The Design And Synthesis Of Allosteric Effectors Of Carbon Monoxide Binding To Hemoglobin

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Doctor of Philosophy (PhD)
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Chemistry
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allosteric effector
beta cleft of hemoglobin
carbon monoxide poisoning
hemoglobin
IRL 2500
medicinal chemistry
Biochemistry
Medicine and Health Sciences
Organic Chemistry
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2018-02-23T20:17:00-08:00
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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.

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Jeffrey D. Winkler
Date of degree
2017-01-01
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