Background: In spite of significant progress made toward the synthesis of triazole amino
acids as structural scaffolds of peptides and leading structures of new drugs, a need still exists for effective
methods of trisubstituted triazole amino acid synthesis.
Methods: A protocol based on ruthenium(II)-catalyzed alkyne-azide cycloaddition (RuAAC) was developed
to synthesize 5-bromo-1,4,5-trisubstituted 1,2,3-triazole-based amino acid – tert-butyl
TzlAA). Two other disubstituted regioisomers, 1,4- and 1,5-TzlAA, were also synthesized to evaluate
the influence of the 5-bromo substituent for triazole ring bioactivity.
Results: Under optimal conditions, 5Br-TzlAA was synthesized within 1 h with 93% yield. NMR confirmed
the structure of 5Br-TzlAA and showed regioselectivity of the RuAAC reaction. None of the
TzlAAs were cytotoxic for the human cell lines investigated and showed a small pro-proliferatory effect
at the highest concentrations (50-100 μg/mL) studied. A small anti-proliferative effect was visible
Conclusion: A simple and effective protocol for the synthesis of 5-bromo-1,4,5-trisubstituted TzlAA
(5Br-TzlAA) was developed. Bioassay results show that N-phthalimido modifying the TzlAAs are well
tolerated by human cells and may be used as leading or scaffold structures to design new biologically