CRYSTAL-STATE CONFORMATION OF 3 AZAPEPTIDES CONTAINING THE AZAPROLINERESIDUE, A BETA-TURN REGULATOR

The molecular structure of three protected AzaPro-containing peptides have been determined by x-ray diffraction: Z-AzaPro-NHiPr (1; Z: benzy loxycarbonyl), Z-AzaPro-L-Ala-NHiPr (2), and Boc-L-Ala-AzaPro-NHiPr (3 ; Boc: tert-butyloxycarbonyl). Starting from the key synthon benzyl-az aprolinate, compounds 1, 2, and 3 have been prepared by combined use o f liquid phase peptide synthesis methods and adequate isocyanates. In all peptides, the following geometric characteristics are retained: (a ) pyramidal character of the two nitrogen atoms of the pyrazolidine ri ng; (b) pseudo cis conformation of the urethane (1, 2) or tertiary ami de (3) function preceding the AzaPro residue; (c) identical absolute v alues of the Azaproline residue torsion angles ''phi, psi,'' respectiv ely 111-degrees and 23-degrees. In compound 2, the two nitrogen atoms of the pyrazolidine ring are R,R but the opposite S,S absolute configu rations are observed in compound 3. In the crystal, compound 3 adopts a folded structure similar to a type VI beta-turn with a weak intramol ecular i + 3 --> i hydrogen bond, while an extended structure is obser ved in compound 2. In the light of our findings, in a peptide chain an d contrary to the Pro residue, an AzaPro residue should prevent the fo rmation of any type of beta-turn with the residue following it but cou ld accommodate a folded structure with a pseudo type VI beta-turn with the preceding residue. If confirmed, this would be of tremendous impo rtance in the design of biologically active peptides and drugs.