Graduation Year

2008

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Chemistry

Major Professor

Mark L. McLaughlin, Ph.D.

Committee Member

Edward Turos, Ph.D.

Committee Member

Bill J. Baker, Ph.D.

Committee Member

Kirpal S. Bisht, Ph.D.

Keywords

cell permeable biomolecules, antisense therapy, solid phase synthesis, hydrazines and hydrazides, regio-selective acylation

Abstract

This report mainly discusses the development of the cysteine based PNA (CPNA), which is an analogue of PNAs. Peptide nucleic acids (PNA), a pseudopeptide DNA mimic, was discovered by Nielsen and his coworker in 1991. PNA is proved to sequence-specifically form a very stable duplex with complementary DNA and RNA strands through Watson-Crick base paring, and it is also capable of binding to duplex DNA by helix invasion. These intriguing properties of PNA implicated great potential for medical and biotechnical applications. Therefore, PNA has attracted many scientists in the fields of chemistry, biology, medicine including drug discovery and genetic diagnostics, molecular recognition. Due to its acyclic, achiral and neutral nature of the backbone, PNA has shown problems such as its poor aqueous solubility, poor cell permeability and instability of PNA-DNA duplexes and triplexes. Accordingly, many synthetic approaches have been directed toward developing modified backbones of PNA. Among those PNA analogs, only few examples including lysine-based monomers, guanidine-based peptide nucleic acids (GPNA) and the aminoethylprolyl PNA (aep-PNA) showed noticeable enhancements with regards to the daunting challenges mentioned above. Reported herein is the summary of our research endeavor to develop the CPNA oligomers with the great water-solubility and cell permeability. Chapter one briefly summarizs the background and history of the PNA as the front-runner of the antisense therapeutic agents. Chapter two discusses the novel protocols that enabled synthesis of the various versions of CPNA monomers for both Fmoc and Boc solid phase synthesis strategies. Chapter three includes the experimental procedures for solution phase preparation of the CPNA monomers. Chapter four starts with the introduction of solid phase synthesis strategy. After the brief review, our efforts on solid phase based synthesis of CPNA oligomers are discussed. Detailed procedures for the solid phase synthesis are summarized in Chapter five. Disclosed In the final chapter is a methodology which enables regioselective mono-acylation of hydrazines. Remarkably, this new protocol gives the mono-acylation on the less-reactive nitrogens of the hydrazines. Carbon disulfide takes the key role for this unique transformation. At the end of the dissertaion, selected NMR and Mass spectra are attached.

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