Donor-Set Switching in Morpholine-Functionalized 8-Hydroxyquinolines: Consequences for Metal Binding and the Bioactivity of RhCp* Complexes

Abstract

Morpholine-functionalized 8-hydroxyquinoline (HQ) derivatives with reduced Schiff base linkers, Morph-Et-HQ and Morph-Pr-HQ, were synthesized and comprehensively characterized to investigate the influence of linker length on donor-set preference, metal binding, and the behavior of RhCp* complexes. Both ligands exhibited excellent aqueous solubility due to the predominance of positively charged species at physiological pH, but showed no cytotoxicity, which is partly attributed to their reduced iron-binding ability compared to classical HQ systems. Solution speciation studies revealed unusual coordination behavior toward Fe(II), Zn(II), and Cu(II), involving tridentate and tetradentate donor sets beyond the classical (N,O) binding modes. In Zn(II) and Cu(II) systems, coordination rearrangements and the coexistence of multiple binding modes were observed. Although the RhCp* complex of Morph-Pr-HQ bearing the longer linker behaved similarly to conventional HQ-based complexes, Morph-Et-HQ exhibits markedly different coordination chemistry. Spectroscopic, pH-potentiometric, NOESY NMR, and density functional theory (DFT) results consistently supported the predominant (N,N,N) coordination of Morph-Et-HQ at pH 7.4, which was associated with moderate cytotoxic activity. Our results demonstrate that minor structural modifications of the linker can shift the preferred coordination mode of morpholine-functionalized HQs from classical (N,O) binding to unconventional nitrogen-donor coordination, strongly influencing their physicochemical and biological properties.