Naphthalimide-tagged ruthenium-arene anticancer complexes: combining coordination with intercalation

Ruthenium(II) arene compounds have been modified with the naphthalimide group, tethered via the arene ligand, i.e. {dichloro[eta(6)-N-(phenylalkyl)(4-dimethylamino)-1,8-naphthalimide](pta)ruthenium(II)} (alkyl = methyl, ethyl, propyl, pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]-decane), or via an imidazole group, i.e. {dichloro(eta(6)-arene)-(N-[3-(imidazol-1-yl)propyl]-1,8-naphthalimide)ruthenium(II)} (II)} (arene = p-cymene, toluene). All the compounds are reasonably cytotoxic (ca. 2-49 mu M) toward cancer cells, and the arene-linked compounds also display selectivity in that they are less cytotoxic toward model healthy cells. Mechanistic studies show that the ruthenium center does not readily react with DNA but preferentially binds to proteins. In contrast, the naphthalimide group is a strong DNA intercalator, and combined, the complexes might be expected to simultaneously cross-link DNA and proteins