Abstract
Three N‐Boc‐protected amino acids, l‐serine, l‐aspartic, and l‐glutamic acid, were either converted into their methyl azidoalkanoates or various alkynes via Bestmann‐Ohira strategy or via reaction with propargylamine and propargyl bromide, respectively. The Cu‐catalyzed click reaction provided a library of amino acid based triazoles, which were further N‐methylated to triazolium iodides or deprotected and precipitated as free amino acid triazole dihydrochlorides. The biological properties of all derivatives were investigated by cytotoxicity assay (against L929 mouse fibroblasts) and broth microdilution method (E. coli ΔTolC and S. aureus). First results reveal complete inactivity for triazolium iodides with cell viabilities and microbial growths nearly 100 %, indicating them as possible analogs of advanced glycation endproducts (AGEs).
Highlights
Triazoles and in particular 1,2,3-triazoles are privileged scaffolds in both organic synthesis, material science, catalysis, chemical biology, and medicinal chemistry.[1a–1i] This is due to their convenient and convergent synthetic access from azides and alkynes via Cu-catalyzed 1,3-dipolar cycloaddition and Cu- or azide-free alternatives.[1e,1f] their possibility to form CH-π interactions to generate mesoionic carbenes makes them attractive as ligands to coordinate both metal ions as well as biological matter such as enzymes
The synthesis of azides 21 and 22 derived from L-aspartic acid and L-glutamic acid is shown in Scheme 2
A library of triazole bisamino acids has been synthesized via Cu-catalyzed click reaction from serine, glutamic acid- and aspartic acid-derived azides and the corresponding alkynes
Summary
Triazoles and in particular 1,2,3-triazoles are privileged scaffolds in both organic synthesis, material science, catalysis, chemical biology, and medicinal chemistry.[1a–1i] This is due to their convenient and convergent synthetic access from azides and alkynes via Cu-catalyzed 1,3-dipolar cycloaddition (i.e. click reaction) and Cu- or azide-free alternatives.[1e,1f] their possibility to form CH-π interactions to generate mesoionic carbenes makes them attractive as ligands to coordinate both metal ions as well as biological matter such as enzymes. The crosslinking of peptides and proteins by bisamino acid triazoles has more recently received growing attention for tailored protein modifications, e.g. as β-turn mimetics and histidine isosters.[5] the synthetic precursors of amino acid triazoles, i.e. the alkynylamino acids 3 are highly interesting compounds themselves, because they are building blocks for click chemistry[3,5,6,7] and Sonogashira cross-coupling for the synthesis of desmosine, isodesmosine and related heterocyclic cationic crosslinkers of connective tissue proteins, and biosynthetic intermediates.[8] Very recently, the biosynthetic pathway of amino acids containing terminal alkynes, e.g. L-ethynylserine 4, propargylglycine 5, and ethynylglycine 6 were discovered in the bacterium Streptomyces cattleya (Scheme 1).[9] Besides the many histidine-containing peptides, crosslinking amino acids and peptides carrying imidazole and imidazolium units have received much interest. From a biological point of view, AGEs play an important role in such diverse areas as browning and processing of food[11] as well as aging of tissue and protein-degenerative diseases, associated with diabetes.[15]
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