Anticancer activity of multinuclear arene ruthenium complexes coordinated to dendritic polypyridyl scaffolds

The rational development of multinuclear arene ruthenium complexes (arene = <i>p</i>-cymene, hexamethylbenzene) from generation 1 (<b>G</b>¹) and generation 2 (<b>G</b>²) of 4-iminopyridyl based poly(propyleneimine) dendrimer scaffolds of the type, DAB-(NH₂)<i>n</i> (<i>n</i> = 4 or 8, DAB = diaminobutane) has been accomplished in order to exploit the ‘enhanced permeability and retention’ (EPR) effect that allows large molecules to selectively enter cancer cells. Four compounds were synthesised, i.e. [{(<i>p</i>-cymene)RuCl₂}₄<b>G</b>¹] (<b>1</b>), [{(hexamethylbenzene)RuCl₂}₄<b>G</b>¹] (<b>2</b>), [{(<i>p</i>-cymene)RuCl₂}₈<b>G</b>²] (<b>3</b>), and [{(hexamethylbenzene)RuCl₂}₈<b>G</b>²] (<b>4</b>), by first reacting DAB-(NH₂)<i>n</i> with 4-pyridinecarboxaldehyde and subsequently metallating the iminopyridyl dendrimers with [(<i>p</i>-cymene)RuCl₂]sub>2</sub> or [(hexamethylbenzene)RuCl₂]₂. The related mononuclear complexes [(<i>p</i>-cymene)RuCl₂(L)] (<b>5</b>) and [(hexamethylbenzene)RuCl₂ (L)] (<b>6</b>) were obtained in a similar manner from <i>N</i>-(pyridin-4-ylmethylene)propan-1-amine (L). The molecular structure of <b>5</b> has been determined by X-ray diffraction analysis and the <i>in vitro</i> anticancer activities of the mono-, tetra- and octanuclear complexes <b>1–6</b> studied on the A2780 human ovarian carcinoma cell line showing a close correlation between the size of the compound and cytotoxicity.