Chemistry and Chemical Biology ETDs

Publication Date

Fall 11-14-2018

Abstract

Small molecule probes are useful tools for the study of biology. In particular, the dye derived fluorescence probes enable to spatiotemporally monitor the events of analytes of interest. The noninvasive feature is particularly attractive for the biological studies in live cells. The challenge is to develop chemical probes capable of detection of the analyte of interest with high specificity.

Toward this end, my Ph. D. study centers on the development of novel chemical probes for the study and understanding of the alternation of important cellar contents and substances and their functions and relationship between normal and disease states. In the first effort, new far-red organelle-targeting probes have been developed. They display excellent selectivity and sensitivity in response to viscosity change in cell imaging studies. The probes are further applied for the investigation of the correlation of the elevated level of mitochondrial viscosity with mitochondrial damage in cellular and animal models. In the second effort, to investigate the relationship between Fe(II) and mitochondrial damage in ischemic stroke, a new mitochondrial targeting Fe(II) probe is designed, synthesized and evaluated by using a Fe(II) induced cleavage of N-O bond chemistry. The relationship between the elevated level of Fe(II) and ROS tied with the ischemia is uncovered by the probe using cellular and animal models. In the third study, based on the unique N-O bond chemistry, a novel photo-triggered ketone prodrug release system is designed and studied. The strategy can be used as a general approach to spatiotemporally deliver drugs. Lastly, the role of iron (Fe(II) and Fe(III)) in the ferroptosis process is elucidated. The studies reveal that that labile Fe(III) is the real ferroptosis inducer instead of labile Fe(II) for the first time. Furthermore, hydroxylamines as new ferroptosis inhibitors through the reduction of Fe(III) to Fe(II) are developed inspired by Fe(II) reduced specific cleavage of N-O bond chemistry.

Language

English

Keywords

chemical probe, viscosity, Fe(II), ferroptosis, photocleavage

Document Type

Dissertation

Level of Degree

Doctoral

Department Name

Department of Chemistry and Chemical Biology

First Committee Member (Chair)

Yang Qin

Second Committee Member

Wei Wang

Third Committee Member

Changjian Feng

Fourth Committee Member

Mark Chalfant Walker

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