Complexation of Divalent Metals by Natural Furoquinoline Alkaloids: An Electrospray Mass Spectrometry and DFT Study

Despite the well-established metal-chelating properties of 8-hydroxyquinoline and related compounds, little is known about the interaction of furoquinoline alkaloids with biologically relevant metal ions. This study highlights the value of combining ESI-MS, energy-resolved mass spectrometry breakdown experiments, and DFT approaches to characterize metal-binding properties of methoxy-substituted furoquinoline alkaloids, enabling the differentiation of positional isomers through characteristic metal-adduct formation and ion fragmentation.

The complexation behavior of the studied alkaloids toward Mg²⁺, Ca²⁺, Co²⁺, Cu²⁺, and Zn²⁺ was studied by electrospray ionization mass spectrometry in a micrOTOF Q II mass spectrometer. Energy-resolved mass spectrometry breakdown experiments were performed to assess the relative stability of the observed adducts. Adduct profiles were graphically compared by PCA of the ESI/MS dataset. Binding modes were evaluated by DFT calculations by B3LYP 6-311+G(2d,3p).

Quinolines 1-5 yielded stable metal adducts with distinct profiles. Ligand oxidation to [M]^+. and Cu(I) adduct formation occurred mainly for furoquinolines 1-3. Methyl-loss fragmentation characterized compounds with an 8-methoxyquinoline motif. Isomeric furoquinolines showed markedly different metal-binding adduct profiles. Flindersiamine 1 showed the strongest metal-binding affinity, yielding intense [3M+Me]²⁺ and [2M+Me]²⁺ adducts, and DFT calculations support its ability to act as an N,O-bidentate ligand.

Metal-adduct profiles obtained by ESI-MS, supported by PCA analysis, provide a robust analytical framework for differentiating positional isomers of methoxy-substituted furoquinoline alkaloids. ESI-MS and DFT studies identified the 8-methoxy substituent as a key determinant of metal complexation in furoquinoline alkaloids, revealing flindersiamine 1 as the strongest Cu²⁺-binding ligand and providing a basis for future studies on the biological properties of these compounds.