Novel Cu(I)-selective chelators based on a bis(phosphorothioyl)amide scaffold.

Area of Science:

• Coordination Chemistry
• Organophosphorus Chemistry
• Medicinal Chemistry

Background:

• Bis(dialkyl/aryl-phosphorothioyl)amide (BPA) derivatives are known for their strong metal-ion binding capabilities.
• Developing selective chelators for soft metal ions is crucial for various applications, including catalysis and medicine.

Purpose of the Study:

• To synthesize and characterize novel bis(1,3,2-dithia/dioxaphospholane-2-sulfide)amide (BTPA/BOPA) chelators.
• To evaluate the metal-ion binding selectivity and antioxidant properties of these novel compounds, particularly their interaction with copper(I).

Main Methods:

• Synthesis of BTPA and BOPA derivatives.
• X-ray crystallography to determine compound structures.
• Solid-state (31)P magic-angle spinning NMR spectroscopy for metal complex characterization.
• Antioxidant activity assays (Fenton reaction) in Cu(I)-H2O2 and Fe(II)-H2O2 systems.
• Radical scavenging assays.
• NMR-monitored metal ion titrations (Cu(I) and Zn(II)).

Main Results:

• Crystal structures revealed distinct gauche (BTPA) and anti (BOPA) geometries.
• BTPA compounds 6, 8, and 10 demonstrated potent antioxidant activity in the Cu(I)-H2O2 system (IC50 29-56 μM), while BOPA analogues were weak.
• High selectivity for Cu(I) over Fe(II) was observed, with IC50 values >500 μM for Fe(II).
• Neither BTPA nor BOPA derivatives exhibited radical scavenging properties, indicating chelation as the primary mechanism.
• NMR titrations confirmed high selectivity of BTPA for Cu(I) over Zn(II).

Conclusions:

• Lipophilic BTPA analogues are effective and highly selective chelators for Cu(I) ions.
• The mechanism of antioxidant activity in the Cu(I)-induced Fenton reaction is predominantly Cu(I)-chelation.
• These findings highlight the potential of BTPA derivatives in applications requiring selective copper chelation.