Designing Molecular Tools For Elucidating The Role Of Labile Copper And Zinc In Biology
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Yu, Jiyao
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Abstract
Intracellular Cu(I) and Zn(II) ions have attracted tremendous attention in present-day literature as they are suggested to play a critical role in human health and disease. However, the current understanding of the homeostatic mechanisms revolving around the transport and exchange of intracellular Cu(I) and Zn(II) remains incomplete. Full elucidation of intracellular metal regulation unlocks the potential to find novel treatment for human diseases and developmental abnormalities. However, d-block metal ions are difficult to detect and trace at the single-cell level. To this end, metal-ion selective ligands and fluorescent probes are powerful tools for investigating metal ion availabilities at physiological levels. As a contribution toward revealing Cu(I) and Zn(II) regulation in cells, this work describes an unconventional design strategy for shifting the excitation wavelength of Zn(II)-selective fluorescent probe from the UV to the visible-light spectral region. The developed Zn(II)-selective fluorescent probe offers a balanced ratiometric-emission response upon Zn(II) binding and is well suited to visualize dynamic changes of cellular Zn(II) by conventional confocal fluorescence microscopy and two-photon excitation microscopy (TPEM). In a second line of investigation, this work describes the rational design of two Cu(I)-selective ligands based on phosphine-sulfide-stabilized phosphine (PSP) donor motifs. The new PSP ligands form Cu(I) complexes with dissociation constants in the low zeptomolar regime. Extensive solution characterizations, ICP-MS, and TPEM studies revealed the potential of these compounds to serve as excellent tools for manipulating copper levels within complex biological systems.
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2022-12-13
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Dissertation