DNA methylation and cytotoxic properties of compound designed to produce N3-methyladenine adducts in estrogen receptor-positive cells.
Presentation
Overview
Overview
Description
This paper describes the development of a compound designed to produce cytotoxic, non-mutagenic N3-methyladenine DNA adducts in estrogen receptor-positive cells. This compound is composed of three units: a central bis-pyrrole triamide unit known to bind to A/T rich regions of DNA in the minor groove, a reactive methyl sulfonate unit tethered to one side of the bis-pyrrole unit in order to achieve DNA-methylation at sites where the compound binds, and an alkyl estradiol unit tethered to the other side of the bis-pyrrrole unit in order to achieve selectivity for cells that express the estrogen receptor. This compound was synthesized and its DNA-methylation and cell toxicity characteristics were investigated. Upon reaction with genomic DNA, the compound predominantly produces N3-methyladenine DNA adducts (over 80 %) and these adducts are produced only at A/T-rich regions. This compound has been found to be toxic to MCF-7 cells, and the toxicity for this compound is at least an order of magnitude higher than that observed with methyl methane sulfonate. Preliminary studies have indicated that the toxicity of the compound is due to DNA methylation, and that this toxicity is mediated by the estrogen receptor. This poster describes the synthesis of the compound, and presents the results from the DNA-methylation and cell-toxicity studies.
