title: Novel Cu(I)-selective chelators based on a bis(phosphorothioyl)amide scaffold.
abstract: 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 (N(-)R3NH(+)) and 8 (NEt) revealed a gauche geometry, while BOPA compound 7 (N(-)R3NH(+)) exhibited an anti-geometry. Solid-state (31)P 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.
authors.affiliation: Department of Chemistry, Bar Ilan University , Ramat-Gan 52900, Israel.
authors.forename: Aviran
authors.initials: A
authors.lastname: Amir
authors.forename: Alon
authors.initials: A
authors.lastname: Ezra
authors.forename: Linda J W
authors.initials: LJ
authors.lastname: Shimon
authors.forename: Bilha
authors.initials: B
authors.lastname: Fischer
mesh_terms: D000577:Amides / Q000737:chemistry*; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy
chemical_list: D000577:Amides; D000975:Antioxidants; D002614:Chelating Agents; D003300:Copper