Design and synthesis of conformationally and topographically constrained amino acids as peptidomimetics

Persistent Link:
http://hdl.handle.net/10150/280486
Title:
Design and synthesis of conformationally and topographically constrained amino acids as peptidomimetics
Author:
Qiu, Wei
Issue Date:
2001
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:
A major goal of peptide research has been to elucidate or understand the relationships between a peptide's three-dimensional structure and its biological activity. De Novo design of peptide mimetics requires assembling all components necessary for molecular recognition and transduction, which needs the proper choice of a template that can place the key side chain residues in 3D space. Two widely used methods are novel β-substituted amino acids and conformationally constrained secondary structure mimetics. In this thesis, we report our efforts to fulfill the aforementioned criteria in synthesizing β-isopropyl aromatic amino acids and constrained reverse turn dipeptide mimetics. Through asymmetric Michael addition reaction, highly topographically constrained β-isopropyl aromatic amino acids have been synthesized. In order to develop a general approach to synthesize these novel amino acids, we re-examined the reaction conditions for Evans' diastereoselective 1,4-addition, and found conditions which gave excellent diastereoselectivities and good chemical yields. A concise and straightforward five-step synthesis of [5.5]-bicyclic reverse turn dipeptide mimetic scaffolds with side chain functionality at the i+1 and i+2 positions has been developed. In the bicyclic structure, two dihedral angles (ψ₂ and φ₃) are greatly restricted. Further development of this synthesis will enable us to prepare various types of reverse turns with different backbone geometry and side chain topography. Enantiomerically pure (S)-trans-cinnamylglycine and (S)-α-trans-cinnamyl-α-alanine have been prepared via reaction of chiral Ni (II)-complexes of glycine and alanine respectively, with cinnamyl halides. Inexpensive and readily available reagents and solvents are used, including a recyclable chiral ligand. The simplicity of the experimental procedures and high stereochemical outcome make this method synthetically attractive for preparing the target amino acids on multi-gram scales. Further studies by incorporating these mimetics into potent peptide analogues will greatly help us to understand the bioactive conformation of the parent peptides.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Chemistry, Biochemistry.; Chemistry, Organic.
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.titleDesign and synthesis of conformationally and topographically constrained amino acids as peptidomimeticsen_US
dc.creatorQiu, Weien_US
dc.contributor.authorQiu, Weien_US
dc.date.issued2001en_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.abstractA major goal of peptide research has been to elucidate or understand the relationships between a peptide's three-dimensional structure and its biological activity. De Novo design of peptide mimetics requires assembling all components necessary for molecular recognition and transduction, which needs the proper choice of a template that can place the key side chain residues in 3D space. Two widely used methods are novel β-substituted amino acids and conformationally constrained secondary structure mimetics. In this thesis, we report our efforts to fulfill the aforementioned criteria in synthesizing β-isopropyl aromatic amino acids and constrained reverse turn dipeptide mimetics. Through asymmetric Michael addition reaction, highly topographically constrained β-isopropyl aromatic amino acids have been synthesized. In order to develop a general approach to synthesize these novel amino acids, we re-examined the reaction conditions for Evans' diastereoselective 1,4-addition, and found conditions which gave excellent diastereoselectivities and good chemical yields. A concise and straightforward five-step synthesis of [5.5]-bicyclic reverse turn dipeptide mimetic scaffolds with side chain functionality at the i+1 and i+2 positions has been developed. In the bicyclic structure, two dihedral angles (ψ₂ and φ₃) are greatly restricted. Further development of this synthesis will enable us to prepare various types of reverse turns with different backbone geometry and side chain topography. Enantiomerically pure (S)-trans-cinnamylglycine and (S)-α-trans-cinnamyl-α-alanine have been prepared via reaction of chiral Ni (II)-complexes of glycine and alanine respectively, with cinnamyl halides. Inexpensive and readily available reagents and solvents are used, including a recyclable chiral ligand. The simplicity of the experimental procedures and high stereochemical outcome make this method synthetically attractive for preparing the target amino acids on multi-gram scales. Further studies by incorporating these mimetics into potent peptide analogues will greatly help us to understand the bioactive conformation of the parent peptides.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectChemistry, Biochemistry.en_US
dc.subjectChemistry, Organic.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.proquest3010257en_US
dc.identifier.bibrecord.b41711749en_US
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