Building photoswitchable 3,4'-AMPB peptides: Probing chemical ligation methods with reducible azobenzene thioesters

Abstract

SummaryPhotoswitchable peptides were synthesized by using cysteine- and auxiliary-based native chemical ligation reactions. For this purpose, the two regioisomeric azobenzene building blocks 3,4'-AMPB thioester 1b and 4,4'-AMPB thioester 2b were employed in the ligation reactions. While 4,4'-AMPB requires the 4,5,6-trimethoxy-2-mercaptobenzyl auxiliary to minimize reduction of the diazene unit, 3,4'-AMPB can be used in combination with the 4,5,6-trimethoxy-2-mercaptobenzyl auxiliary as well as the N α-2-mercaptoethyl auxiliary. Thus, 3,4'-AMPB derivatives/peptides proved to be significantly less prone to reduction by aliphatic and aromatic thiols than were the 4,4'-AMPB compounds.

Synthesis of hemithioindigo‐based chromopeptides by using the Tmb auxiliary in native chemical ligation studies

“…The peptide motifs in peptides 4a , b (Scheme ) are derived from specific binding sequences for class 1 PDZ recognition requiring an H‐(S/T)‐X‐(V/I/L)‐OH sequence . Previously, the sequence of peptide 4b was applied in ligation studies with the Tmb auxiliary and Boc‐protected azobenzene ω ‐amino acids . Both binding motifs are associated with H5N1 influenza infections , and the SEV sequence is also associated with breast cancer .…”

“…Nowadays, Na ascorbate is used for substituting thiol additives , e.g. for preventing TCEP‐induced desulfurization , and in the current study, it is also necessary for minimizing degradation of the Tmb peptides by thiyl radical formation . Na ascorbate is a nontoxic, highly water‐soluble, and cost‐saving radical scavenger .…”

“…Steering and fine‐tuning of the nucleophilic ligation conditions and tailor‐made substitution pattern of photoswitches help to minimize side reactions. Recently, we have investigated ligation methodologies using the 4,5,6‐trimethoxy‐2‐mercaptobenzyl (Tmb) auxiliary, the [1‐(2,4‐dimethoxyphenyl)‐2‐mercaptoethyl] auxiliary, and cysteine in combination with two regioisomeric Boc‐protected azobenzene ω ‐amino acid building blocks . These auxiliaries are easily removed from the ligated products with TFA and scavengers, and they have been developed for non‐cysteine ligation sites .…”

“…These auxiliaries are easily removed from the ligated products with TFA and scavengers, and they have been developed for non‐cysteine ligation sites . When the ligation conditions in DMF/Na 2 HPO 4 buffer mixtures are fine‐tuned, by an appropriate choice of the auxiliary and azobenzene substitution pattern reactions of the Tmb auxiliary in combination with the Boc‐protected 3,4′‐(aminomethylphenylazo)benzoic acid thioester proved to be most versatile, because this azobenzene building block was found to be significantly more stable toward reduction by aliphatic or aromatic thiols . In this report, we focused on Boc‐protected HTI ω ‐amino acid building blocks p HTI thioester 2a and m HTI thioester 2b (Scheme ), because of their better solubility in DMF/buffer mixtures in comparison with non‐protected analogs.…”

Supramolecular Plastics Processed from Small Molecule-based Coacervates

“…The proton signals of cysteine moieties shifted upfield due to the cleavage of adjacent disulfate. In the second stage, the azobenzene groups were further reduced into diphenylhydrazine groups 53,54 , accompanied by the fading of solution colour, and protons m1 and m2 near the azobenzene bond significantly shifted upfield. The bulk coacervate material reformed after full oxidation in air overnight (Fig.…”