Synthesis of Amino-Acid-Nucleoside Conjugates

Representative derivatives of uridine-conjugated amino acids that have been suitably protected for Fmoc solid-phase chemistry have been prepared through efficient procedures that use click reactions as key steps, including thiol-ene radical reactions and copper-catalyzed azide alkyne cycloaddition (CuAAC) reactions. Several linkers between the amino acid and nucleoside units, including alkyl chains and a triazole ring, have been successfully employed. Alkyl chains offer retention of flexibility, to allow the bisubstrate analogues to adopt an appropriate orientation, whilst the triazole ring can promote additional interactions at the active sites of target enzymes. Furthermore, a neutral surrogate of the pyrophosphate unit has been prepared by using a Staudinger-Vilarrasa reaction as a key step. Neutral analogues are promising surrogates for avoiding difficulties owing to cell-membrane permeability.