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The new pseudodipeptide Boc-azaTic-Leu-OMe (1), incorporating the conformationally and topographically constrained 3,4-dihydro-2(1H)-phthalazinecarboxylic acid (azaTic) residue, has been synthesized together with the three related models Boc-azaTic-NHMe (3), MeCO-azaTic-Gly-OMe (4), and azaTic-Leu-OMe (6). Both the epimers of 1, generated by opposite absolute configuration at an azaTic nitrogen stereogenic centre, have been found in the asymmetric unit of the crystal. The conformational perturbations, deriving by the introduction of the azaTic residue into a peptide backbone, are described and the nature of the NH…N interaction, which gives rise to a typical backbone folding closing a 5-membered ring, has been studied.

3,4-Dihydro-2(1 H )-phthalazinecarboxylic acid (azaTic) is a new conformationally restricted analogue of phenylalanine which, due to its α-aza-nature, should allow, in addition to the topographical control typical of the Tic residue, a definite local perturbation of the backbone conformation. Two azaTic models, namely azaTic-NH 2 ( 2 ) and MeCO-azaTic-NHMe ( 5 ), have been synthesized and their conformation has been determined and compared to that of the related Tic and azaPro models.

4-Aminotetrahydrothiopyran-4-carboxylic acid (Thp) is an unusual achiral cyclic α,α-disubstituted amino acid mimicking the natural Met residue. The conformational energy map computed for Ac-Thp-NHMe shows that the γ-turn is the lowest minimum. 1 H-NMR and IR studies performed on For-Thp-Leu-OMe ( 2a ), a short peptide unable to give a 4…>1 H-bond, indicate that the γ-turn is adopted in CDCl 3 solution, whereas is not retained in (CD 3 ) 2 SO. An analogous conformational behaviour in solution has been observed for the strictly related For-Ac 6 c-Leu-OMe ( 2b ), containing 1-aminocyclohexane carboxylic acid (Ac 6 c).

In order to study the influence of the conformation on the activity and bioselectivity, the new tetrapeptide ligand of the chemotactic formylpeptide receptors HCO-Met-Leu-Δ Z Phe-Phe-OMe ( 2 ) has been studied. Compound 2 has been designed so as to induce a preferential β-turn conformation with the N -formyl group located outside the backbone loop. The crystallographic analysis reveals that 2 adopts only in part the expected conformation due to the presence of a water molecule isnide the turn. Details on the H-bonding network stabilizing the “open-turn” are given. The tetrapeptide 2 is active towards human neutrophils, stimulating directed migration, superoxide anion generation and lysozyme release. The influence of the backbone conformation on the bioselectivity is discussed.