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

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    Author
    Zhang, Junyi
    Issue Date
    2003
    Keywords
    Chemistry, Organic.
    Advisor
    Hruby, Victor J.
    
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    Show full item record
    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)
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Chemistry
    Degree Grantor
    University of Arizona
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