Ru(II)-mediated synthesis and bioactivity evaluation of 1,4,5- trisubstituted N-phthalimido protected 5-bromo-1,2,3-triazolic amino acid

Piotr Mucha , Małgorzata Pieszko , Anna Miszka , Jarosław Ruczyński , Piotr Rekowski , Izabela Załuska , Agnieszka Kozłowska , Adriana Schumacher , Milena Deptuła , Michał Pikuła

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.Conclusions: 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.
Author Piotr Mucha PChZBCz
Piotr Mucha,,
- Laboratory of Chemistry of Biologically Active Compounds
, Małgorzata Pieszko PChZBCz
Małgorzata Pieszko,,
- Laboratory of Chemistry of Biologically Active Compounds
, Anna Miszka PChZBCz
Anna Miszka,,
- Laboratory of Chemistry of Biologically Active Compounds
, Jarosław Ruczyński PChZBCz
Jarosław Ruczyński,,
- Laboratory of Chemistry of Biologically Active Compounds
, Piotr Rekowski PChZBCz
Piotr Rekowski,,
- Laboratory of Chemistry of Biologically Active Compounds
, Izabela Załuska PChZBCz
Izabela Załuska ,,
- Laboratory of Chemistry of Biologically Active Compounds
, Agnieszka Kozłowska PChZBCz
Agnieszka Kozłowska,,
- Laboratory of Chemistry of Biologically Active Compounds
, Adriana Schumacher
Adriana Schumacher,,
-
, Milena Deptuła
Milena Deptuła,,
-
, Michał Pikuła
Michał Pikuła,,
-
Journal seriesLetters in Organic Chemistry, ISSN 1570-1786
Issue year2018
Vol15
Pages282-289
Publication size in sheets0.3
Keywords in Englishclick chemistry, N-phthalimido 1, 2, 3-triazole amino acid, trisubstituted 1, 2, 3-triazole, proliferative activity, cytotoxicity
DOIDOI:10.2174/1570178614666170720112745
Languageen angielski
Score (nominal)15
ScoreMinisterial score = 15.0, 20-12-2017, ArticleFromJournal
Ministerial score (2013-2016) = 15.0, 20-12-2017, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 0.73 (2) - 2016=0.691 (5)
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