Synthesis of two methylolanthanin derivatives and the investigation of their lanthanide and iron binding capabilities

Lanthanides (Lns) have recently been recognized as essential cofactors for certain bacterial enzymes, such as methanol dehydrogenase (MDH), yet their poor bioavailability under physiological conditions has long suggested the existence of Ln-binding metallophores termed lanthanophores. In this context methylolanthanin (MLL), a chelator which is potentially involved in Ln-uptake of methylotrophic bacteria, was recently isolated and characterized. Herein we synthesized two novel MLL derivatives, ortho- and meta-MLL, for comparative studies in order to gain a deeper insight into the unusual 4-hydroxy benzoate moiety of native para-MLL. For this we implemented UV-vis titrations, time-resolved laser-induced fluorescence spectroscopy (TRLFS) and ion mobility spectrometry-mass spectrometry (IMS-MS) complemented by density functional theory (DFT) calculations to investigate metal-binding behavior in both solution and gas phases to trivalent Lns. As our binding studies revealed that both artificial chelators tend to precipitate Lns similar to the native para-MLL under biologically relevant conditions (pH: 6.0), rather than solubilizing them, the solubility products of their Eu³⁺ complexes were determined. Due to the structural resemblance of the MLL derivatives to the siderophore rhodopetrobactin B (RPB B), we also investigated iron binding. In this regard ortho-MLL stood out in our analysis and showed a distinctly different binding behavior from the other two derivatives.