More than 150 RNA chemical modifications have been identified to date. Among them, methylation of adenosine at the N-6 position (m⁶A) is crucial for RNA metabolism, stability and other important biological events. In particular, this is the most abundant mark found in mRNA in mammalian cells. The presence of a methyl group at the N-1 position of adenosine (m¹A) is mostly found in ncRNA and mRNA and is mainly responsible for stability and translation fidelity. These modifications are installed by m⁶A and m¹A RNA methyltransferases (RNA MTases), respectively. In human, deregulation of m⁶A RNA MTases activity is associated with many diseases including cancer. To date, the molecular mechanism involved in the methyl transfer, in particular substrate recognition, remains unclear. We report the synthesis of new SAM-adenosine conjugates containing a triazole linker branched at the N-1 or N-6 position of adenosine. Our methodology does not require protecting groups for the functionalization of adenosine at these two positions. The molecules described here were designed as potential bisubstrate analogues for m⁶A and m¹A RNA MTases that could be further employed for structural studies. This is the first report of compounds mimicking the transition state of the methylation reaction catalyzed by m¹A RNA MTases.

Ruthenium(II) alkyne azide cycloaddition (RuAAC) is an attractive reaction to access 1,5‐triazole derivatives and is applicable to internal alkynes. Here, we explore RuAAC to introduce molecular diversity on the diazabicyclooctane (DBO) scaffold of β‐lactamase inhibitors. The methodology presented is fully regioselective and enabled synthesis of a series of 1,5‐triazole DBOs and trisubstituted analogues. Molecular modelling and biological evaluation revealed that the DBO substituents provided putative stabilizing interactions in the active site of broad‐spectrum β‐lactamase KPC‐2 and promising activity against a hyperpermeable strain of Escherichia coli producing KPC‐2.