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$sp2$ in neuropeptide Phe-Met-Arg-Phe-NH$sb2$ (FMRF-NH$sb2$, one letter code for amino acids) was systematically replaced by each of the isomers of cyclo-Met giving four peptidomimetics, namely F${$2S,3R-cyclo-M$}$RF-NH$sb2$, F${$2R,3S-cyclo-M$}$RF-NH$sb2$, F${$2S,3S-cyclo-M$}$RF-NH$sb2$ and F${$2R,3R-cyclo-M$}$RF-NH$sb2$. A peptidomimetic containing two 2,3-methanoamino acids substituted in the 2 and 4 positions (ie F${$2S,3S-cyclo-M$}$R${$2R,3R-cyclo-F$}$-NH$sb2$) was also prepared. Generally, 2,3-methanoamino acids are compatible with solid phase chemistry, although they are more sterically hindered than their corresponding natural amino acids.Anti-opiate activities, and proteolytic stabilities of the peptidomimetics were studied. The peptidomimetics were more active (in vivo) than the FMRF-NH$sb2$ but bind less strongly to the appropriate receptor sites. This observation seems to be related to the enhanced bio-availability of the peptidomimetics, because the F${$E-cyclo-M$}$RF-NH$sb2$ analogs were much more proteolytically stable than the parent peptide with respect to leucine aminopeptidase digestion.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${$2S,3S-cyclo-M$}$R${$2R,3R-cyclo-F$}$-NH$sb2$ in the $sp1$H-NMR spectrum.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 ($gamma$-turn) was observed for peptidomimetic F${$2S,3S-cyclo-M$}$RF-NH$sb2$.

[发布机构] Rice University

[效力级别] chemistry