Folding of dinuclear platinum anticancer complexes within the cavity of para-sulphonatocalix[4]arene

25 July 2013

The binding of three dinuclear platinum complexes, where the bridging ligand of the complexes is N,N0- (alkane-1,n-diyl)diisonicotinamide (n = 4, 6 or 8 for butane, hexane and octane, respectively) to the macrocycle para-sulphonatocalix[4]arene (sCX[4]) has been studied by 1H nuclear magnetic resonance (NMR) spectroscopy and molecular modelling. The NMR spectra show two important features, large upfield shifts of the methylene proton resonances of up to 1.8 ppm, which clearly places them within the shielding environment of the macrocycle’s cavity, and a loss of chemical symmetry of the metal complexes with extra resonances observed upon sCX[4] binding. Molecular models of the platinum–sCX[4] host–guest complexes show significant folding of the metal complexes’ aliphatic chain and a non-symmetrical interaction with the macrocycle. One side of the metal complexes forms three hydrogen bonds to sCX[4], whereas the opposite side of the metal complexes forms just one hydrogen bond, giving rise to the loss of chemical symmetry in the 1H NMR spectra. As the dinuclear platinum complexes are model anticancer drugs, the effect of sCX[4] binding was investigated in vitro in the human ovarian carcinoma cell line A2780 and its cisplatin-resistant sub-line A2780cp70. Whilst the free metal complexes are a magnitude of order more active than cisplatin in the A2780 cell line, they are all highly cross-resistant with cisplatin in the A2780cp70 line. Binding by sCX[4] has little affect on the metal complexes’ cytotoxicity in the sensitive cell line, but has a large effect in the resistant cell line. The two shortest metal complexes become less active when bound by sCX[4], whereas the longest metal complex becomes more cytotoxic.