Synthesis of SAM-Adenosine Conjugates for the Study of m6A-RNA Methyltransferases

RNA methyltransferases (RNMTs) catalyze the methylation of RNA using S-adenosyl-l-methionine (SAM) as the methyl donor. Methylation at the N-6 position of adenosine is the most abundant modification found in nearly all classes of RNAs and contributes to the regulation of many biological processes in the three domains of life. However, this family of enzymes remains relatively unexplored by the medicinal chemistry community and new molecules are needed for their studies. Since RNMTs are suitable for bisubstrate binding, we report here the synthesis of SAM-adenosine conjugates as bisubstrate analogues for RNMTs responsible for methylation of the N6-position of adenosine. Six compounds were synthesized by connecting an analogue of SAM to an adenosine unit chosen to mimic the RNA substrate, via alkyl and urea linkers.