Enhanced Binding of Zn2+ Using a Sulfur Version of o-Aminophenol-Triacetate (APTRA): Introducing S-APTRA and Derivatives.

Ortho-aminophenol-N,N,O-triacetate (APTRA) is a pentadentate ligand adopted for the selective binding of Mg2+. It has been incorporated into fluorescent sensors for Mg2+, though it binds Ca2+ and Zn2+ more avidly. Here, the synthesis of a sulfur analogue of APTRA is reported, namely ortho-aminothiophenol-N,N,S-triacetate, referred to as S-APTRA. The binding of this new pentadentate ligand to Zn2+, Ca2+, and Mg2+ has been monitored in buffered aqueous solution by UV absorption spectroscopy. The replacement of the phenolic oxygen of APTRA by a sulfur atom renders S-APTRA capable of binding Zn2+ in a biologically relevant range (Kd = 6.6 ± 0.3 nM) with high selectivity over Mg2+ and Ca2+. The enhanced selectivity for Zn2+ is in line with the principles of "hard and soft acids and bases." A tetradentate analogue omitting the S-appended carboxylate group, S-APDIA, is also reported. Its lower denticity leads to decreased affinity for Zn2+ (Kd = 8 ± 1 μM). The oxidation of S-APTRA and S-APDIA by m-CPBA leads to the sulfoxides SO-APTRA and SO-APDIA, which bind Zn2+ yet more weakly (Kd = 260 ± 20 mM and 3.6 ± 0.3 mM, respectively). This new family of ligands may prove appealing in the development of new carboxylate-based zinc sensors.