Synthesis of Stable Aminoacyl‐tRNA Analogues Containing Triazole as a Bioisoster of Esters

Stable analogues: An effective synthetic route involving cycloaddition between alkynes and azidonucleosides to afford a new class of stable aminoacyl‐tRNA analogues such as depicted is presented. Biological evaluation showed that theses new compounds act as potent inhibitors of FemXWv aminoacyl transferase, a novel drug target. magnified image Aminoacyl‐tRNAs have important roles in a variety of biological processes, including protein synthesis by ribosomes, targeting of proteins for degradation by the proteasome, and bacterial cell wall synthesis. Here we describe the synthesis of stable aminoacyl‐tRNA analogues containing 1,4‐ and 1,5‐substituted 1,2,3‐triazole rings. The procedure involves i) Cu‐ and Ru‐catalysed cycloadditions of 3′‐azidoadenosine and alkynes, which produced the 1,4 and 1,5 regioisomers of the triazoles, respectively, ii) coupling between the resulting triazole‐deoxyadenosine derivatives and a deoxycytidine phosphoramidite, and iii) the enzymatic ligation of the substituted dinucleotides with a 22 nt RNA microhelix that mimics the acceptor arm of tRNA. Nucleoside and nucleotide compounds were characterized by MS spectrometry and 1H, 31P and 13C NMR spectroscopy and were assayed for inhibition of FemXWv, an alanyltransferase essential for the formation of the peptidoglycan network of Gram‐positive bacterial pathogens. The low IC50 values obtained (2 to 4 μM) indicate that the five‐membered triazole rings acted as bioisosters of esters and can be used for the design of stable aminoacyl‐tRNA analogues.