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

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Graduate College

Grantor dc:publisher

The University of Arizona.

Year dc:date.issued

2003

Author dc:creator

• Zhang, Junyi

Advisor dc:contributor.advisor

• Hruby, Victor J.

• Chemistry, Organic.

Statement dc: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.

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/10150/289964

OAI identifier oai:identifier

oai:repository.arizona.edu:10150/289964