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Ru(II)-mediated Synthesis and Bioactivity Evaluation of 1,4,5- trisubstituted N-phthalimido Protected 5-bromo-1,2,3-triazolic Amino Acid

[ Vol. 15 , Issue. 4 ]

Author(s):

Piotr Mucha*, Malgorzata Pieszko, Anna Miszka, Jaroslaw Ruczynski, Piotr Rekowski, Izabela Zaluska, Agnieszka Kozlowska, Adriana Schumacher, Milena Deptula and Michal Pikula   Pages 282 - 289 ( 8 )

Abstract:


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 5-bromo-1-(2-(1,3-dioxo-2,3dihydro-1H-isoindol-2-yl)ethyl]-1H-1,2,3-triazole-4-carboxylate (5Br- 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 for 1,4-TzlAA.

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 active molecules.

Keywords:

Click chemistry, N-phthalimido 1, 2, 3-triazole amino acid, trisubstituted triazole, proliferative activity, cytotoxicity, RuAAC.

Affiliation:

Faculty of Chemistry, University of Gdansk Wita Stwosza 63, Gdansk 80-308, Faculty of Chemistry, University of Gdansk Wita Stwosza 63, Gdansk 80-308, Faculty of Chemistry, University of Gdansk Wita Stwosza 63, Gdansk 80-308, Faculty of Chemistry, University of Gdansk Wita Stwosza 63, Gdansk 80-308, Faculty of Chemistry, University of Gdansk Wita Stwosza 63, Gdansk 80-308, Faculty of Chemistry, University of Gdansk Wita Stwosza 63, Gdansk 80-308, Faculty of Chemistry, University of Gdansk Wita Stwosza 63, Gdansk 80-308, Department of Embryology, Medical University of Gdansk, Dębinki 1, Gdansk 80-211, Department of Embryology, Medical University of Gdansk, Dębinki 1, Gdansk 80-211, Department of Clinical Immunology and Transplantology, Medical University of Gdansk, Dębinki 7, Gdansk 80-308

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