Design and stereoselective synthesis of novel bicyclicbeta-turn dipeptide mimetics and cis-4-substitutedproline analogues for peptides and peptidomimetics

Persistent Link:
http://hdl.handle.net/10150/289964
Title:
Design and stereoselective synthesis of novel bicyclicbeta-turn dipeptide mimetics and cis-4-substitutedproline analogues for peptides and peptidomimetics
Author:
Zhang, Junyi
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:
A central goal of modern biology is to develop a detailed, predictive understanding of the relationships of three-dimensional structure and biological function. However, to establish the biologically active conformation is challenging because most small linear peptides are inherently flexible, and at present, our knowledge of 3D structural information of ligand-receptor complexes is very limited. Hence, some strategies have been developed to prepare peptidomimetics with constrained conformations. Both local conformational constraints and global conformational constraints can provide important insights into the structural and topographical basis of biological activity. A series of novel cis-4-substituted proline analogues were designed and synthesized. Highly stereoselective alkylations at the gamma-position of glutamic ester were achieved, followed by reduction, mesylation, and cyclization to afford the proline derivatives in good yields and high diastereoselectivity. These cis-4-substituted proline analogues could be used as conformation ally restricted templates in local constrained peptidomimetics. We also have developed a general and efficient approach for the synthesis of indolizidinone amino acids with stereospecific appendages of side chain functionality at both the C-4 and C-8 positions, which can serve as restricted reverse turn mimetics in global constrained peptidomimetics. Our synthetic reverse turn mimetic targets were designed to serve as surrogates of the dipeptides Phe-Gly and Phe-Arg which contain two important pharmacophore elements in Leu-Enkephalin and melanotropin peptides, respectively. Introduction of side chain functionality at C-8 was achieved by using beta-substituted pyroglutamate as a synthetic precursor which was prepared via Michael addition reaction between a Ni(II) complex of the chiral Schiff base of glycine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone and 3-(trans-enoyl)-oxazolidin-2-one. The side chains at C-4 were introduced by bromination of dehydroamino acid intermediates followed by Suzuki cross-coupling.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
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 stereoselective synthesis of novel bicyclicbeta-turn dipeptide mimetics and cis-4-substitutedproline analogues for peptides and peptidomimeticsen_US
dc.creatorZhang, Junyien_US
dc.contributor.authorZhang, Junyien_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.abstractA central goal of modern biology is to develop a detailed, predictive understanding of the relationships of three-dimensional structure and biological function. However, to establish the biologically active conformation is challenging because most small linear peptides are inherently flexible, and at present, our knowledge of 3D structural information of ligand-receptor complexes is very limited. Hence, some strategies have been developed to prepare peptidomimetics with constrained conformations. Both local conformational constraints and global conformational constraints can provide important insights into the structural and topographical basis of biological activity. A series of novel cis-4-substituted proline analogues were designed and synthesized. Highly stereoselective alkylations at the gamma-position of glutamic ester were achieved, followed by reduction, mesylation, and cyclization to afford the proline derivatives in good yields and high diastereoselectivity. These cis-4-substituted proline analogues could be used as conformation ally restricted templates in local constrained peptidomimetics. We also have developed a general and efficient approach for the synthesis of indolizidinone amino acids with stereospecific appendages of side chain functionality at both the C-4 and C-8 positions, which can serve as restricted reverse turn mimetics in global constrained peptidomimetics. Our synthetic reverse turn mimetic targets were designed to serve as surrogates of the dipeptides Phe-Gly and Phe-Arg which contain two important pharmacophore elements in Leu-Enkephalin and melanotropin peptides, respectively. Introduction of side chain functionality at C-8 was achieved by using beta-substituted pyroglutamate as a synthetic precursor which was prepared via Michael addition reaction between a Ni(II) complex of the chiral Schiff base of glycine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone and 3-(trans-enoyl)-oxazolidin-2-one. The side chains at C-4 were introduced by bromination of dehydroamino acid intermediates followed by Suzuki cross-coupling.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)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.proquest3107058en_US
dc.identifier.bibrecord.b44667462en_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.