Ruthenium(II)-bisdemethoxycurcumin conjugate complexes as potent antitumour agents through simultaneous inhibition of 20S proteasome and HMG-CoA reductase

Abstract

The synthesis of new conjugated bisdemethoxycurcumin ligands, each incorporating a distinct acyl substituent—cyclic, aliphatic, heteroaromatic, or branched—in place of the native hydroxyl groups, have been reported. These ligands were employed to prepare the corresponding Ru(II)-cymene complexes, which were comprehensively characterized by FT-IR, NMR spectroscopy, elemental analysis, and ESI-MS. Single-crystal X-ray diffraction was used to elucidate the solid-state structures of two ligands and two metal complexes. Density Functional Theory (DFT) calculations provided further insights into the structural and electronic features of both the free ligands and their complexes. The anticancer potential of the Ru(II)-cymene compounds was assessed in vitro against a panel of human cancer cell lines (HepG2, Caco-2, and MCF-7), as well as non-tumorigenic controls. The complexes exhibited selective, cell-type-specific cytotoxicity, primarily mediated through proteotoxic stress—evidenced by proteasome inhibition and p62 accumulation—and HMG-CoA reductase-dependent downregulation of PCNA expression.