Original multivalent copper(II)-conjugated phosphorus dendrimers and corresponding mononuclear copper(II) complexes with antitumoral activities

摘要

Novel multivalent copper(II)-conjugated phosphorus dendrimers and their corresponding mononuclear copper(II) complexes were synthesized, characterized, and screened for antiproliferative activity against human cancer cell lines. Selected copper ligands were grafted on the surface of phosphorus dendrimers of generation Gn (n = 1 to 3): N-(pyridin-2-ylmethylene)ethanamine for dendrimers 1Gn, N-(di(pyridin-2-yl)methylene)ethanamine for dendrimers 2Gn, and 2-(2-methylenehydrazinyl)pyridine for dendrimers 3Gn. The results indicated that the most potent derivatives are 1Gn and 1Gn-Cu versus 2Gn, 2Gn-Cu, and 3Gn, 3Gn-Cu. A direct relationship between the growth inhibitory effect and the number of terminal moieties or the amount of copper complexed to the dendrimer was observed in copper-complexed 1 series and noncomplexed 1 series. These data clearly suggested that cytotoxicity increased with the number of terminal moieties available and was boosted by the presence of complexed Cu atoms. Importantly, no cytotoxic effect was observed with CuCl2 at the same concentrations. Finally, 1G3 and 1G 3-Cu have been selected for antiproliferative studies against a panel of tumor cell lines: 1G3 and 1G3-Cu demonstrated potent antiproliferative activities with IC50 values ranging 0.3-1.6 μM. Interestingly, the complexation of the terminal ligands of 1G3 dendrimers by copper(II) metal strongly increased the IC50 values in noncancer cells lines referred to as "safety" cell lines.