MODIFICATIONS OF THE AMIDE BOND AND CONFORMATIONAL CONSTRAINTS IN PSEUDOPEPTIDE ANALOGS

We have investigated the conformational effects of modifying the amide group in model dipeptides. The N-methyl amide psi[CO-NMe], N-hydroxy amide psi[CO-N(OH)], N-amino amide psi[CO-N(NH2)], retro amide psi[NH- CO], reduced amide in the neutral psi[CH2-NH] and protonated psi[CH2-N +H2] state, and hydrazide psi[CO-NH-NH] have been introduced as surrog ates of the amide link in pseudopeptide derivatives of the Pro-Gly or Ala-Gly model dipeptides protected on both termini by an amide group. These compounds have been studied in solution by proton nmr and ir spe ctroscopy, and in the solid state by x-ray diffraction, giving an exte nded data set of experimental structural and conformational informatio n on pseudopeptide sequences. The conformational effects depend both o n the nature and the position of the modified amide link. Some modific ations appear to have no intrinsic conformational induction (N-amino a nd retro amide), but destabilize any local folded structure by hydroge n-bond breaking. Because of the formation of strong intramolecular int eractions, others are capable of stabilizing a beta-turn (for example protonated reduced amide), or of inducing a particular local conformat ion such as a beta- or gamma-like turn (for example N-hydroxy amide). The particular geometry of the cis N-methyl amide and of the ''hydrazi no'' proline favors the formation of a sharp turn of the main chain. A ll these structural data are of interest to the design of bioactive pe ptide mimics.