Solution and solid phase synthesis of peptidomimetics /
Practical asymmetric syntheses of four 2,3-methanoleucines in optically pure form were developed. Large quantities of cyclo-leucine: with suitable protecting groups for solid phase synthesis were obtained. The peptide with the primary sequence N[]-Bu-Asn-Leu-Thr-NHMe is a fair substrate for the enzy...
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| Format: | Thesis Book |
| Language: | English |
| Published: |
[Place of publication not identified] :
[publisher not identified] ;
1999.
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| Subjects: | |
| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=725942701&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | Practical asymmetric syntheses of four 2,3-methanoleucines in optically pure form were developed. Large quantities of cyclo-leucine: with suitable protecting groups for solid phase synthesis were obtained. The peptide with the primary sequence N[]-Bu-Asn-Leu-Thr-NHMe is a fair substrate for the enzyme oligosaccharyltransferase (OT) in the process of N-linked glycosylation, and it is believed that a conformational bias, an Asx turn formed by H-bonding between a carbonyl oxygen of the Asn side chain and the Thr[]NH, enhances the reactivity of the primary amide nitrogen. To investigate conformational constraints that could be imposed by 2,3-methanoleucines, two peptidomimetics, N[]-Bu-Asn-(2R,3S)-cyclo-Leu-Thr-NHMe and N[]-Bu-Asn-(2R,3S)-cyc1o-Leu-Thr-NHMe, were prepared and subjected to conformational analyses via the combination of NMR, CD and molecular simulation techniques. Conformational effects of 2,3-methanoamino acids in reptiles are rationalized on the basis of their parameters: (i) different N-C[]-CO ankles of cyclopentane amino acids compared to that of natural amino acids. (ii) fixed side chain orientations. A small biased library of 96 peptidomimetics prepared on Geysen's pins was designed to probe the side chain restrictions of 2,3-methanoleucines. Half of the 96 peptidomimetics were analogs of YGGFLRF, the other half contained analogs of YGGFL. Substitution of cyclo-Leu for Leu facilitates the evaluation of cyclo-Leu side chain effect. Each of the peptidomimetics was characterized by MALDI-MS and HPLC. The results of bioassays indicated that the side chain stereochemistry of cyclo-Leu does have an effect on the bioactivities in the YGGFLRF series while the effect is little or none in YGGFL series. Stille coupling, Suzuki coupling and Ni[]-mediated coupling were investigated in an effort to synthesize vancomycin AB ring analogs on solid support. However, the expected microcycles were not identified probably due to the rigidity of this 12- membered ring. A novel solid phase linker was developed to facilitate simultaneous Suzuki coupling, macrocyclization and resin-release. |
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| Item Description: | Vita. "Major Subject: Chemistry". |
| Physical Description: | xvi, 209 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilm Inc. |
| Bibliography: | Includes bibliographical references (leaves 103-112). |