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

Abstract

Three pyrenyl-arene ruthenium complexes (M₁11–M₃33) of the general formula [Ru(η⁶-arene-pyrenyl)Cl₂(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 (L₁1), ether (L₂2) and amide (L₃3), respectively. Furthermore, the pyrenyl moieties of the M_nnn complexes were encapsulated within the hydrophobic cavity of the water soluble metalla-cage, [Ru₆(η⁶-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_nnn⊂Ru₆(η⁶-p-cymene)₆(tpt)₂(donq)₃]⁶⁺ ([M_nnn⊂cage]⁶⁺). The antitumor activity of the pyrenyl-arene ruthenium complexes (M_nnn) and the corresponding host–guest systems [M_nnn⊂cage][CF₃SO₃]₆ were evaluated in vitro in different types of human cancer cell lines (A549, A2780, A2780cisR, Me300 and HeLa). Complex M₂2, which contains an ether group within the alkane chain, demonstrated at least a 10 times higher cytotoxicity than the reference compound [Ru(η⁶-p-cymene)Cl₂(pta)] (RAPTA-C). All host–guest systems [M_nnn⊂cage]⁶⁺ showed good anticancer activity with IC₅₀ values ranging from 2 to 8 μM 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 M₂2 complex when encapsulated in the metalla-cage [Ru₆(η⁶-p-cymene)₆(tpt)₂(donq)₃]⁶⁺.