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

Abstract

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 (K_d = 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⁺ (K_d = 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 (K_d = 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.

A sulfonated analogue of APTRA strongly binds Zn²⁺ in aqueous solution with high affinity over Ca²⁺ and Mg²⁺, offering a route to new carboxylate-based zinc sensors. The affinity for Zn²⁺ is attenuated for the corresponding sulfoxide ligand and for tetradentate analogues that omit the S-linked acetate group.