Date on Master's Thesis/Doctoral Dissertation

5-2008

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Chemistry

Committee Chair

Taylor, K. Grant

Author's Keywords

RDG; Cyclic peptides; Bone-targeted drugs; Estrogen; Doxorubicin; Arginine-glycine-aspartic acid

Subject

Peptides

Abstract

Chapter I . Seven novel head-to-tail cyclic pentapeptides and pseudopentapeptides containing the arginine-glycine-aspartic acid (RGD) tripeptide motif were synthesized. All of the peptides were constructed using solid phase peptide synthesis. Functionalities of varying degrees of flexibility were incorporated into the cyclic peptide to pose as "linkers." Chosen as linkers for this study were the following: 3-aminomethylbenzoic acid ("3AMB"), 4-aminomethylbenzoic acid, aminocaproic acid, 8-amino-3,6-dioxaoctanoic acid, glycine-phenylalanine, glycine-glycine, and two pseudopeptides, GlyØ[CH 2 S]Gly and GlyØ[CH 2 S]Phe. The cyclic peptide c(D-F-3AMB-RGD) was chosen for structural evaluation using nuclear magnetic resonance (NMR) spectroscopy. Studies performed in 100% DMSO-d 6 and DMSO-d 6 :H 2 O (2:1) allowed two structural constraints to be placed on the peptide in both systems to generate two working models. A comparison of the structures in the two solvent systems based on the NH-C á H dihedral angles of Arg and Phe, revealed that a rather dramatic conformational change took place when water was added to the system. Broadening of the Asp proton signals in 100% DMSO was indicative of restricted conformational exchange, possibly due to the formation of an internal Asp-Arg salt bridge. The signal broadening is relieved upon the addition of 30% water, indicating a disruption of the salt bridge. All of the backbone amide protons except for that of aspartic acid were found to display a temperature-dependent change in chemical shift, indicating that the Asp NH is involved in an intramolecular hydrogen bond in the presence of water, most likely with the carboxylate of its own side-chain. Chapter II . Ten new bone-targeted molecules were designed, synthesized, purified, and characterized, including two "universal" bone-targeting agents based on a model of the A-ring of tetracycline: 2-(2-(2-(3-carbamoyl-2-hydroxy-4-methoxyphenylamino)-2-oxoethoxy)ethoxy)ethanaminium chloride and 5-(2-(2-(2-(3-carbamoyl-2-hydroxy-4-methoxyphenylamino)-2-oxoethoxy)ethoxy)ethylamino)-5-oxopentanoic acid. To demonstrate the potential of the "universal" bone-targeting agents, as well as produce potentially highly specific bone therapeutic or diagnostic agents, bone-targeted conjugates of estradiol, doxombicin, fluorescein, and genistein were synthesized. The resulting compounds preserved the putative pharmacophore while incorporating the bone-targeting elements. Each of these conjugates displayed significantly different solubility properties and, consequently, demanded different methods of isolation and purification.

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