Biphenyl-based unnatural amino acids designed to nucleate Beta-sheet structure and progress towards triphenyl-based non-peptide Alpha-helix mimetics /
The syntheses of 3'-aminoethyl-2-biphenylpropionic acid (1) and 2-amino-3'biphenylcarboxylic acid (2) are described. These residues were designed to nucleate sheet structure in aqueous solution when incorporated into small, amphiphilic peptides in place of the i + I and i + 2 residues of t...
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| Format: | Thesis Book |
| Language: | English |
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[Place of publication not identified] :
[publisher not identified] ;
1995.
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| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=742536281&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | The syntheses of 3'-aminoethyl-2-biphenylpropionic acid (1) and 2-amino-3'biphenylcarboxylic acid (2) are described. These residues were designed to nucleate sheet structure in aqueous solution when incorporated into small, amphiphilic peptides in place of the i + I and i + 2 residues of the P- turn. N-Benzyl-3'-(-2-benzylamidoethyl)-2biphenylpropamide (3) and N-Benzyl-(-2-benzylamido)-3'-biphenylamide (4) were synthesized and studied as model compounds to investigate the hydrogen bonding capabilities of I and 2, respectively. Residues 1 and 2 were incorporated into small peptides in order to evaluate their ability to nucleate B-sheet structure formation in aqueous solution. Amino acid 1 was found to be capable of nucleating the formation of sheet structure in basic aqueous buffer. 1H NMR studies in aqueous solution determined the presence of a hydrophobic cluster involving the aromatic rings of 1 and the side chains of the flanking hydrophobic a-amino acids under conditions in which the peptide was otherwise unstructured. Additionally, exchange rates of the amide protons suggest that 1 adopts the 15- membered, hydrogen bonded ring conformation which is necessary for the peptide to adopt 0-sheet structure. Residue 2, which is incapable of adopting a hydrophobic cluster conformation was unable to nucleate P-sheet structure when incorporated into a small peptide. These results support the idea that the hydrophobic cluster facilitates B- sheet folding by acting as a nucleation site. Analytical ultracentrifugation studies indicate that intramolecular folding of small peptides incorporating I is followed by rapid self-association. These equilibria were successfully unlinked by incorporating N-methylated amino acids into the sequence so as to disrupt the lateral hydrogen bonding which facilitates self-assembly. Preliminary ultracentrifuge and far-UV CD studies suggest that a well-defined, monomeric peptide was obtained. In a synthetically related project, the design of triphenyl-based a-helix mimics and the synthesis of a model compound, 2-N,N-diisopropyl-4- trimethylsilyl-3'(diisopropylcarbamoyl)-3"- (diisopropylcarbamoyl)triphenylcarboxamide (5), for such mimics was accomplished. The synthesis of 5 is presented along with optimization studies for several reactions in the synthetic scheme and suggestions for further development. Finally, an improved synthesis of the dibenzofuran-based amino acid, 4-(2'aminoethyl)-6-dibenzofuranpropionic acid (6) has been developed and is presented. |
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| Item Description: | Vita. "Major Subject: Chemistry". In title, symbols for Greek letters Alpha and Beta are used. |
| Physical Description: | xiii, 151 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilms Inc. |
| Bibliography: | Includes bibliographical references. |