Six diiodido-diamine platinum(II) complexes, either cis or trans configured, were prepared, differing only in the nature of the amine ligand (isopropylamine, dimethylamine, or methylamine), and their antiproliferative properties were evaluated against a panel of human tumor cell lines. Both series of complexes manifested pronounced cytotoxic effects, with the trans isomers being, generally, more effective than their cis counterparts. Cell cycle analysis revealed different modes of action for these new Pt(II) complexes with respect to cisplatin. The reactivity of these platinum compounds with a number of biomolecules, including cytochrome c, two sulfur containing modified amino acids, 9-ethylguanine, and a single strand oligonucleotide, was analyzed in depth by mass spectrometry and NMR spectroscopy. Interestingly, significant differences in the reactivity of the investigated compounds toward the various model biomolecules were observed: in particular we observed that trans complexes preferentially release their iodide ligands upon biomolecule binding, while the cis isomers may release the amine ligands with retention of iodides. Such differences in reactivity may have important mechanistic implications and a relevant impact on the respective pharmacological profiles.

Three (15)N-labelled trans-Pt(ii) amine complexes with isopropylamine ((15)N-ipa), methylamine ((15)N-ma) and dimethylamine ((15)N-dma) have been prepared and characterized. 2D [(1)H,(15)N] HSQC NMR spectroscopy was used to obtain the rate and equilibrium constants for the aquation of trans-[PtCl(2)((15)N-ipa)((15)N-ma)] ((15)N-1), trans-[PtCl(2)((15)N-dma)((15)N-ma)] ((15)N-2) and trans-[PtCl(2)((15)N-dma)((15)N-ipa)] ((15)N-) in 100 mM NaClO(4) solutions at 298 K. New (15)N shift ranges for H(2)N-Pt(II)-N and HN-Pt(II)-N groups are reported. Formation of the diaqua complex was not observed for and accounted for <2% of the species at equilibrium for 1 and 2 . The first aquation step is significantly faster for 2 (k(1) = 14 x 10(-5) s(-1)) than for the two complexes with the bulkier ipa ligand (k(1) = 5.5 x 10(-5) s(-1) (), 6.1 x 10(-5) s(-1) (3)), but 2 is the least aquated of the three complexes at equilibrium. The pK(a) values for the monoaqua adducts of 1-3 are similar (5.98, 5.85 and 5.91, respectively) and 0.4 pH units lower than the related cis complex cis-[PtCl(2)(dma)(2)], indicating a smaller proportion of more reactive aqua species will exist at physiological pH. The pK(a) values for the diaqua adduct of 2 (4.59 and 7.98) are 0.3-0.6 pH units higher than those of 1(4.31 and 7.30) and 3 (4.28 and 7.29), which have very similar values. The speciation profiles of 1-3 , calculated on the basis of the calculated equilibrium and dissociation constants, indicate that <1% hydrolyzed species will exist under physiological conditions in cancer cells. The cytotoxicity of 1-3 (non-(15)N-labelled) was assessed in three cancer lines (SF268, MCF-7 and NCI-H460). The new trans-Pt(ii) diamine complex 2 is more active than 1 and 3 in all cases and is more potent than cisplatin in the MCF-7 adenocarcinoma cell line.

Novel and surprising biological properties were disclosed for the platinum(II) complex cis-diiodidodiisopropylamineplatinum(II). Remarkably, this new platinum(II) complex manifests pronounced antiproliferative properties in vitro, in some cases superior to those of cisplatin. A peculiar reactivity with the model protein cytochrome c was indeed highlighted based on the loss of amine ligands and retention of iodides.

Two novel [2+2] metallo-assemblies based on a guanosine-substituted terpyridine ligand (1) coordinated to palladium(II) (2 a) and platinum(II) (2 b) are reported. These supramolecular assemblies have been fully characterized by NMR spectroscopy, ESI mass spectrometry and elemental analyses. The palladium(II) complex (2 a) has also been characterized by single crystal X-ray diffraction studies confirming that the system is a [2+2] metallo-rectangle in the solid state. The stabilities of these [2+2] assemblies in solution have been confirmed by DOSY studies as well as by variable temperature (1)H NMR spectroscopy. The ability of these dinuclear complexes to interact with quadruplex and duplex DNA was investigated by fluorescent intercalator displacement (FID) assays, fluorescence resonance energy transfer (FRET) melting studies, and electrospray mass spectrometry (ESI-MS). These studies have shown that both these assemblies interact selectively with quadruplex DNA (human telomeric DNA and the G-rich promoter region of c-myc oncogene) over duplex DNA, and are able to induce dimerization of parallel G-quadruplex structures.

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