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Novel Cu(I)-Selective Chelators Based on a Bis(phosphorothioyl)amide Scaffold

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journal contribution
posted on 04.08.2014, 00:00 by Aviran Amir, Alon Ezra, Linda J. W. Shimon, Bilha Fischer
Bis­(dialkyl/aryl-phosphorothioyl)­amide (BPA) derivatives are versatile ligands known by their high metal-ion affinity and selectivity. Here, we synthesized related chelators based on bis­(1,3,2-dithia/dioxaphospholane-2-sulfide)­amide (BTPA/BOPA) scaffolds targeting the chelation of soft metal ions. Crystal structures of BTPA compounds 6 (NR3NH+) and 8 (NEt) revealed a gauche geometry, while BOPA compound 7 (NR3NH+) exhibited an anti-geometry. Solid-state 31P magic-angle spinning NMR spectra of BTPA 6-Hg­(II) and 6-Zn­(II) complexes imply a square planar or tetrahedral geometry of the former and a distorted tetrahedral geometry of the latter, while both BTPA 6-Ni­(II) and BOPA 7-Ni­(II) complexes possibly form a polymeric structure. In Cu­(I)-H2O2 system (Fenton reaction conditions) BTPA compounds 6, 8, and 10 (NCH2Ph) were identified as most potent antioxidants (IC50 32, 56, and 29 μM, respectively), whereas BOPA analogues 7, 9 (NEt), and 11 (NCH2Ph) were found to be poor antioxidants. In Fe­(II)-H2O2 system, IC50 values for both BTPA and BOPA compounds exceeded 500 μM indicating high selectivity to Cu­(I) versus the borderline Fe­(II)-ion. Neither BTPA nor BOPA derivatives showed radical scavenging properties in H2O2 photolysis, implying that inhibition of the Cu­(I)-induced Fenton reaction by both BTPA and BOPA analogues occurred predominantly through Cu­(I)-chelation. In addition, NMR-monitored Cu­(I)- and Zn­(II)-titration of BTPA compounds 8 and 10 showed their high selectivity to a soft metal ion, Cu­(I), as compared to a borderline metal ion, Zn­(II). In summary, lipophilic BTPA analogues are promising highly selective Cu­(I) ion chelators.