Enhanced selectivity for Mg²⁺with a phosphinate-based chelate: APDAPversusAPTRA

Abstract

o-Aminophenol-N,N,O-triacetate, known as APTRA, is one of the most well-established ligands for targeting magnesium ions but, like other aminocarboxylate ligands, it binds Ca much more strongly than Mg. The synthesis of an O-phosphinate analogue of APTRA is reported here, namely o-aminophenol-N,N-diacetate-O-methylene-methylphosphinate, referred to as APDAP. Metal binding studies monitored using UV-visible spectroscopy show that the affinity of APDAP for Ca is reduced by over two orders of magnitude compared to APTRA, and for Zn by over three orders of magnitude, whereas the affinity for Mg is attenuated to a much lesser extent, by a factor of only about 7. The selectivity towards Mg is thus substantially improved. DFT calculations support the notion that longer P-O and P-C bonds in APDAP (compared to corresponding C-O and C-C bonds in APTRA) favour a larger angle at the metal, an effect that is less unfavourable for smaller ions like Mg than for larger ions such as Ca. Derivatives of APDAP can be anticipated that will offer improved sensing of Mg in the presence of Ca, in the physiologically important millimolar concentration range.

Tuning Mg(II) Selectivity: Comparative Analysis of the Photophysical Properties of Four Fluorescent Probes with an Alkynyl‐Naphthalene Fluorophore

“…[28] Described here is the first example of incorporation of the APDAPc helate into af luorescence system to analyse the binding of Mg 2 + ,Ca 2 + and Zn 2 + . [28] Described here is the first example of incorporation of the APDAPc helate into af luorescence system to analyse the binding of Mg 2 + ,Ca 2 + and Zn 2 + .…”

“…[17] Following addition of Mg 2 + , for example, a3 0nmh ypsochromicshift in the excitation maximum was reported. [28] This ligand has very recently been shown to display a dramatically enhanced selectivity for Mg 2 + , [28] with a1 00-fold reduction in the affinity for Ca 2 + comparedt ot he parent APTRA chelate. Using an alkynyl-naphthalene fluorophore, we have attempted to tune magnesium selectivity by changing the positiono ft he oxygen and nitrogen donor groups on the aromatic framework, incorporatingaphosphinate at the expense of ac arboxylate group, and by modifying the ligand denticity aroundt he metal ion.…”

APTRA‐Based Luminescent Lanthanide Complexes Displaying Enhanced Selectivity for Mg2+

“…[17] Enhanced selectivity for Mg 2 + has been achieved for as eries of b-keto acid ligands, [18,19] but the low denticityo ft hese systems gives rise to the formationo fc ompeting ternary adducts with nucleosides in vivo, limiting their direct biological application. [21,22] By using UV/Visible absorption spectroscopy, APDAP has been shown to display as ignificantly enhanced selectivity for Mg 2 + ,a saconsequence of a1 10-fold reduction in affinity for Ca 2 + . Some promising progress has been reported recently with the development of oaminophenol-N,N-diacetate-O-methylene-methylphosphinate (APDAP), an ew pentadentate phosphinate-based analogue of APTRA.…”

“…[20] Ligands that are able to bind magnesium in water with high selectivity overc alcium are unknown. [21] The incorporation of the APDAPc helate into an alkynyl-naphthalenef luorophore has also enabled Mg 2 + concentrations to be studied in ac ompetitive binding environment. [21,22] By using UV/Visible absorption spectroscopy, APDAP has been shown to display as ignificantly enhanced selectivity for Mg 2 + ,a saconsequence of a1 10-fold reduction in affinity for Ca 2 + .…”

“…[21,22] By using UV/Visible absorption spectroscopy, APDAP has been shown to display as ignificantly enhanced selectivity for Mg 2 + ,a saconsequence of a1 10-fold reduction in affinity for Ca 2 + . [21] The incorporation of the APDAPc helate into an alkynyl-naphthalenef luorophore has also enabled Mg 2 + concentrations to be studied in ac ompetitive binding environment. [22] Such behaviour suggestst hat the APDAPc helate has the potential to be used to monitor Mg 2 + fluxes in regions of the body not previously explored, because of their elevated Ca 2 + concentrations.…”