The Design, Synthesis, and Testing for Inhibition of Polymyxins Resistance Protein, Arna, and the Conversion of Esters to Acid Chlorides Using Thionyl Chloride

Greenberg, Jacob Arthur

Graduate Thesis Or Dissertation

The Design, Synthesis, and Testing for Inhibition of Polymyxins Resistance Protein, Arna, and the Conversion of Esters to Acid Chlorides Using Thionyl Chloride Public Deposited

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Citeable URL: https://scholar.colorado.edu/concern/graduate_thesis_or_dissertations/d504rk43d

Abstract

One of the most commonly found drug resistant Gram-negative bacteria is Pseudomonas aeruginosa, and more than 80% of CF patients die of progressive lung disease caused by P. aeruginosa. It has been found that 44% of isolates express a resistance mechanism for the innate immune system’s Cationic Antimicrobial Peptides (CAMPs) from as early as 3 months old. This resistance is accomplished through the addition of positively charged moiety 4-aminoarabinose to the lipid-A portion of lipopolysaccharide, which is ordinarily negatively charged. The addition of this moiety decreases the overall negative charge associated with the cell, therefore the effectiveness of CAMPs and antibiotics that act in this fashion. The goal of this project was to design and synthesize selective inhibitors of ArnA a protein in this modification pathway. A synthetic scheme with modular approach in our design was employed and several compounds using this strategy were synthesized. At concentrations of 1 mmol none of the synthesized compounds displayed inhibitory activity. This led to the redesign of our modular strategy to incorporate new, robust functionality in the designed inhibitors.

The reaction of tert-butyl esters with SOCl₂ at room temperature provides acid chlorides in unpurified yields of 89% or greater. Benzyl, methyl, ethyl, and isopropyl esters are essentially unreactive under these conditions, allowing for the selective conversion of tert-butyl esters to acid chlorides in the presence of other esters.

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