SYNTHESIS AND PHENOTYPIC DISCOVERY OF MOLECULAR PROBES OF BIOLOGICAL SYSTEMS
Issue Date
2015-12-31Author
Meinig, James Matthew
Publisher
University of Kansas
Format
178 pages
Type
Dissertation
Degree Level
Ph.D.
Discipline
Medicinal Chemistry
Rights
Copyright held by the author.
Metadata
Show full item recordAbstract
The Peterson laboratory has had a long-standing interest in fluorescent probes of biological systems. My research in the Peterson group has focused on the design, synthesis, and biological evaluation of fluorescent small molecules that exhibit specific patterns of subcellular localization and studies of their downstream biological effects. The relationship between this approach and the strategy of phenotypic drug discovery is described in Chapter 1. Chapter 2 describes the discovery of the intrinsic blue fluorescence of the potent anti- cancer/anti-viral compound AKT inhibitor-IV (AKTIV), and how we used this property to discover that its mechanism of biological action involves accumulation in mitochondria and associated effects on mitochondrial morphology and cellular bioenergetics. Chapter 3 describes the synthesis of a novel class of hydrophobic fluorinated rhodol fluorophores that selectively accumulate in the endoplasmic reticulum. These fluorophores were shown to enable delivery of linked small- molecules to control a specific biological pathway in this organelle. Building on these studies, Chapter 4 describes screening of a variety of fluorescent probes against the vertebrate model organism zebrafish (Danio rerio). These studies led to the discoveries that hydrophobic rhodamines can be used to target zebrafish mitochondria, and acid-activated fluorophores can accumulate in acidic tissues of the embryonic yolk. Chapter 5 describes another project involving the synthesis of novel cholesteryl dimers and analysis of the in vitro stability of liposomes that incorporate these compounds.
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