Highly Cytotoxic Ruthenium(II)-Arene Complexes from Bulky 1-Pyrenylphosphane Ligands.

In the present study, the potential anti-neoplastic properties of a series of ruthenium half-sandwich complexes of formula [Ru(η6-arene)Cl2(PR1R2(1-pyrenyl))] (η6-arene = p-cymene and R1 = R2 = methyl for 1; η6-arene = methylbenzoate and R1 = R2 = methyl for 2; η6-arene = p-cymene and R1 = R2 = phenyl for 3; η6-arene = methylbenzoate and R1 = R2 = phenyl for 4; η6-arene = p-cymene, R1 = methyl and R2 = phenyl for 5; η6-arene = methylbenzoate, R1 = methyl and R2 = phenyl for 6) have been investigated. The six structurally related organoruthenium(II) compounds have been prepared in good yields and fully characterized; the X-ray structures of three of them, i.e., 1, 2, and 4, were determined. Although the piano-stool compounds contain a large polycyclic aromatic moiety, viz. a 1-pyrenyl group, they do not appear to interact with DNA. However, all the piano-stool complexes show significant cytotoxic properties against five human cell lines, namely, lung adenocarcinoma (A549), melanoma (A375), colorectal adenocarcinoma (SW620), breast adenocarcinoma (MCF7), and nontumorigenic epithelial breast (MCF10A), with IC50 values in the micromolar range for most of them. In addition, the most active compound, i.e., 2, induces a remarkable decrease of cell viability, that is in the nanomolar range, against two human neuroblastoma cell lines, namely, SK-N-BE(2) and CHLA-90. Complexes 1-6 are all capable of inducing apoptosis, but with various degrees of magnitude. Whereas 1, 3, 5, and 6 have no effect on the cell cycle of A375 cells, 2 and 4 can arrest it at the G2/M phase; furthermore, 2 (which is the most efficient compound of the series) also stops the cycle at the S phase, behaving as the well-known anticancer agent cisplatin. Finally, 2 is able to inhibit/reduce the cell migration of neuroblastoma SK-N-BE(2) cells.

Photoswitching the cytotoxic properties of platinum(II) compounds.

The photoactivation of potential anticancer metal complexes is a hot topic of current research as it may lead to the development of more selective drugs. Photoactivated chemotherapy (PACT) with coordination compounds is usually based on a (photo)chemical reaction taking place at the metal center. Herein, a new strategy is exploited that consists of "photomodifying" a ligand coordinated to metal ions. Platinum(II) complexes from photoswitchable 1,2-dithienylethene-containing ligands have been prepared, which exhibit two interconvertible photoisomeric forms that present distinct DNA-interacting properties and cytotoxic behaviors.

Custom-fit ruthenium(II) metallopeptides: a new twist to DNA binding with coordination compounds.

A new bipyridine building block has been used for the solid-phase synthesis of dinuclear DNA-binding ruthenium(II) metallopeptides. Detailed spectroscopic studies suggest that these compounds bind to the DNA by insertion into the DNA minor groove. Moreover, the potential of the solid-phase peptide synthesis approach is demonstrated by the straightforward synthesis of an octaarginine derivative that shows effective cellular internalization and cytotoxicity linked with strong DNA interaction, as evidenced by steady-state fluorescence spectroscopy and AFM studies.

pH-Driven preparation of two related platinum(ii) complexes exhibiting distinct cytotoxic properties.

Reaction of cis-[PtCl2(DMSO)2] with the ligand 4-methyl-2-N-(2-pyridylmethylene)aminophenol (Hpyrimol, LH) in methanol at room temperature produces the complexes [PtCl2LH] or [PtClL], under acidic or basic conditions, respectively. The two platinum compounds exhibit distinct DNA-interacting properties, [PtCl2LH] showing a higher affinity for the biomolecules. Furthermore, [PtClL] is clearly more cytotoxic than [PtCl2LH] in three different cancer cell lines. Solution studies reveal the occurrence of intricate solvation processes generating different aquated/hydroxido species, whose nature depends on the starting metal complex and the pH of the medium.

