Aza-Isotryptophan: Synthesis, Pictet–Spengler Chemistry, Incorporation and Conformational Analysis in Peptides, and Activity in Modulators of the Cluster of Differentiation-36 Receptor

Isotryptophan (Itr) is the rare 2-indoyl counterpart of the essential amino acid tryptophan. Considering the potential to explore novel side chain χ-space in a residue prone to adopt backbone turn conformers, azaItr has been effectively synthesized and employed in Pictet–Spengler and peptide chemistry. β-Turn geometry was characterized in model peptides of the Ala-azaItr-d-Phe triad by X-ray and NMR analyses. Moreover, azaItr analogs of growth hormone-releasing peptide 6 (GHRP-6) demonstrated a promising cluster of differentiation-36 receptor (CD36) binding affinity and modulatory effect on the inflammatory response induced by the activated complex composed of the latter coreceptor in the Toll-like receptor-2/6 heterodimer.