Syntheses, bioactivities and conformations of peptidomimetics containing 2,3-methanoamino acids.

摘要

Asymmetric syntheses of E- and Z-2,3-methanomethionine (ie E- and Z-cyclo-Met), protected Z-2,3-methanoarginine, and Z-2,3-methanoaspartic acid derivatives have been developed. These functionalized 2,3-methanoamino acids were prepared from a common intermediate: 1- ((tert-butoxy)carbonyl) -2-oxo-3-oxa-bicyclo (3.1.0) hexane.;Peptidomimetics containing some of these 2,3-methanoamino acids mentioned above were synthesized via a solid phase approach. The Met;Anti-opiate activities, and proteolytic stabilities of the peptidomimetics were studied. The peptidomimetics were more active (in vivo) than the FMRF-NH;Solution conformations of the peptidomimetics were investigated by NMR. Incorporation of 2,3-methanoamino acids into peptides induced NMR observable conformational rigidity. This was evident from: (i) interresidue ROE crosspeaks centered at the methanologs; (ii) unusual chemical shifts and temperature coefficients of some NH signals; and, (iii) line boardening for F;The NMR data was correlated with the structures obtained from quenched molecular dynamics (QMD), which was performed by using a set of empirical parameters. Structures obtained from the QMD studies gave good correlation with the experimental data. Defined secondary structure (