Magnesium-selective ligands in luminescence-based systems.

Abstract

Magnesium is the most abundant divalent cation in vivo. Despite this, Mg2+ homeostasis remains poorly understood compared to other biologically relevant cations. Literature-based chelates lack structural variety, with a number of intrinsic problems limiting their applications in vivo. The o‑aminophenol-N,N,O-triacetic acid (APTRA) chelate for example, is used extensively to sense Mg2+, but displays a higher selectivity towards Ca2+ and Zn2+, over Mg2+.
The synthesis of a series of four binding chelates is described, containing both carboxylate and phosphinate ligating groups. A new phosphinate analogue of APTRA, o-aminophenol-N,N-diacetic acid phosphinate (APDAP) was synthesised with a much improved Mg2+ / Ca2+ selectivity, notwithstanding a 110‑fold lower affinity for Ca2+, compared to APTRA. All ligands are analogues of APTRA, and have been conjugated into naphthalene-, lanthanide(III)- and ruthenium(II)-based systems to study the affinity and selectivity of Mg2+, Ca2+ and Zn2+, via absorbance and luminescence spectroscopy.
The incorporation of the binding groups into an alkynyl-naphthalene fluorophore provided a model system to study the binding of Mg2+, Ca2+ and Zn2+. The APDAP-based naphthalene derivative displayed a significantly higher selectivity towards Mg2+ than the carboxylate analogues. A 10-fold weaker affinity for Ca2+ was reported, allowing the binding of Mg2+ to be investigated in a competitive medium, in the presence of biologically relevant cations at concentrations similar to those found in human serum.
A dramatically enhanced selectivity towards Mg2+ was observed in the metal-based APTRA analogues compared to the naphthalene series and literature APTRA sensors. Lanthanide complexes containing a pyridylalkynylaryl chromophore displayed the highest selectivity for Mg2+, with a 28‑fold reduced affinity for Ca2+. The binding of Mg2+ in competitive media is described, using the first example of a europium-based luminescent probe to monitor ‘free’ Mg2+ in newborn calf serum. A dissociation constant of 0.6(1) mM was calculated, comparable to the ‘free’ Mg2+ concentration in human serum.