5-aza-5,6-dihydro-dC-CE Phosphoramidite

Cytosine-5-methyltransferases are found in everything from archaebacteria to mammals and when the regulation of cytosine-5-methyltransferases goes awry, cancer can result. The mechanism of action for this family of enzymes involves attack of a cysteine thiol group on the C6 position of cytosine, leading to a transient dihydrocytosine intermediate, which then facilitates the nucleophilic attack by C5 on the activated methyl group of the S-adenosyl-L-methionine cofactor. As with many enzymes, the intermediate can be trapped using a suicide substrate and 5-fluoro-cytosine has been used extensively in this role. An alternate strategy is to use a transition-state mimic that binds to the active site with high affinity. An excellent candidate was found in 5-aza-5,6-dihydrocytosine. Despite not being covalently bound to the enzyme, it was found1,2 to be a more potent inhibitor of cytosine-5-methyltransferases than 5-fluoro-cytosine. 5-Aza-5,6-dihydro-dC is compatible with standard oligonucleotide synthesis and deprotection conditions and is an excellent tool for use in methyltransferase research.