Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Jeffrey D. Winkler

Abstract

The development of small molecule allosteric inhibitors of carbon monoxide (CO) binding to hemoglobin (Hb) is important for the treatment of CO poisoning. We have found that the synthetic peptide IRL 2500 leads to inhibition of CO binding, but with concomitant hemolytic activity. We describe herein the design, synthesis and biological evaluation of analogs of IRL 2500 that inhibit CO binding without hemolysis. The most potent compounds that we have prepared to date contain heteroaromatic biaryls in place of the biphenyl moiety of IRL 2500. These compounds show improved solubility and reduced hemolytic activity. We also describe the synthesis of conformationally constrained analogs of IRL 2500 based on a piperazine-derived scaffold.

Available for download on Sunday, June 14, 2020

Files over 3MB may be slow to open. For best results, right-click and select "save as..."

Share

COinS