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dc.contributor.advisor Burgess, Kevin
dc.creatorHo, Kwok-Kan
dc.date.accessioned 2009-06-04T00:12:37Z
dc.date.available 2009-06-04T00:12:37Z
dc.date.issued 1994
dc.identifier.urihttps://hdl.handle.net/1911/16737
dc.description.abstract 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$.
dc.format.extent 312 p.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.subjectOrganic chemistry
Pharmaceutical chemistry
Biochemistry
dc.title Syntheses, bioactivities and conformations of peptidomimetics containing 2,3-methanoamino acids
dc.type.genre Thesis
dc.type.material Text
thesis.degree.department Chemistry
thesis.degree.discipline Natural Sciences
thesis.degree.grantor Rice University
thesis.degree.level Doctoral
thesis.degree.name Doctor of Philosophy
dc.identifier.citation Ho, Kwok-Kan. "Syntheses, bioactivities and conformations of peptidomimetics containing 2,3-methanoamino acids." (1994) Diss., Rice University. https://hdl.handle.net/1911/16737.


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