Conformationally Preorganized High-Affinity Ligands for Copper Biology with Hinged and Rigid Thiophene Backbones
- 20 January 2023
- journal article
- research article
- Published by American Chemical Society (ACS) in Inorganic Chemistry
- Vol. 62 (4), 1287-1296
- https://doi.org/10.1021/acs.inorgchem.2c03524
Abstract
Copper-selective ligands are essential tools for probing the affinity of cuproproteins or manipulating the cellular copper availability. They also harbor significant potential as anti-angiogenic agents in cancer therapy or as therapeutics to combat copper toxicity in Wilson’s disease. To achieve the high Cu(I) affinities required for competing effectively with cellular cuproproteins, we recently devised a ligand design based on phosphine sulfide-stabilized phosphine (PSP) donor motifs. Building on this design strategy, we integrated two PSP donors within preorganized ligand architectures composed of either a hinged bithiophene backbone (bithipPS) or a single rigid thiophene bridge (thipPS). Extensive characterization based on X-ray crystal structures, solution NMR data, spectrophotometric titrations, and electrochemical studies established that bithipPS adapts well to the coordination preferences of Cu(I) to form a discrete air-stable mono-nuclear Cu(I) complex with a dissociation constant of 4 zM. In contrast, the wider bite angle of thipPS introduces some strain upon Cu(I) coordination to yield an almost 10-fold lower affinity with a Kd of 35 zM. As revealed by ICP-MS and two-photon excitation microscopy studies with the Cu(I)-selective fluorescent probe crisp-17, both ligands are effective at removing cellular copper from live mouse fibroblasts with rapid kinetics. Altogether, the stability and redox properties of PSP-ligand Cu(I) complexes can be effectively tuned by judicious balancing of their geometrical preorganization and conformational flexibility.Funding Information
- National Institute of General Medical Sciences (GM136404)
This publication has 32 references indexed in Scilit:
- Chelation therapy in Wilson's disease: from d-penicillamine to the design of selective bioinspired intracellular Cu(i) chelatorsDalton Transactions, 2012
- An impaired mitochondrial electron transport chain increases retention of the hypoxia imaging agent diacetylbis(4-methylthiosemicarbazonato)copper IIProceedings of the National Academy of Sciences of the United States of America, 2011
- Unification of the Copper(I) Binding Affinities of the Metallo-chaperones Atx1, Atox1, and Related ProteinsOnline Journal of Public Health Informatics, 2011
- Copper(II) complexes of a biphenyl-based ligand: Tuning the needs of the metal with those of the ligandPolyhedron, 2009
- OLEX2: a complete structure solution, refinement and analysis programJournal of Applied Crystallography, 2009
- A general and efficient method for the palladium-catalyzed cross-coupling of thiols and secondary phosphinesTetrahedron, 2004
- C-Terminal Domain of the Membrane Copper Transporter Ctr1 from Saccharomyces cerevisiae Binds Four Cu(I) Ions as a Cuprous-Thiolate Polynuclear Cluster: Sub-femtomolar Cu(I) Affinity of Three Proteins Involved in Copper TraffickingJournal of the American Chemical Society, 2004
- Enforcing geometrical constraints on metal complexes using biphenyl-based ligands: spontaneous reduction of copper(II) by sulfur-containing ligandsJ. Chem. Soc., Dalton Trans., 1999
- Preparation, structure, and properties of pseudotetrahedral, D2d complexes of copper(II), nickel(II), cobalt(II), copper(I), and zinc(II) with the geometrically constraining bidentate ligand 2,2'-bis(2-imidazolyl)biphenyl. Examination of electron self-exchange for the Cu(I)/Cu(II) pairJournal of the American Chemical Society, 1990
- Tables of Standard Electrode PotentialsJournal of the Electrochemical Society, 1978