Aza‐amino acid scanning of chromobox homolog 7 (CBX7) ligands

Abstract

An aza-amino acid scan of peptide inhibitors of the chromobox homolog 7 (CBX7) was performed to study the conformational requirements for affinity to the methyllysine reader protein. Twelve azapeptide analogues were prepared using three different approaches employing respectively N-(Fmoc)aza-amino acid chlorides and submonomer azapeptide synthesis to install systematically aza-residues at the first four residues of the peptide, as well as to provide aza-lysine residues possessing saturated and unsaturated side chains. The aza-peptide ligands were evaluated in a chromobox homolog 7 binding assay, providing useful insight into structural requirements for affinity. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

Azapeptide Synthesis Methods for Expanding Side-Chain Diversity for Biomedical Applications

“…Aza-glycine alkylation with 1-bromo-3-chloropropane, 1-bromo-4-chlorobutane, and (E)-and (Z)-1,4-dichloro-2-butene effectively provides the corresponding aza-ω-chloroalkylglycines. 21,54,55 Displacement of the ω-chloride with azide and amines gave ultimate access to aza residues possessing basic side chains, i.e., aza-Lys (saturated and E-and Z-unsaturated), aza-Orn, and aza-Arg mimics (Scheme 9). 21,54,55 Both aza-Lys and aza-Orn GHRP-6 analogues (e.g., 73a) were prepared by displacement of the corresponding aza-ωchloroalkylglycine (e.g., 67) with sodium azide, elongation to the full-length azapeptide, chemoselective azide reduction using tris(2-carboxyethyl)phosphine (TCEP), and resin cleavage.…”

“…21,54,55 Displacement of the ω-chloride with azide and amines gave ultimate access to aza residues possessing basic side chains, i.e., aza-Lys (saturated and E-and Z-unsaturated), aza-Orn, and aza-Arg mimics (Scheme 9). 21,54,55 Both aza-Lys and aza-Orn GHRP-6 analogues (e.g., 73a) were prepared by displacement of the corresponding aza-ωchloroalkylglycine (e.g., 67) with sodium azide, elongation to the full-length azapeptide, chemoselective azide reduction using tris(2-carboxyethyl)phosphine (TCEP), and resin cleavage. Guanidinylation of aza-ornithine (e.g., 70) using 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea gave access to aza-Arg analogues (e.g., 73b).…”

“…21 Similarly, chloride displacement from aza-ωchlorobutenylglycines gave aza-Lys mimics with restricted (E)and (Z)-alkene side chains that were used to study GHRP-6 54 as well as peptide inhibitors of chromobox homologue 7. 55…”

“…However, alkylation of aza-glycine with α,ω-dihaloalkanes proved to be more straightforward for generating libraries of aza-lysine residues possessing olefin and saturated side chains. Aza-glycine alkylation with 1-bromo-3-chloropropane, 1-bromo-4-chlorobutane, and ( E )- and ( Z )-1,4-dichloro-2-butene effectively provides the corresponding aza-ω-chloroalkylglycines. ,, Displacement of the ω-chloride with azide and amines gave ultimate access to aza residues possessing basic side chains, i.e., aza-Lys (saturated and E - and Z -unsaturated), aza-Orn, and aza-Arg mimics (Scheme ). ,, …”

“…By this method, 13 GHRP-6 analogues possessing aza-Lys and aza-Orn residues at the Ala 3 , Trp 4 , and Lys 6 positions were synthesized with crude purities of 23–63% in isolated yields of 2–9% . Similarly, chloride displacement from aza-ω-chlorobutenylglycines gave aza-Lys mimics with restricted ( E )- and ( Z )-alkene side chains that were used to study GHRP-6 as well as peptide inhibitors of chromobox homologue 7 …”