High-affinity sequence-selective DNA binding by iridium(III) polypyridyl organometallopeptides.

We demonstrate the application of solid-phase peptide synthesis methods for the straightforward assembly of polynuclear Ir(III) organometallopeptides, and show that their oligoarginine derivatives exhibit high DNA binding affinity, sequence selectivity, and high cytotoxicity towards a set of cancer cell lines.

The effect of potential supramolecular-bond promoters on the DNA-interacting abilities of copper-terpyridine compounds.

Three copper(ii) coordination compounds have been prepared from three different 2,2':6',2''-terpyridine-based ligands, which have been selected to investigate the potential role of supramolecular interactions on the DNA-interacting and cytotoxicity properties of the corresponding metal complexes. Hence, the ligands 4'-((naphthalen-2-yl)methoxy)-2,2':6',2''-terpyridine () and 4'-((1H-benzo[d]imidazol-2-yl)methoxy)-2,2':6',2''-terpyridine () have been synthesized from commercially-available 4'-chloro-2,2':6',2''-terpyridine (), and their copper(ii) complexes have been obtained by reaction with copper(ii) nitrate. The DNA-interacting abilities of the corresponding compounds [Cu()(H2O)(NO3)2] (), [Cu()(NO3)(H2O)](NO3)(MeOH) () and [Cu()(NO3)(H2O)](NO3) () have been investigated using different techniques, and cytotoxicity assays with several cancer cell lines have revealed interesting features, viz. the more efficient complex is , which although it does not act as a DNA cleaver, displays the most effective DNA-interacting and cytotoxic properties, compared to and .

Highly cytotoxic DNA-interacting copper(II) coordination compounds.

Four new Schiff-base ligands have been designed and prepared by condensation reaction between hydrazine derivatives (i.e. 2-hydrazinopyridine or 2-hydrazinoquinoline) and mono- or dialdehyde (3-tert-butyl-2-hydroxybenzaldehyde and 5-tert-butyl-2-hydroxyisophthalaldehyde, respectively). Six copper(II) coordination compounds of various nuclearities have been obtained from these ligands, which are formulated as [Cu(L1)Cl](CH3OH) (1), [Cu(L2)NO3] (2), [Cu2(L3)(ClO4)2(CH3O)(CH3OH)](CH3OH) (3), [Cu2(L4)(ClO4)(OH)(CH3OH)](ClO4) (4), [Cu8(L3)4(NO3)4(OH)5](NO3)3(CH3OH)5(H2O)8 (5) and [Cu3(HL2')4Cl6](CH3OH)6 (6), as revealed by single-crystal X-ray studies. Their DNA-interacting abilities have been investigated using different characterization techniques, which suggest that the metal complexes act as efficient DNA binders. Moreover, cytotoxicity assays with several cancer cell lines show that some of them are very active, as evidenced by the sub-micromolar IC50 values achieved in some cases.

Dual role of Cu²âº ions on the aggregation and degradation of soluble Aß oligomers and protofibrils investigated by fluorescence spectroscopy and AFM.

The neuropathological character of copper(II) ions (Cu(2+)) upon interaction with soluble human amyloid-ß(1-42) that subsequently generates senile plaques and/or reactive oxygen species (ROS) is considered as one of the very important features of Alzheimer's disease. The present study carried out by using fluorescence spectroscopy and atomic-force microscopy (AFM) indeed confirms the dual role played by Cu(2+), namely as mediator of protein aggregation and as generator of ROS leading to irreversible protein alteration, which most likely involve two distinct copper-binding sites. The AFM investigations clearly evidence the copper-induced aggregation of Aß oligomers and protofibrils, while comparative fluorescence measurements with copper and zinc reveals the crucial involvement of redox-active copper in the generation of Aß-cross-linked structures.