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.