X‑ray Absorption Spectroscopy Proves the Trigonal-Planar Sulfur-Only Coordination of Copper(I) with High-Affinity Tripodal Pseudopeptides

A series of tripodal ligands <b>L</b> derived from nitrilotriacetic acid (NTA) and extended by three converging metal-binding cysteine chains were previously found to bind selectively copper­(I) both in vitro and in vivo. The ligands <b>L</b>^<b>1</b> (ester) and <b>L</b>^<b>2</b> (amide) were demonstrated to form copper­(I) species with very high affinities, close to that reported for the metal-sequestering metallothioneins (MTs; log <i>K</i>^Cu‑MT ≈ 19). Here, an in-depth study by Cu K-edge X-ray absorption spectroscopy (XAS) was performed to completely characterize the copper­(I) coordination sphere in the complexes, previously evidenced by other physicochemical analyses. The X-ray absorption near-edge structure (XANES) spectra shed light on the equilibrium between a mononuclear complex and a cluster for both <b>L</b>^<b>1</b> (ester) and <b>L</b>^<b>2</b> (amide). The exclusive symmetric CuS₃ geometry adopted in the mononuclear complexes (Cu–S ≈ 2.23 Å) was clearly demonstrated by extended X-ray absorption fine structure (EXAFS) analyses. The EXAFS analyses also proved that the clusters are organized on a symmetric CuS₃ core (Cu–S ≈ 2.26 Å) and interact with three nearby copper atoms (Cu---Cu ≈ 2.7 Å), consistent with the Cu₆S₉-type clusters previously characterized by pulsed gradient spin echo NMR spectroscopy. XAS data obtained for other architectures based on the NTA template (<b>L</b>^<b>3</b> acid, <b>L</b>^<b>4</b> without a functionalized carbonyl group, etc.) demonstrated the formation of polymetallic species only, which evidence the necessity of the proximal ester or amide group to stabilize the CuS₃ mononuclear species. Finally, XAS was demonstrated to be a powerful method to quantify the equilibrium between the two copper­(I) environments evidenced with <b>L</b>^<b>1</b> and <b>L</b>^<b>2</b> at different copper concentrations and to determine the equilibrium constants between these two complexes

d‑Penicillamine Tripodal Derivatives as Efficient Copper(I) Chelators

New tripodal metal-chelating agents derived from nitrilotriacetic acid (NTA) and extended by three unnatural amino acids d-penicillamine (d-Pen) are presented. d-Pen is actually the drug most extensively used to treat copper (Cu) overload in Wilson’s disease and as such is a very attractive building block for the design of chelating agents. d-Pen is also a bulkier analogue of cysteine, with the β-methylene hydrogen atoms replaced by larger methyl groups. The hindrance of the <i>gem</i>-dimethyl group close to the thiol functions is demonstrated to influence the speciation and stability of the metal complexes. The ligands <b>L</b>^<b>4</b> (ester) and <b>L</b>^<b>5</b> (amide) were obtained from NTA and commercial d-Pen synthons in four and five steps with overall yields of 14 and 24%, respectively. Their ability to bind Cu­(I), thanks to their three thiolate functions, has been investigated using both spectroscopic and analytical methods. UV, CD, and NMR spectroscopy and mass spectrometry evidence the formation of two Cu­(I) complexes with <b>L</b>^<b>5</b>: the mononuclear complex Cu<b>L</b>^<b>5</b> and one cluster (Cu₂<b>L</b>^<b>5</b>)₂. In contrast, the bulkier ethyl ester derivative <b>L</b>^<b>4</b> cannot accommodate the mononuclear complex in solution and thus forms exclusively the cluster (Cu₂<b>L</b>^<b>4</b>)₂. Cu K-edge X-ray absorption spectroscopy (XAS and EXAFS) confirms that Cu­(I) is bound in trigonal-planar sulfur-only environments in all of these complexes with Cu- - -S distances ranging from 2.22 to 2.23 Å. Such <i>C</i>₃-symmetric CuS₃ cores are coordination modes frequently adopted in Cu­(I) proteins such as metallothioneins. These two ligands bind Cu­(I) tightly and selectively, which makes them promising chelators for intracellular copper detoxification in vivo

Tristhiolato Pseudopeptides Bind Arsenic(III) in an AsS₃ Coordination Environment Imitating Metalloid Binding Sites in Proteins

The AsIII binding of two NTA-based tripodal pseudopeptides, possessing three cysteine (ligand L1) or d-penicillamine residues (ligand L2) as potential coordinating groups for soft semimetals or metal ions, was studied by experimental (UV, CD, NMR, and ESI-MS) and theoretical (DFT) methods. All of the experimental data, obtained with the variation of the AsIII:ligand concentration ratios or pH values in some instances, evidence the exclusive formation of species with an AsS3-type coordination mode. The UV-monitored titration of the ligands with arsenous acid at pH = 7.0 provided an absorbance data set that allowed for the determination of apparent stability constants of the forming species. The obtained stabilities (logK′ = 5.26 (AsL1) and logK′ = 3.04 (AsL2)) reflect high affinities, especially for the sterically less restricted cysteine derivative. DFT calculated structures correlate well with the spectroscopic results and, in line with the 1H NMR data, indicate a preference for the all-endo conformers resembling the AsIII environment at the semimetal binding sites in various metalloproteins

Metal-Controlled Diastereoselective Self-Assembly and Circularly Polarized Luminescence of a Chiral Heptanuclear Europium Wheel

The chiral dissymmetric tetradentate ligand (<i>S</i>)-6′-(4-phenyloxazolin-2-yl)-2,2′-bipyridine-6-carboxylate (S-Phbipox) leads to the diastereoselective assembly of a homochiral Eu³⁺ triangle and a highly emissive (quantum yield = 27%) heptanuclear wheel that is the largest example of a chiral luminescent complex of Eu³⁺ reported to date. The nuclearity of the assembly is controlled by the solvent and the Eu³⁺ cation. All of the compounds show large circularly polarized luminescence with an activity that varies with the nature of the assembly (highest for the homochiral trimer)

Metal-Controlled Diastereoselective Self-Assembly and Circularly Polarized Luminescence of a Chiral Heptanuclear Europium Wheel

The chiral dissymmetric tetradentate ligand (<i>S</i>)-6′-(4-phenyloxazolin-2-yl)-2,2′-bipyridine-6-carboxylate (S-Phbipox) leads to the diastereoselective assembly of a homochiral Eu³⁺ triangle and a highly emissive (quantum yield = 27%) heptanuclear wheel that is the largest example of a chiral luminescent complex of Eu³⁺ reported to date. The nuclearity of the assembly is controlled by the solvent and the Eu³⁺ cation. All of the compounds show large circularly polarized luminescence with an activity that varies with the nature of the assembly (highest for the homochiral trimer)

Metal-Controlled Diastereoselective Self-Assembly and Circularly Polarized Luminescence of a Chiral Heptanuclear Europium Wheel

The chiral dissymmetric tetradentate ligand (<i>S</i>)-6′-(4-phenyloxazolin-2-yl)-2,2′-bipyridine-6-carboxylate (S-Phbipox) leads to the diastereoselective assembly of a homochiral Eu³⁺ triangle and a highly emissive (quantum yield = 27%) heptanuclear wheel that is the largest example of a chiral luminescent complex of Eu³⁺ reported to date. The nuclearity of the assembly is controlled by the solvent and the Eu³⁺ cation. All of the compounds show large circularly polarized luminescence with an activity that varies with the nature of the assembly (highest for the homochiral trimer)