Copper complexes with adamantane ring-conjugated ligands as promising agents for the treatment of glioblastoma

Platinum drugs are the mainstay of the metal-based compounds in the treatment of cancer, even if their use is limited by severe side effects and resistance phenomena. This weakness has encouraged scientific research to develop other metallodrugs with lower cytotoxicity and acting on different targets. Copper, for example, is a trace element essential for all aerobic life forms and since tumour tissues have a higher demand for copper, Cu complexes may modulate cancer cell survival through reactive oxygen species, excessive accumulation, proteasome inhibition and anti-angiogenesis. Cu-based complexes have recently shown interesting antitumor and anti-metastatic properties on diverse kinds of solid tumours. We have designed and synthesized new Cu(I) and Cu(II) complexes which were evaluated as potential agents for the treatment of glioblastoma (GBM) [2]. The bis(pyrazol-1-yl)- and bis(3,5-dimethylpyrazol-1-yl)-acetic acids were selected as bifunctionalizable coordinating agents and conjugated to the drug amantadine for the synthesis of the new chelating ligands LAd and L2Ad. Amantadine was selected as it has recently proved to show antiproliferative effects in different human tumour cell lines, including hepatocarcinoma, melanoma, and glioblastoma cells. Phosphane co-ligands were employed for the synthesis of the Cu(I) complexes to stabilize copper in +1 oxidation state and confer different solubility properties to the corresponding complexes. The electronic and molecular structures of the new complexes were investigated by X-ray photoelectron spectroscopy, near edge X-ray absorption and for [Cu(L2Ad)2]Br2 by X-ray diffraction analysis. Interesting results emerged from the biological study of the new complexes and the corresponding uncoordinated ligands, which were investigated for their antitumor potential on different GBM cell lines and for their ability to enhance the chemosensitivity to temozolomide, the standard post-surgical treatment of GBM.