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CHARACTERIZATION OF THE RNA BINDING MODE OF A PLATINUM-ACRIDINE AGENT

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abstract
Pt-ACRAMTU (ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea) is a DNA-targeted anticancer agent that shows activity in a broad range of solid tumor cell lines. Unlike the classical platinum-based cross-linking drugs, this agent produces its cytotoxic effect by two synergistic DNA binding mechanisms: monofunctional platination and intercalation of the acridine chromophore. The RNA binding of platinum drugs has been studied to a much lesser extent. Recently, the RNA interactions of platinum-containing drugs and drug conjugates have been reported. In the current study, an RNA hairpin has been generated through in vitro transcription and treated with Pt-ACRAMTU. Our goal was to determine if specific RNA structural motifs are susceptible to intercalator-driven platination. Acidic digestion assays in conjunction with liquid chromatography-electrospray mass spectrometry analysis (LC-ESMS) was used to determine the specific bases modified by platinum. In addition, the RNA conformational changes induced by ACRAMTU and PT-ACRAMTU were also analyzed by circular dichroism (CD) spectroscopy.
subject
Biochemistry
Medicinal Chemistry
contributor
Vasquez-Valdivieso, Montserrat Guadalupe (author)
Alexander, Rebecca (committee chair)
Bierbach, Ulrich (committee member)
Dos Santos, Patricia (committee member)
date
2009-08-18T15:15:36Z (accessioned)
2010-06-18T18:58:30Z (accessioned)
2009-08-18T15:15:36Z (available)
2010-06-18T18:58:30Z (available)
2009-08-18T15:15:36Z (issued)
degree
Chemistry (discipline)
identifier
http://hdl.handle.net/10339/14770 (uri)
language
en (iso)
publisher
Wake Forest University
rights
Release the entire work immediately for access worldwide. (accessRights)
title
CHARACTERIZATION OF THE RNA BINDING MODE OF A PLATINUM-ACRIDINE AGENT
type
Thesis

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