The design and synthesis of novel amino acids and their usein synthesis of beta-turn mimetics and their incorporation into biological active peptides

Persistent Link:
http://hdl.handle.net/10150/289938
Title:
The design and synthesis of novel amino acids and their usein synthesis of beta-turn mimetics and their incorporation into biological active peptides
Author:
Gu, Xuyuan
Issue Date:
2003
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Peptide ligands represent the most important hormones and neurotransmitters in physiological processes. Although native biologically active peptides have a great potential for medical applications, they often need to be modified to overcome certain inherent problems. A new research area called peptidomimetics has been developed in the last twenty years. The first generation of β-turn mimetics was focused on mimicking the β-turn backbone. In the last decade, many types of bicyclic β-turn dipeptides (BTD) have been design and synthesized. However, these methods do not have straightforward ways to introduce side chain groups on both rings. The introduction of functionalities on BTD, as the second generation of β-turn mimetics, is the major goal of my dissertation. By retrosynthetic analysis, convergent synthetic methodologies were initiated for [5,5]- and [6,5]-BTDs. Two kinds of nonproteinous amino acids are required in the strategies. One is the β-substituted cysteine derivatives and the other is β-substituted ω-unsaturated amino acids. The racemic β-vinylphenylalanine was synthesized by using Kazmaier-Claisen rearrangement, and the ω-unsaturated amino acids and β-substituted δ,ε-unsaturated amino acids were synthesized by using Ni(II)-complexes as chiral auxiliaries. Using these starting materials, [5,5]-BTD analogues were synthesized by a five-step strategy. The synthesis of [6,5]-BTDs has to proceed without formation of the 5-membered hemiaminal, which blocks further reaction. A Nᵅ-TFA protection group was used in this strategy and finally an efficient methodology was developed to generate the side chain groups into [6,5]-BTD analogues in nine steps. During the development of these methods, we solved the challenge to synthesize all 16 or 32 of the possible diastereomeric dipeptide mimetics. A novel idea to solve these problems was to synthesize the targeted peptide mimetics by solid phase methods in a combinatorial fashion, as the third generation of β-turn mimetics. We have succeeded in the synthesis of [3,3,0]-BTD²,³-Leu-enkephalins by unconventional solid phase synthesis, and four analogues have been synthesized and purified. This method is ready to expand to other sizes of BTD and to other target peptides with different functionalities.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Chemistry, Organic.; Chemistry, Pharmaceutical.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Chemistry
Degree Grantor:
University of Arizona
Advisor:
Hruby, Victor J.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleThe design and synthesis of novel amino acids and their usein synthesis of beta-turn mimetics and their incorporation into biological active peptidesen_US
dc.creatorGu, Xuyuanen_US
dc.contributor.authorGu, Xuyuanen_US
dc.date.issued2003en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractPeptide ligands represent the most important hormones and neurotransmitters in physiological processes. Although native biologically active peptides have a great potential for medical applications, they often need to be modified to overcome certain inherent problems. A new research area called peptidomimetics has been developed in the last twenty years. The first generation of β-turn mimetics was focused on mimicking the β-turn backbone. In the last decade, many types of bicyclic β-turn dipeptides (BTD) have been design and synthesized. However, these methods do not have straightforward ways to introduce side chain groups on both rings. The introduction of functionalities on BTD, as the second generation of β-turn mimetics, is the major goal of my dissertation. By retrosynthetic analysis, convergent synthetic methodologies were initiated for [5,5]- and [6,5]-BTDs. Two kinds of nonproteinous amino acids are required in the strategies. One is the β-substituted cysteine derivatives and the other is β-substituted ω-unsaturated amino acids. The racemic β-vinylphenylalanine was synthesized by using Kazmaier-Claisen rearrangement, and the ω-unsaturated amino acids and β-substituted δ,ε-unsaturated amino acids were synthesized by using Ni(II)-complexes as chiral auxiliaries. Using these starting materials, [5,5]-BTD analogues were synthesized by a five-step strategy. The synthesis of [6,5]-BTDs has to proceed without formation of the 5-membered hemiaminal, which blocks further reaction. A Nᵅ-TFA protection group was used in this strategy and finally an efficient methodology was developed to generate the side chain groups into [6,5]-BTD analogues in nine steps. During the development of these methods, we solved the challenge to synthesize all 16 or 32 of the possible diastereomeric dipeptide mimetics. A novel idea to solve these problems was to synthesize the targeted peptide mimetics by solid phase methods in a combinatorial fashion, as the third generation of β-turn mimetics. We have succeeded in the synthesis of [3,3,0]-BTD²,³-Leu-enkephalins by unconventional solid phase synthesis, and four analogues have been synthesized and purified. This method is ready to expand to other sizes of BTD and to other target peptides with different functionalities.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectChemistry, Organic.en_US
dc.subjectChemistry, Pharmaceutical.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineChemistryen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorHruby, Victor J.en_US
dc.identifier.proquest3106993en_US
dc.identifier.bibrecord.b4466042xen_US
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