Bioconjugated heteroscorpionate ligands and related copper(II) complexes. Syntheses, biological activity and XAS studies

Polydentate nitrogen-containing donor ligands derived from poly(pyrazol-1-yl)methanes bearing organic functional groups on the bridging carbon have recently attracted considerable attention and their coordination chemistry towards main group and transition metals have been extensively studied. These intriguing heteroscorpionate ligands present different types of functional groups, which successfully broadens the scope of their applications. We have investigated the use of nitroimidazole (2-methyl-5-nitro-imidazole) and glucosamine as biomolecules to conjugate to scorpionate ligands, as nitroimidazole conjugates of bis(thiosemicarbazonato)copper(II) showed additive or synergistic selectivity for tumor hypoxia compared to their individual components and in addition there is evidence describing the in vivo role of glucosamine conjugates in the transport and accumulation of compounds in tumors. In particular, we designed two new nitroimidazole and glucosamine conjugated heteroscorpionate ligands, 2,2-bis(3,5-dimethyl-1H-pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide (LMN) and 1,3,4,6-tetra-O-acetyl-2-{[bis(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]amino}-2-deoxy--D-glucopyranose (LDAC), useful for the synthesis of novel copper derivatives to be evaluated for their cytotoxic activity. The new copper(II) complexes {[(LMN)2Cu]Cl2} and {[(LDAC)2Cu]Cl2} as well as the corresponding uncoordinated ligands were evaluated for their cytotoxic activity towards a panel of several human tumour cell lines representative of ovarian (2008 and C13*), cervical (A431), colon (HCT-15), lung (A549), pancreas (Capan-1) and breast (MCF-7) cancer along with melanoma (A375). Both copper(II) complexes show similar spectra of cytotoxicity and very low resistance factors (RF < 2) against C13* ovarian cancer cells which have acquired resistance to cisplatin. Single crystal structural characterization was undertaken for the LMN ligand: in the absence of a coordinated metal core, the overall arrangement of the ligand is determined by some loose intra- and inter-molecular nonbonding contacts. X-ray Absorption Spectroscopy (XAS) has been used to probe the local structure of the two copper(II) complexes.