The Significant Influence of a Second Metal on the Antiproliferative Properties of the Complex [Ru(η6 -C10 H14 )(Cl2 )(dmoPTA)].

Complexes [Ru(η6 -C10 H14 )(Cl2 )(HdmoPTA)](OSO2 CF3 ) (1), [Ru(η6 -C10 H14 )(Cl2 )(dmoPTA)] (2) and [Ru(η6 -C10 H14 )(Cl2 )-µ-dmoPTA-1κP:2κ2 N,N'-MCl2 ] (M=Zn (3), Co (4), Ni (5), dmoPTA=3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) have been synthesized and characterized by elemental analysis and spectroscopic techniques. The crystal structures of 1, 3 and 5 were obtained by single-crystal X-ray diffraction. The antiproliferative activity of the complexes was evaluated against colon cancer cell line Caco-2/TC7 by using the MTT protocol. The monometallic ruthenium complexes 1 and 2 were found to be inactive, but the bimetallic complexes 3, 4 and 5 display an increased activity (IC50 3: 9.07±0.27, 4: 5.40±0.19, 5: 7.15±0.30 µM) compared to cisplatin (IC50 =45.6±8.08 µM). Importantly, no reduction in normal cell viability was observed in the presence of the complexes. Experiments targeted to obtain information on the possible action mechanism of the complexes, such as cell cycle, ROS and gene expression studies, were performed. The results showed that the complexes display different properties and action mechanism depending on the nature of metal, M, bonded to the CH3 NdmoPTA atoms.

Insights into the κ-P,N Coordination of 1,3,5-Triaza-7-phosphaadamantane and Derivatives: κ-P,N-Heterometallic Complexes and a 15N Nuclear Magnetic Resonance Survey.

Complexes {[(PTA)2CpRu-µ-CN-1κC:2κ2N-RuCp(PTA)2-ZnCl3]}·2DMSO (13) {[ZnCl2(H2O)]-(PTA-1κP:2κ2N)(PTA)CpRu-µ-CN-1κC:2κ2N-RuCp(PTA)(PTA-1κP:2κ2N)-[ZnCl2(H2O)]}Cl (14), [RuCp(HdmoPTA)(PPh3)(PTA)](CF3SO3)2 (20), [RuCp(HdmoPTA)(HPTA)(PPh3)](CF3SO3)3 (21), and [RuCp(dmoPTA)(PPh3)(PTA)](CF3SO3) (22) were obtained and characterized, and their crystal structure together with that of the previously published complex 18 is reported. The behavior of the 1,3,5-triaza-7-phosphatricyclo[3.3.1.13,7]decane (PTA) and 3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (dmoPTA) ligands against protonation and κN-coordination is discussed, on the basis of 15N nuclear magnetic resonance data collected on 22 different compounds, including PTA (1), HdmoPTA (7H), and some common derivatives as free ligands (2-6 and 8), along with mono- and polymetallic complexes containing PTA and/or HdmoPTA (9-22). 15N detection via 1H-15N heteronuclear multiple bond correlation allowed the construction of a small library of 15N chemical shifts that shed light on important features regarding κN-coordination in PTA and its derivatives.

Synthesis and Antiproliferative Activity of [RuCp(PPh3)2(HdmoPTA)](OSO2CF3)2 (HdmoPTA = 3,7-H-3,7-Dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane).

The complex [RuCp(PPh3)2(HdmoPTA)](OSO2CF3)2 (2; HdmoPTA = 3,7-H-3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) was synthesized and characterized. Its crystal structure was determined by single-crystal X-ray diffraction. The complex showed a more potent antiproliferative activity than cisplatin against a representative panel of human cancer cells.

First water-soluble backbone Ru-Ru-Ni heterometallic organometallic polymer.

The water-soluble backbone heterometallic polymer {[(PTA)2 CpRu-µ-CN-RuCp(PTA)2 -µ-NiCl3 ]}n (2) is synthesized using a reproducible and robust method and fully characterized by X-ray single crystal diffraction. The Ru-Ru-Ni polymer is found to be stable in the solid state and soluble in water. Nuclear magnetic resonance (NMR) and light scattering studies show that the polymer is stable in water for several days in air.

Tetranuclear Ru2Cu2 and Ru2Ni2 complexes with nanomolar anticancer activity.

Complexes [{RuCp(PPh3)2-µ-dmoPTA-1κP:2κ2-N,N'-CuCl}2-µ-Cl-µ-OCH3](CF3SO3)2·(CH3OH)4 (1) and [{RuCp(PPh3)2-µ-dmoPTA-1κP:2κ2-N,N'-NiCl}2-µ-Cl-µ-OH](CF3SO3)2 (2) have been synthesized and characterized. Their antiproliferative activities were assessed against six human solid tumours showing nanomolar GI50 values. The effects of 1 and 2 on SW1573 cells colony formation, HeLa cells action mechanism and their interaction with the pBR322 DNA plasmid were evaluated.

Study of the biological activity of photoactive bipyridyl-Ru(II) complexes containing 1,3,5-triaza-7-phosphaadamantane (PTA).

