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.

Stabilization of Aliphatic Phosphines by Auxiliary Phosphine Sulfides Offers Zeptomolar Affinity and Unprecedented Selectivity for Probing Biological CuI

“…As soft Lewis bases,phosphine ligands form exceptionally stable complexes with Cu I , [9] making them promising candidates for the development of alternative high-affinity Cu I chelators.W hile phosphorus is essential to life,i to ccurs almost exclusively in the + 5oxidation state as free phosphate or phosphoric acid derivatives.Incontrast, P III compounds are not encountered in biology, [10] consistent with the susceptibility of aliphatic phosphines to rapid and irreversible oxidation by O 2 or disulfides.T oa ddress this challenge,w e thought to explore the utility of phosphine sulfide substituents,w hich might stabilize nearby phosphines through an electron-withdrawing effect while also acting as auxiliary coordination donors toward Cu I . [11] As indicated by the high aqueous solubility of Me 3 PS (> 1m), the P=Sb ond is substantially polarized, suggesting that the sulfur center may offer coordination properties intermediate between thioethers and thiolates.T ot est this design concept, we devised a phosphine sulfide-stabilized phosphine ligand, PSP-1 (Figure 1), which features an identical donor topology and chelate ring size compared to MCL-1,o ur tightest-binding Cu I affinity standard built upon an amine-thioether framework. [6] Prepared in as ingle step from lithiated Me 3 PS and (PhO) 3 P, PSP-1 was isolated as acolorless crystalline solid.…”

“…To address this challenge, we thought to explore the utility of phosphine sulfide substituents, which might stabilize nearby phosphines through an electron-withdrawing effect while also acting as auxiliary coordination donors toward Cu I . [11] As indicated by the high aqueous solubility of Me 3 PS(>1M), the P=S bond is substantially polarized, suggesting that the sulfur center may offer coordination properties intermediate between thioethers and thiolates. To test this design concept, we devised a p hosphine s ulfide-stabilized p hosphine ligand, PSP-1 (Figure 1), which features an identical donor topology and chelate ring size compared to MCL-1 , our tightest-binding Cu I affinity standard built upon an amine-thioether framework.…”

Stabilization of Aliphatic Phosphines by Auxiliary Phosphine Sulfides Offers Zeptomolar Affinity and Unprecedented Selectivity for Probing Biological CuI

“…In contrast, P III compounds are not encountered in biology, consistent with the susceptibility of aliphatic phosphines to rapid and irreversible oxidation by O 2 or disulfides. To address this challenge, we thought to explore the utility of phosphine sulfide substituents, which might stabilize nearby phosphines through an electron‐withdrawing effect while also acting as auxiliary coordination donors toward Cu I . As indicated by the high aqueous solubility of Me 3 PS (>1 m ), the P=S bond is substantially polarized, suggesting that the sulfur center may offer coordination properties intermediate between thioethers and thiolates.…”

Synthesis and Antioxidant Properties of New Substituted 8‐Methyl‐6‐phenyl‐5,6‐dihydro‐4H‐1,3,2‐benzodioxaphosphocine‐2‐oxide Derivatives

“…Also their role has been expanded in the field of fire and flame proofing as flame retardants such as Melamine salt of pentaerythritol phosphite and hexa(phosphaphenanthrene aminophenoxyl)‐cyclotriphosphazene . They also act as metal chelators and corresponding metal complexes that serve as highly active catalysts in organocatalysis .…”