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Stabilization of Aliphatic Phosphines by Auxiliary Phosphine Sulfides Offers Zeptomolar Affinity and Unprecedented Selectivity for Probing Biological Cu I
Author(s) -
Morgan M. Thomas,
Yang Bo,
Harankhedkar Shefali,
Nabatilan Arielle,
Bourassa Daisy,
McCallum Adam M.,
Sun Fangxu,
Wu Ronghu,
Forest Craig R.,
Fahrni Christoph J.
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201804072
Subject(s) - phosphine , chemistry , bioinorganic chemistry , thioether , ligand (biochemistry) , chelation , protonation , selectivity , combinatorial chemistry , copper , amine gas treating , coordination complex , stereochemistry , organic chemistry , receptor , biochemistry , catalysis , metal , ion
Full elucidation of the functions and homeostatic pathways of biological copper requires tools that can selectively recognize and manipulate this trace nutrient within living cells and tissues, where it exists primarily as Cu I . Buffered at attomolar concentrations, intracellular Cu I is, however, not readily accessible to commonly employed amine and thioether‐based chelators. Herein, we reveal a chelator design strategy in which phosphine sulfides aid in Cu I coordination while simultaneously stabilizing aliphatic phosphine donors, producing a charge‐neutral ligand with low‐zeptomolar dissociation constant and 10 17 ‐fold selectivity for Cu I over Zn II , Fe II , and Mn II . As illustrated by reversing ATP7A trafficking in cells and blocking long‐term potentiation of neurons in mouse hippocampal brain tissue, the ligand is capable of intercepting copper‐dependent processes. The phosphine sulfide‐stabilized phosphine (PSP) design approach, which confers resistance towards protonation, dioxygen, and disulfides, could be readily expanded towards ligands and probes with tailored properties for exploring Cu I in a broad range of biological systems.