<p><b>Part I: Design of a Photolabile Backbone Amide Linker for
the Synthesis of C-terminally Modified Peptides</b></p>
<p>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. </p>
<p><b>Part II: Development of II-HMG CoA Reductase Inhibitors for use
as Gram-Positive Selective Antimicrobials. </b></p>
<p>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. </p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/13023227 |
| Date | 16 December 2020 |
| Creators | Mary L Niedrauer (9437744) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/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/13023227 |
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