Fig. 4. Synthesis of macrocyclic H3K4me3 6mer peptides. (A) Crystal structure of H3K4me3 peptide bound to PHD3 (PDB 3GL6)7 highlighting residues Lys4 and Thr6 selected for tethering. (B) Series B: macrolactamization through a tandem amide coupling-intramolecular SN2 reaction sequence to afford lactam tripeptide intermediate B-17. (C) Series C: cysteine–dimethyllysine stapling strategy which enabled the preparation of thioether tripeptide intermediate C-18 and sulfone tripeptide intermediate C-20 from linear precursor 19. (D) Series D: macrocyclic triazole-containing peptide intermediates D-23–26, forged through Cu(i)-catalyzed alkyne–azide cycloaddition chemistry. (E) Competitive FP assay data of full-length, cleaved macrocyclic peptides. Structure of linkers are shown.
