The chemical diversification of biomolecules set forth a significant area that constitutes an important intersection between chemistry and biology. Amino acids and peptides, are the fundamental building blocks of proteins, play an ubiquitous role in all living organisms. While significant efforts have been geared to the chemical modifications of amino acid residues, particularly the functionalization of reactive functional groups such as Lysine-NH2 and Cysteine –SH, the exploration of aromatic amino acid residues of Tryptophan, Tyrosine, Phenylalanine, and Histidine has been relatively limited. Therefore, this review highlights on the strategies for side chain functionalization of these four aromatic amino acids in peptides, with a focus on elucidating the underlying mechanisms. We have also illustrated the usage of these chemical modifications in the chemical and biological realm.

We developed a simple strategy to diiodinated tyrosine (Tyr) amino acid at the 3‐ and 5‐ positions from the commercially available Fmoc/Boc‐L‐Tyrosine monomer. The iodinated tyrosine monomer have been further adopted to generate a variety of iodinated Fmoc tyrosine dimers. Upon Fmoc elimination, we obtained diketopiperazine (DKP) analogues of Cyclo(L‐Tyr‐L‐Tyr) with varied number of iodine atoms. We also report the biological studies of these iodinated DKP analogues in three different cancer cell lines. We demonstrate that the number of iodine atoms in the Cyclo(L‐Tyr‐L‐Tyr) DKP analogues, and the presence of electron‐rich phenolic group are essential structural parameters to have pronounced cytotoxic activity in three different cancer cell lines.

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Previous strategies of peptoid folding have been to identify single dominant interaction, whereas peptide research showed that multiple, weak, and cooperative interactions might be a better strategy for understanding folding....