Painting argyrins blue: Negishi cross-coupling for synthesis of deep-blue tryptophan analogue β-(1-azulenyl)-l alanine and its incorporation into argyrin C

• Published in: Bioorganic & medicinal chemistry 2018-10, Vol.26 (19), p.5259-5269
• Main Authors: Stempel, Erik, Kaml, Robert Franz-Xaver, Budisa, Nediljko, Kalesse, Markus
• Format: Article
• Language: English
• Subjects: Alanine - analogs & derivatives; Alanine - chemical synthesis; Alanine - chemistry; Argyrin; Azulene; Azulenes - chemical synthesis; Azulenes - chemistry; Circular Dichroism; Cyclic peptide; Fluorescent label; Modified amino acids; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Sesquiterpenes - chemical synthesis; Sesquiterpenes - chemistry; Spectrophotometry, Ultraviolet; Tryptophan - analogs & derivatives; Tryptophan - chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2018.03.037

[Display omitted] The argyrins are a family of non-ribosomal peptides that exhibits different biological activities through only small structural changes. Ideally, a biologically active molecule can be tracked and observed in a variety of biological and clinical settings in a non-invasive manner. As a step towards this goal, we report here a chemical synthesis of unnatural deep blue amino acid β-(1-azulenyl)-l alanine with different fluorescence and photophysical properties, which allows a spectral separation from the native tryptophan signal. This might be especially useful for cell localization studies and visualizing the targeted proteins. In particular, the synthesis of β-(1-azulenyl)-l alanine was achieved through a Negishi coupling which proved to be a powerful tool for the synthesis of unnatural tryptophan analogs. Upon β-(1-azulenyl)-l alanine incorporation into argyrin C, deep blue octapeptide variant was spectrally and structurally characterized.