Cu(I) and Cu(II) Complexes Based on Lonidamine-Conjugated Ligands Designed to Promote Synergistic Antitumor Effects
Abstract
Bis(pyrazol-1-yl)- and bis(3,5-dimethylpyrazol-1-yl)-acetates were conjugated with the 2-hydroxyethylester and 2-aminoethylamide derivatives of the antineoplastic drug lonidamine to prepare Cu(I) and Cu(II) complexes that mightact through synergistic mechanisms of action due to the presence of lonidamine and copper in the same chemical entity. Synchrotron radiation-based complementarytechniques [X-ray photorlectron spectroscopy and near-edge X-ray absorptionfinestructure (NEXAFS)] were used to characterize the electronic and molecularstructures of the complexes and the local structure around the copper ion (XAFS) inselected complexes.
All complexes showed significant antitumor activity, proving tobe more effective than the reference drug cisplatin in a panel of human tumor celllines, and were able to overcome oxaliplatin and multidrug resistance. Noticeably,these Cu complexes appeared much more effective than cisplatin against 3Dspheroids of pancreatic PSN-1 cancer cells; among these, PPh3-containing Cu(I)complex15appeared to be the most promising derivative.
Mechanistic studies revealed that15induced cancer cell death by means of an apoptosis-alternative cell death