Investigation, optimization and synthesis of sulfamoyloxy-linked aminoacyl-AMP analogues

Aminoacyl-tRNA synthetases (aaRSs) constitute a family of enzymes that transfer amino acids to their corresponding tRNA molecules to form aminoacyl-tRNAs and have been validated as potential drug targets. Sulfamoyloxy-linked aminoacyl-AMP analogues are potent inhibitors of aaRSs. In this article, we report the synthesis of several new sulfamoyl analogues of aa-AMP that up to now have been difficult or even impossible to prepare with current synthetic strategies. The developed synthetic strategy relies on performing the synthesis under neutral conditions followed by global deprotection using catalytic hydrogenation affording the desired 5′-O-(N-aminoacyl)sulfamoyladenosine compounds.