Material Science, Kyoto University, Japan
- Ministry of Education, Culture, Sports, Science, and Technology, Japan
- CREST of Japan Science and Technology (JST)
- National Cancer Institute (NIH)
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We designed and synthesized conjugates between pyrrole-imidazole polyamides and seco-CBI that alkylate within the coding regions of the histone H4 genes. DNA alkylating activity on the histone H4 fragment and cellular effects against K562 chronic myelogenous leukemia cells were investigated. One of the conjugates, 5-CBI, showed strong DNA alkylation activity and good sequence specificity on a histone H4 gene fragment. K562 cells treated with 5-CBI down-regulated the histone H4 gene and induced apoptosis efficiently. Global gene expression data revealed that a number of histone H4 genes were down-regulated by 5-CBI treatment. These results suggest that sequence-specific DNA alkylating agents may have the potential of targeting specific genes for cancer chemotherapy. (C) 2009 Elsevier Ltd. All rights reserved.
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