Graduation Year

2012

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Chemistry

Major Professor

Mark L. McLaughlin, Ph.D.

Committee Member

Roman Manetsch, Ph.D.

Committee Member

Bill Baker, Ph.D.

Committee Member

David Flanigan, Ph.D.

Keywords

α-helix, Β-sheet, MDM2, NMR, p53

Abstract

Many currently relevant diseases such as cancer arise from altered biological pathways that rely on protein-protein interactions. The proteins involved in these interactions contain certain functional domains that are responsible for the protein's biological activities. These domains consist of secondary structural elements such as α-helices and Β-sheets which are at the heart of the protein's biological activity. Therefore, designing drugs that inhibit protein-protein interactions by binding to these key secondary structural elements should provide an effective treatment for many diseases. Presented in this dissertation are the designs, syntheses, and biological evaluations for both novel α-helix and novel Β-sheet mimics.

The α-helix mimics were designed to inhibit the interactions between the tumor suppressor protein p53 and its inhibitor protein, MDM2. We also targeted the interactions between the Bak/Bcl-xL proteins. Using the knowledge gained from Hamilton's 1,4-terphenylene scaffold, we designed our inhibitors to be non-peptidic small molecule α-helix mimics. These molecules were designed to bind to the NH2-terminal domain of MDM2 protein thus preventing it from binding to the p53 protein thereby allowing p53 to induce apoptosis. The α-helix mimetic scaffold is designed around a central functionalized pyridazine ring while maintaining the appropriate distances between the ith, ith+4, and ith+7 positions of a natural alpha helix.

The Β-sheet mimics were designed as inhibitors for the integrin mediated extracellular matrix cell adhesion found in Multiple Myeloma. We have designed, synthesized, and incorporated novel Β-turns to induce the formation of Β-hairpins as well as to cyclize the peptides in order to increase their binding affinities and reduce proteolytic cleavage. Given that many protein-protein interactions occur through hydrophobic interactions; our primary Β-turn promoter was designed with the ability to alter the Β-hairpin's hydrophobicity depending on the sulfonyl group used in the turn. The synthesis of several different sulfonyl chlorides for use in our Β-turn promoter is included in this section. We have also provided a detailed structural analysis and characterization of these new cyclic peptides via NMR and CD spectrometry. Using standard 2D NMR methods, we have elucidated the 3D conformation of several peptides in solution. We have also studied the structure activity relationships (SAR) for these cyclic peptides and then correlated these results with those obtained from the NMR studies.

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