Apigenin Derivatization Strategy to Improve Cytotoxicity of Rhenium(V) Complexes for Lymphoblastic Leukemia

Introducing naturally occurring molecules with a distinct biological profile into metal-based frameworks is a promising strategy for developing next-generation metallodrugs. This work provides the first comprehensive data set for oxidorhenium(V) complexes featuring O,O-chelating ligands that integrates full characterization of compounds, anticancer activity, and multi-omics-derived mechanistic insights. Reacting the Re(V) precursor [ReOCl3(PPh3)2] (P) with apigenin (HL1) results in a O,O-flavone coordination, like a typical acetylacetonate ligand. Considering the limited solubility of the parent and resulting molecules, we protected two –OH groups in the 7- and 4′-positions with acetyl (HL2), TBDMS (HL3), methoxy (HL4), and benzyloxy (HL5) groups to overcome solubility issues of the obtained complexes ([ReOCl2(PPh3)(L1‒5)]). In vitro testing of all compounds was conducted on five cancer cell lines (Jurkat, MM1.S, HT29, MCF7, and LNCaP). Complexes 1–3, P and HL2, exhibited potent cytotoxic activity against Jurkat cells. Additionally, investigation of their effect on a primary cell line derived from embryonic kidney (HEK293) showed no impact on cell viability within the tested concentration range (0–10 µM), indicating less sensitivity compared to Jurkat cells. To investigate the underlying mechanisms, untargeted proteomics and metabolomics were performed in Jurkat cells. Multi-omics analysis showed that complexes 1–2 were associated with chromatin/DNA-maintenance and antigen-presentation signatures, whereas complex 3 induced a broader suppressive phenotype; globally, metabolomics highlighted nucleotide-sugar/sialylation and sterol/retinoid/thyroid-related pathways. Overall, these findings indicate that ligand coordination reshapes the biological output of the Re(V) core, generating distinct phenotypes that support these compounds as tunable scaffolds for further development and mechanistic optimization in anticancer settings.