Helical conformational dynamics and photoisomerism of alternating pyridinedicarboxamide/m-(phenylazo)azobenzene oligomers.

Alternating sequences of pyridine-2,6-dicarboxamides and meta-(phenylazo)azobenzenes have been assembled into oligomers composed of four (8) and eight (9) azobenzene linkages. X-ray crystallography confirmed that oligomer 8 adopts a two-turn helical conformation with a helical pitch of approximately 3.4 Angstroms in the solid state. The presence of a two- and four-turn helical conformation of 8 and 9, respectively, in polar and nonpolar solvents was elucidated by the anisotropic upfield shifting of protons located within the helices, NOE enhancements between protons oriented toward the helix interior, and the diastereotopicity of the terminal benzyloxycarbonyl (CBz) methylene protons. (1)H NMR line shape analysis of the CBz methylene hydrogens at the chain ends revealed a dynamic equilibria interconverting M and P helical conformations with energetic barriers (DeltaG) of 11.1 (DeltaS = -19.4 +/- 1.6 cal mol(-1) K(-1); DeltaH = 6.5 +/- 0.4 kcal/mol) for 8 and 13.8 kcal/mol (DeltaS = -6.6 +/- 6.2 cal mol(-1) K(-1); DeltaH = 11.8 +/- 1.8 kcal/mol) for 9. Irradiation of the oligomers with 350 nm light induces an E --> Z isomerization of the azo linkages that decreases in efficacy at longer helix lengths. The suppression of E --> Z isomerization is a consequence of the contrasting behavior of the azo linkages located at the helix termini, which afford Z/E ratios similar to those of model compound 7d, and the internal azo groups, which undergo significantly lower Z/E conversion ratios compared with 7e.

The synthesis of azapeptidomimetic beta-lactam molecules as potential protease inhibitors.

Synthetic methods for the construction of a novel peptidomimetic structure are reported. The structure incorporates a beta-lactam and an azapeptide in a peptide backbone with the intention of generating rationally designed substrate-based protease inhibitors. The beta-lactam is formed by subjecting serine or threonine-azapeptides to Mitsunobu reaction conditions. Importantly, the azapeptidomimetic beta-lactam structure permits extended binding inhibition and the synthetic methods to create tetrapeptidomimetic structures are described.