Scaffolds for generation of multimeric ligands : synthesis and applications /
Stereoisomers 3a-d were prepared to access the effect of D-amino acids on the preferred conformation of cyclic peptidomimetics. Their preferred conformations in solution were determined by NMR, CD, and molecular simulation studies. It was shown that the stereochemistry of the pseudo i + 2 residue...
| Main Author: | |
|---|---|
| Format: | Thesis Book |
| Language: | English |
| Published: |
[Place of publication not identified] :
[publisher not identified] ;
2002.
|
| Subjects: | |
| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=765105811&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | Stereoisomers 3a-d were prepared to access the effect of D-amino acids on the preferred conformation of cyclic peptidomimetics. Their preferred conformations in solution were determined by NMR, CD, and molecular simulation studies. It was shown that the stereochemistry of the pseudo i + 2 residue gave the maximum conformation change. Second generation peptidomimetics were designed to be more rigid while simultaneously retaining the key structural features that are critical for binding to target proteins. Solid phase syntheses of conformational constrained peptidomimetics 4 and 10 were developed including modifications of 4 to give the amine and guanidine derivatives 7 - 9. Their conformational biases were studied and their activities were accessed by several biological assays. Bifunctional linker-scaffolds (compounds 11 - 12) were designed to meet several criteria for solid phase syntheses of bivalent ligands. They have two amine-functionalized arms that can be simultaneously or differentially derivatized. The 2-nitrobenzene sulfonamide linker is compatible with both Boc- and Fmoc- chemistries. New cleavage procedure was investigated so that final products can be released with high purities. The linker-scaffolds 11 - 12 were used to prepare a small library of bivalent ligands targeted to a protein receptor having charged cavities separated by approximately 10 [A]. These systems were made from guanidine, carboxylic acid, and sulfonic acid constituents. Efficient approach toward fluorescein labeling dimeric systems has been developed. Dichlorotriazinylaminofluorescein (DTAF) was used as a scaffold that allows dimerization of unprotected cyclic peptidomimetics. A key step in our synthesis is the ability of monochlorotriazine scaffold to selectively couple to a piperidine group on peptidomimetics at very mild reaction condition. The fluorescent properties of these molecules also allow direct binding studies to be performed. The used of this methodology in a search for neurotrophin mimics will be discussed. |
|---|---|
| Item Description: | Vita. "Major Subject: Chemistry". |
| Physical Description: | xiv, 222 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilm Inc. |
| Bibliography: | Includes bibliographical references (leaves 103-117). |