Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)



Committee Chair

Mark A. Lipton

Committee Member 1

David H. Thompson

Committee Member 2

Suzanne C. Bart

Committee Member 3

Jean A. Chmielewski


The first part of this dissertation involves the rational design, synthesis and biological evaluation of small molecules targeting Class II HMGR. Inhibitors of this generation were designed based on information derived from the crystal structures of first generation analogues complexed in the active site of E. faecalis HMGR. On the basis of this information, polar functional groups were installed to engage specific active site residues. Of the second generation analogue set, two compounds were found to possess improved enzymatic inhibition compared to that of the most biologically active first generation analogue. Additionally, these two analogues were found to inhibit penicillin resistance in two strains of MRSA. The most effective of these was able to increase the effects of oxacillin against MRSA by 94%. We have proposed that this effect stems from a reduction in the essential bacterial carotenoid staphyloxanthin which is necessary to the maturation of penicillin binding protein PBP2a and an important virulence factor in S. aureus.

The second part of this dissertation summarizes our efforts to contribute new methods for the preparation of C-terminal modified and cyclic peptides on the solid-phase using the backbone amide linker (BAL) approach. To this end, an improved one-step preparation of 1,1-dimethylallyl esters (DMA) was developed for the C-terminal protection of amino acids. Additionally, these DMA-protected amino acids were used in conjunction with the BAL and found to resist diketopiperazine formation during the synthesis of a series of tripeptide esters. Finally, a novel precursor to the 2-hydroxy-4-carboy-6-nitrobenzyl (Hcnb) photolabile BAL was developed. This precursor possesses an aldehyde handle which facilitates facile loading of the first amino acid onto the solid support by reductive amination. A concise and robust method for its preparation was developed and its use during Hcnb-based peptide synthesis was explored.