Part I. A Photolabile Backbone-Amide Linker for Solid-Phase Synthesis of C-Terminally Modified Peptides Part II. Class-II HMG-CoA Reductase Inhibitors For Use as Antimicrobials

Mary L Niedrauer, Purdue University

Abstract

Part I: Design of a Photolabile Backbone Amide Linker for the Synthesis of C-terminally Modified Peptides A new photolabile backbone amide linker has been developed for the on-resin synthesis of cyclic and C-terminally modified peptides. The linker (Hcnb) is stable to strongly acidic conditions and instead releases the completed peptide through photolytic cleavage at 365 nm. Hcnb possesses four degrees of orthogonality and is amenable to the preparation of cyclic peptides, C-terminally modified peptides, and fully protected peptides due to its photolabile backbone amide linkage. The Hcnb precursor can be conveniently synthesized in 4 steps from commercially available 4-methyl-3,5-dinitrobenzoic acid. The C-terminal amino acid residue is loaded via reductive amination of the precursor followed by an O→N transacylation for the addition of the second residue in quantitative yields, even when employing sterically bulky residues. Standard Fmoc- or Boc-based synthesis can then be utilized to complete the desired peptide. Hcnb has been used to demonstrate the linear synthesis and subsequent on-resin cyclization of various cyclic peptides of interest, as well as synthesis of C-terminal thioesters on-resin. Part II: Development of II-HMG CoA Reductase Inhibitors for use as Gram-Positive Selective Antimicrobials. Bacterial resistance to antibiotic drugs is an issue that humans have faced since the first use of sulfa drugs in the 1930s. In recent years, the rate of production of new antimicrobial drugs has diminished, as they are no longer financially beneficial to pharmaceutical companies due to short term use and rapid resistance development. This places the burden of the development of new antimicrobial drug on the academic research field. In the work presented here, progress has been made toward the development of a novel class of antimicrobial compounds. These small molecule inhibitors target II-HMG CoA Reductase, a key enzyme involved in cell wall synthesis in gram-positive bacteria. Based on analysis of co-crystal structures obtained from first- and second- generation inhibitors, structural alterations were made to design a new generation of compounds. Efforts have also been made toward identification of a potential secondary target of these inhibitors.

Degree

Ph.D.

Advisors

Lipton, Purdue University.

Subject Area

Design|Analytical chemistry|Chemistry|Electrical engineering|Medical imaging|Microbiology|Optics|Organic chemistry|Pharmaceutical sciences|Polymer chemistry

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