Development of new therapeutic Metal(III)-chelating agents derived from Curcumin

With the aim to develop new anti-cancer approaches, which encompass therapies based on drug combinations, we are searching for innovative anti-tumor multi-targets treatments.1 In this research Curcumin represents our referring and starting point for the design of new derivatives. Curcumin, a natural occurring molecule, was shown to inhibit growth of several types of malignant cells and its biological activity was also related to its iron chelating ability.2,3 Recently curcumin proceeded onto clinical trials however its use is limited by a poor stability and bioavailability. In order to improve these features, we have synthesized new derivatives which potentially conjugate anti-proliferative and anti-oxidant effects with metal chelating capacity, especially towards Fe(III) and Ga(III), reducing free iron level and potentially delivering a chemotherapic metal ion such as Ga(III). We have performed a complete characterization of the chelating ability of new ligands in vitro by means of potentiometry, UV-Vis spectroscopy and NMR spectrometry. Stability and cellular uptake together with cytotoxicity towards different cell lines were also investigated for all ligands and their Ga(III) complexes in order to shed light on their potential anti-cancer effects especially against human colon cancer cells, unravelling the molecular basis of their biological activity.