Photomodulation of conformational states. Synthesis of cyclic peptides with backbone-azobenzene moieties

Abstract

The search for photoresponsive conformational transitions accompanied by changes in physicochemical and biological properties led us to the design of small cyclic peptides containing azobenzene moieties in the backbone. For this purpose, (4-aminomethyl)phenylazobenzoic acid (H-AMPB-OH) and (4-amino)phenylazobenzoic acid (H-APB-OH) were synthesized and used to cyclize a bis-cysteinyl-octapeptide giving monocyclic derivatives in which additional conformational restriction could be introduced by conversion to bicyclic structures with a disulphide bridge. While synthesis with H-AMPB-OH proceeded smoothly on a chlorotrityl-resin with Fmoc/tBu chemistry, the poor nucleophilicity of the arylamino group of H-APB-OH required special chemistry for satisfactory incorporation into the peptide chain. Additional difficulties were encountered in the reductive cleavage of the S-tert-butylthio group from the cysteine residues since concomitant reduction of the azobenzene moiety took place at competing rates. This difficulty was eventually bypassed by using the S-trityl protection. Side-chain cyclization of the APB-peptide proved to be difficult, suggesting that restricted conformational freedom was already present in the monocyclic form, a fact that was fully confirmed by NMR structural analysis. Conversely, the methylene spacer in the AMPB moiety introduced sufficient flexibility for facile and quantitative side-chain cyclization to the bicyclic form. Both of the monocyclic peptides and both of the bicyclic peptides are photoresponsive molecules which undergo cis/trans isomerization reversibly.

Ultrafast spectroscopy reveals subnanosecond peptide conformational dynamics and validates molecular dynamics simulation

“…The synthesis of linear and cyclic APB-peptides was reported before (18). The sample was dissolved in DMSO to a final concentration of 0.8 mM (linear APB-peptide) and 2.3 mM (cyclic APB-peptide), respectively, and exchanged between individual laser shots by pumping the solution with sufficient flow rate through the fused silica cuvette (0.5-mm optical path length).…”

“…1, which is backbone-cyclized with a suitably functionalized (4-aminophenyl)azobenzoic acid (APB) (17,18). The APB molecule has been chosen as optical trigger, because azobenzene dyes are known to photoisomerize at the central NON bond within fractions of picoseconds at high quantum yields (19) and with large changes in geometry.…”

Photoresponsive Supramolecular Architectures Based on Polypeptide Hybrids

“…Boc-4-(aminomethyl)phenylazobenzoic Acid (8). 31 Boc-p-nitrobenzylamine (1 g, 4 mmol) and NH 4 Cl (690 mg, 13 mmol) were dissolved in 5:1 EtOH/H 2 O (25 mL). Then, Zn dust (940 mg, 14.4 mmol) was added, and the obtained suspension was stirred at rt for 2 h. The suspension was filtered through Celite, the filtrate was cooled to 0°C, and a cold solution of FeCl 3 ·6H 2 O (6.33 g, 23.4 mmol) in 5:1 EtOH/H 2 O (35 mL) was added.…”

Orthogonal Protecting Groups and Side‐Reactions in Fmoc/tBu Solid‐Phase Peptide Synthesis

“…When a Cys residue is involved, it is advisable to use a lower excess of base (i.e., DIPEA) [164], during the coupling and to reduce the time of piperidine-mediated Fmoc deprotection of the N a -amino function [165].…”