Original Multivalent Copper(II)-Conjugated Phosphorus Dendrimers and Corresponding Mononuclear Copper(II) Complexes with Antitumoral Activities

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 G_<i>n</i> (<i>n</i> = 1 to 3): <i>N</i>-(pyridin-2-ylmethylene)­ethanamine for dendrimers <b>1G</b>_<b>n</b>, <i>N</i>-(di­(pyridin-2-yl)­methylene)­ethanamine for dendrimers <b>2G</b>_{<b><i>n</i></b>}, and 2-(2-methylenehydrazinyl)­pyridine for dendrimers <b>3G</b>_{<b><i>n</i></b>}. The results indicated that the most potent derivatives are <b>1G</b><i>_<b>n</b></i> and <b>1G</b>_{<b><i>n</i></b>}<b>-Cu</b> versus <b>2G</b><i>_<b>n</b></i>, <b>2G</b>_{<b><i>n</i></b>}<b>-Cu</b>, and <b>3G</b>_{<b><i>n</i></b>}, <b>3G</b><i>_<b>n</b></i><b>-Cu</b>. 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 <b>1</b> series and noncomplexed <b>1</b> 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, <b>1G</b>_<b>3</b> and <b>1G</b>_<b>3</b><b>-Cu</b> have been selected for antiproliferative studies against a panel of tumor cell lines: <b>1G</b>_<b>3</b> and <b>1G</b>_<b>3</b><b>-Cu</b> demonstrated potent antiproliferative activities with IC₅₀ values ranging 0.3–1.6 μM. Interestingly, the complexation of the terminal ligands of <b>1G</b>_<b>3</b> dendrimers by copper­(II) metal strongly increased the IC₅₀ values in noncancer cells lines referred to as “safety” cell lines