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

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 (γ-turn) was observed for peptidomimetic F$\{$2S,3S-cyclo-M$\}$RF-NH$\sb2$.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Natural Sciences

Grantor

Rice University

Year dc:date.issued

1994

Author dc:creator

• Ho, Kwok-Kan

Advisor dc:contributor.advisor

• Burgess, Kevin

• Organic chemistry
• Pharmaceutical chemistry
• Biochemistry

Statement dc:rights

• Copyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/1911/16737

OAI identifier oai:identifier

oai:repository.rice.edu:1911/16737