5′-(N-aminoacyl)-sulfonamido-5′-deoxyadenosine: Attempts for a stable alternative for aminoacyl-sulfamoyl adenosines as aaRS inhibitors

• Aminoacylated 5′-sulfonamido-5′-dA analogues (aaSoAs) were synthesized.
• Deletion of 5′-oxygen of aaSA analogues leads to loss of affinity for aaRSs.
• Aspartyl derivative 15f exhibits aaRS inhibition comparable to its aaSA analogue.
• Amino acid removal of either aaSoAs or aaSAs leads to affinity loss for aaRS.

Synthesis of aminoacyl-sulfamoyl adenosines (aaSAs) and their peptidyl conjugates as aminoacyl tRNA synthetase (aaRS) inhibitors remains problematic due to the low yield of the aminoacylation and the subsequent conjugation reaction causing concomitant formation of a cyclic adenosine derivative. In an effort to reduce this undesirable side reaction, we aimed to prepare the corresponding aminoacyl sulfonamide (aaSoA) analogues as more stable alternatives for aaSA derivatives. Deletion of the 5′-oxygen in aaSA analogues should render the C-5′ less electrophilic and therefore improve the stability of the aminoacyl sulfamate analogues. We therefore synthesized six sulfonamides and compared their activity against the respective aaSA analogues. However, except for the aspartyl derivative, the new compounds are not able to inhibit the corresponding aaRS. Possible reasons for this loss of activity are discussed by modeling and comparison of the newly synthesized aaSoA derivatives with their parent aaSA analogues.

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