Cellular delivery of pyrenyl-arene ruthenium complexes by a water-soluble arene ruthenium metalla-cage

Three pyrenyl-arene ruthenium complexes (M-1-M-3) of the general formula [Ru(eta(6)-arene-pyrenyl) Cl-2(pta)] (pta = 1,3,5-triaza-7-phosphaadamantane) have been synthesised and characterised. Prior to the coordination to ruthenium, pyrene was connected to the arene ligand via an alkane chain containing different functional groups: ester (L-1), ether (L-2) and amide (L-3), respectively. Furthermore, the pyrenyl moieties of the M-n complexes were encapsulated within the hydrophobic cavity of the water soluble metalla-cage, [Ru-6(eta(6)-p-cymene)(6)(tpt)(2)(donq)(3)](6+) (tpt = 2,4,6-tri-(pyridin-4-yl)-1,3,5-triazine; donq = 5,8-dioxydo-1,4-naphthoquinonato), while the arene ruthenium end was pointing out of the cage, thus giving rise to the corresponding host-guest systems [M-n subset of Ru-6(eta(6)-p-cymene)(6)(tpt)(2)(donq)(3)](6+)([M-n subset of cage](6+)). The antitumor activity of the pyrenyl-arene ruthenium complexes (M-n) and the corresponding host-guest systems [M-n subset of cage][CF3SO3](6) were evaluated in vitro in different types of human cancer cell lines (A549, A2780, A2780cisR, Me300 and HeLa). Complex M-2, which contains an ether group within the alkane chain, demonstrated at least a 10 times higher cytotoxicity than the reference compound [Ru(eta(6)-p-cymene)Cl-2(pta)] (RAPTA-C). All host-guest systems [M-n subset of cage](6+) showed good anticancer activity with IC50 values ranging from 2 to 8 mu M after 72 h exposure. The fluorescence of the pyrenyl moiety allowed the monitoring of the cellular uptake and revealed an increase of uptake by a factor two of the M-2 complex when encapsulated in the metalla-cage [Ru6(eta(6)-p-cymene)(6)(tpt)(2)(donq)(3)](6+).