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While RNA MTases are promising drug targets, new molecules are needed to fully understand their roles in disease and to develop effective drugs that can modulate their activity. Since RNA MTases are suitable for bisubstrate binding, we report an original strategy for the synthesis of a new family of m6A MTases bisubstrate analogues. Six compounds containing a S\u2010adenosyl\u2010L\u2010methionine (SAM) analogue unit covalently tethered by a triazole ring to the N\u20106 position of an adenosine were synthesized. A procedure using two transition\u2010metal\u2010catalyzed reactions was used to introduce the \u03b1\u2010amino acid motif mimicking the methionine chain of the cofactor SAM. First, a copper(I)\u2010catalyzed alkyne\u2010azide iodo\u2010cycloaddition (iCuAAC) reaction afforded the 5\u2010iodo\u20101,4\u2010disubstituted\u20101,2,3\u2010triazole which was functionalized by palladium\u2010catalyzed cross\u2010coupling to connect the \u03b1\u2010amino acid substituent. Docking studies of our molecules in the active site of the m6A ribosomal MTase RlmJ show that the use of triazole as a linker provides additional interactions and the presence of the \u03b1\u2010amino acid chain stabilizes the bisubstrate. The synthetic method developed here enhances the structural diversity of bisubstrate analogues to explore the active site of RNA modification enzymes and to develop new inhibitors.<\/jats:p>","DOI":"10.1002\/chem.202301134","type":"journal-article","created":{"date-parts":[[2023,5,24]],"date-time":"2023-05-24T04:49:42Z","timestamp":1684903782000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Synthesis of Bisubstrate Analogues for RNA Methylation Studies using two Transition\u2010Metal\u2010Catalyzed Reactions"],"prefix":"10.1002","volume":"29","author":[{"given":"Dylan","family":"Coelho","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, CNRS Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques  75006 Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurent","family":"Le Corre","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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