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

The synthesis of an azide-bearing <italic>N</italic>-mustard cofactor, 8-azido-5&rsquo;-(diaminobutyric acid)-<italic>N</italic>-iodoethyl-5&rsquo;-deoxyadenosine ammonium hydrochloride (<bold>2.1</bold>), has been accomplished with a small amount of impurity in several steps from commercially available 2&rsquo;,3&rsquo;-isopropylidene adenosine (<bold>2.2</bold>). This cofactor was designed to efficiently mimic <italic>S</italic>-adenosyl-L-methionine (SAM) by incorporating an <italic>N</italic>-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 <italic>C</italic>8 position of the adenine base prior to the incorporation of <italic>N</italic>-mustard and amino acid moieties. Cofactor <bold>2.1</bold> was found to be effectively transferred onto DNA by <italic>M.TaqI</italic>, 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.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2011

Author dc:creator

• Mai, Van

• DNA Methylation

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/33500

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/33500