title: DNA site-specific N3-adenine methylation targeted to estrogen receptor-positive cells.
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.
authors.affiliation: Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Wilmington, NC 28403-5932, USA.
authors.forename: Rigel J
authors.initials: RJ
authors.lastname: Kishton
authors.forename: Sean E
authors.initials: SE
authors.lastname: Miller
authors.forename: Heather
authors.initials: H
authors.lastname: Perry
authors.forename: Tera
authors.initials: T
authors.lastname: Lynch
authors.forename: Mayur
authors.initials: M
authors.lastname: Patel
authors.forename: Vinayak K
authors.initials: VK
authors.lastname: Gore
authors.forename: Giridhar R
authors.initials: GR
authors.lastname: Akkaraju
authors.forename: Sridhar
authors.initials: S
authors.lastname: Varadarajan
mesh_terms: D000225:Adenine / Q000737:chemistry*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D019175:DNA Methylation; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D000077267:Fulvestrant; D006801:Humans; D056004:Molecular Dynamics Simulation; D009429:Netropsin / Q000494:pharmacology; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol; D009429:Netropsin; D004247:DNA; D000225:Adenine