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 (FCh / DMB / LChBAC)
Piotr Mucha,,
- Laboratory of Chemistry of Biologically Active Compounds
, Małgorzata Pieszko (FCh / DMB / LChBAC)
Małgorzata Pieszko,,
- Laboratory of Chemistry of Biologically Active Compounds
, Anna Miszka (FCh / DMB / LChBAC)
Anna Miszka,,
- Laboratory of Chemistry of Biologically Active Compounds
, Jarosław Ruczyński (FCh / DMB / LChBAC)
Jarosław Ruczyński,,
- Laboratory of Chemistry of Biologically Active Compounds
, Piotr Rekowski (FCh / DMB / LChBAC)
Piotr Rekowski,,
- Laboratory of Chemistry of Biologically Active Compounds
, Izabela Załuska (FCh / DMB / LChBAC)
Izabela Załuska ,,
- Laboratory of Chemistry of Biologically Active Compounds
, Agnieszka Kozłowska (FCh / DMB / LChBAC)
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, (A 15 pkt)
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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