New anticancer copper complexes containing ligands conjugated with biologically active molecules

Copper complexes might represent suitable alternatives to the platinum-based drugs for the treatment of tumors. Our efforts have been recently focused on design and synthesis of novel Cu(I) and Cu(II) complexes with heteroscorpionate ligands based on bis(azol-1-yl)acetic acids conjugated with biologically active species such as the N-methyl-D-aspartate receptor antagonist (6,6-diphenyl-1,4-dioxan-2-yl)methanamine (NMDA-ANT) and Lonidamine (LND). In particular, LND, an antineoplastic drug able to sensitize tumors to radio-, chemo- and photodynamic-therapy, has been converted into 2-hydroxyethylester and 2-aminoethylamide derivatives to be conjugated with chelating ligands. Both the above-mentioned groups (NMDA-ANT and LND) have been chosen with the aim to synthesize complexes acting through a synergistic mechanism of action due to the presence of both copper and moieties able to interact with the cancer cells in the same chemical entity. In particular Cu(II) complexes have been obtained using CuCl2 as an acceptor while Cu(I) complexes have been synthesized employing as starting materials [(CH3CN)4Cu(I)] and phosphanes such as triphenylphosphine (PPh3) and 1,3,5-triaza-7-phosphaadamantane (PTA) in order to modulate the lipophilic and hydrophilic properties of the resulting compounds. The molecular and electronic structure of such complexes were probed by Synchrotron Radiation-induced X-ray Photoelectron Spectroscopy and Near Edge X-ray Absorption Fine Structure spectroscopy to obtain further information about the influence of the metal coordination on the electronic structure of the ligands, and in the near edge (XANES) and extended (EXAFS) regions to understand the local coordination chemistry and electronic structure around Cu. All the novel complexes have shown a significant in vitro antitumor activity against several human cancer cell lines of different histology and cisplatin resistant or with multi-drug resistant phenotype, being significantly more active than the reference drugs and the related free ligands, even against 3D spheroids of lung, pancreatic and ovarian cancer cells, which more closely mimic the heterogeneity and complexity of in vivo tumors.