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Synthetic Generation of an Azide-Bearing N-Mustard Cofactor Mimic of S-Adenosyl-L-Methionine

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abstract
The synthesis of an azide-bearing N-mustard cofactor, 8-azido-5’-(diaminobutyric acid)-N-iodoethyl-5’-deoxyadenosine ammonium hydrochloride (2.1), has been accomplished with a small amount of impurity in several steps from commercially available 2’,3’-isopropylidene adenosine (2.2). This cofactor was designed to efficiently mimic S-adenosyl-L-methionine (SAM) by incorporating an N-mustard and an amino acid moiety surrounding an adenosine core. In addition, an azide functionality was introduced for post-alkylation modification. The crucial factors that led to this success were (1) the choice of the proper alcohol protecting group and (2) the installation of the azide functionality at the C8 position of the adenine base prior to the incorporation of N-mustard and amino acid moieties. Cofactor 2.1 was found to be effectively transferred onto DNA by M.TaqI, providing an azide-bearing modified DNA that will allow for subsequent chemoselective ligation chemistry that is hypothesized to facilitate the detection of biological methylation sites.
subject
DNA Methylation
Nitrogen Mustard
S-adenosyl-L-methionine
contributor
Mai, Van (author)
Comstock, Lindsay R (committee chair)
Alexander, Rebecca W (committee member)
King, S. Bruce (committee member)
date
2011-07-14T20:36:30Z (accessioned)
2011-07-14T20:36:30Z (available)
2011 (issued)
degree
Chemistry (discipline)
identifier
http://hdl.handle.net/10339/33500 (uri)
language
en (iso)
publisher
Wake Forest University
title
Synthetic Generation of an Azide-Bearing N-Mustard Cofactor Mimic of S-Adenosyl-L-Methionine
type
Thesis

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