Bioorganic & Medicinal Chemistry 2011-09-01

DNA site-specific N3-adenine methylation targeted to estrogen receptor-positive cells.

Rigel J Kishton, Sean E Miller, Heather Perry, Tera Lynch, Mayur Patel, Vinayak K Gore, Giridhar R Akkaraju, Sridhar Varadarajan

Index: Bioorg. Med. Chem. 19 , 5093-102, (2011)

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Abstract

A compound that can target cells expressing the estrogen receptor (ER), and produce predominantly 3-MeA adducts in those cells has been designed and synthesized. This compound produces mainly the 3-MeA adduct upon reaction with calf thymus DNA, and binds to the ER with a relative binding affinity of 51% (estradiol = 100%). The compound is toxic to ER-expressing MCF-7 breast cancer cells, and pre-treatment with the ER antagonist fulvestrant abrogates the toxicity. Pre-treatment of MCF-7 cells with netropsin, which inhibits N3-adenine methylation by the compound, resulted in a threefold decrease in the toxicity. These results demonstrate the feasibility of this strategy for producing 3-MeA adducts in targeted cells.Copyright © 2011 Elsevier Ltd. All rights reserved.