The water-soluble ruthenium complex cis-[Ru(dcbpyH)2(PTAH)2]Cl2·3H2O (1) (dcbpy = 4,4'-dicarboxy-2,2'-bipyridine; PTA = 1,3,5-triaza-7-phosphaadamantane) has been synthesized and characterised by NMR, IR spectroscopy, elemental analysis, and single-crystal X-ray diffraction. The optical properties of 1 were studied, including photoactivation under visible light, as well as its biological properties, together with those of the previously published Ru complexes cis-[Ru(bpy)2(PTA)2]Cl2 (2), trans-[Ru(bpy)2(PTA)2](CF3SO3)2 (3) and cis-[Ru(bpy)2(H2O)(PTA)](CF3SO3)2 (4) (bpy = 2,2'-bipyridine). Anticancer activities of the complexes against human lung (A549), cervical (HeLa) and prostate (PC3) carcinoma cells were evaluated under dark conditions and upon photoactivation with visible light. None of the complexes exhibited cytotoxic activity in the absence of light irradiation (IC50 > 100 µM). However, after photoactivation, the cytotoxicity of complexes 1, 2 and 3 against the three cell lines markedly increased, resulting in IC50 values between 25.3 µM and 9.3 µM. Notably, these complexes did not show toxicity against red blood cells. These findings show the potential of complexes 1, 2 and, particularly, 3 for selective and controlled cancer photochemotherapy. The reactivity of the Ru complexes against DNA under UV-Vis irradiation was studied by analysing plasmid mobility. Experimental data shows that 4 unfolds supercoiled DNA (SC DNA) both in the dark and under visible irradiation, while 1 and 3 are only active under light, being 2 inactive in either case. The unfolding activities of complexes 3 and 4 were dependent on the air present in the reaction. The measured intracellular levels of reactive oxygen species (ROS) upon irradiation with complexes 1, 2 and 3 suggest that their mechanism of action is related to oxidative stress.

Evaluation of the Antiproliferative Properties of CpRu Complexes Containing N-Methylated Triazaphosphaadamantane Derivatives.

Piano-stool-{CpRu} complexes containing 1,3,5-triaza-7-phosphaadamantane (PTA), N-methyl-1,3,5-triaza-7-phosphaadamantane (mPTA), and 3,7-dimethyl-1,3,7-triaza-5-phosphabyciclo[3.3.1]nonane (dmoPTA) were evaluated as drugs against breast cancer. The evaluated compounds include two new examples of this family, the complexes [RuCp(DMSO-κS)(HdmoPTA)(PPh3)](CF3SO3)2 (8) and [RuCp(PPh3)2-µ-dmoPTA-1κP-2κ2N,N'-PdCl2](CF3SO3) (11), which have been synthesized and characterized by NMR, IR, and single-crystal X-ray diffraction. The cytotoxic activity of compounds was evaluated against MDA-MB-231 breast cancer cells, and the three most active complexes were further tested against the hormone-dependent MCF-7 breast cancer cell line. Their cell death mechanism and ruthenium uptake were also evaluated, as well as their binding ability to human serum albumin.

Photo-generation of H2 by heterometallic complexes.

Multiple and different metals in a complex can accomplish single and sequential multi-step reactions, providing valuable procedures to obtain chemicals in one-pot synthetic routes. Biology has shown how cooperative catalysis is a powerful method for the synthesis of complicated molecules. One of the most attractive targets for current chemists is the synthesis of H2 by a simple and economical procedure, mainly if it is produced from water using visible light as the energy source. This review aims to show how heterometallic complexes have been recently used to catalyze the photochemical production of H2.

Neutron Scattering Techniques for Studying Metal Complexes in Aqueous Solution.

Neutron scattering combined with ab initio calculations provides a powerful tool for studying metal complexes in different solvents and, particularly, in water. The majority of traditional characterization techniques in catalysis provide only limited information on homogeneous catalytic processes. Neutron scattering, on the other hand, thanks to its sensitivity to hydrogen atoms, and therefore water molecules, can be used to build detailed models of reaction paths and to observe, at a molecular level, the influence of solvent molecules on a catalytic process. In this Mini-Review we describe several examples on how neutron scattering combined with ab initio calculations can be used to examine the nature of the interaction of water molecules with catalytically active metal complexes in solution.

Ru complexes containing Cp, mPTA and natural purine bases (mPTA = methyl-N-1,3,5-triaza-7-phosphaadamantane): Evaluation of their antiproliferative activity, solubility and redox properties.

Complexes [RuCp(Adeninate-κN9)(mPTA)2](Cl0.5)(CF3SO3)2.5·H2O (1·H2O), [RuCp(Guaninate-κN7)(mPTA)2](CF3SO3)2·H2O (2·H2O), [RuCp(Theophyllinate-κN7)(mPTA)2](CF3SO3)2·1.5H2O (3·1.5H2O) and [RuCp(Pur-κN)(mPTA)(PPh3)](CF3SO3) (4-6) (Pur = Adeninate, Guaninate, Teophyllinate; mPTA = N-methyl -1,3,5-triaza-7-phosphaadamantane) have been synthesized and characterized. Structure of complexes 1·H2O and 3·1.5H2O were determined by single-crystal X-ray diffraction. Solubility in water, Log P, electrochemical properties and antiproliferative activities of the complexes (against cisplatin-sensitive T2 and cisplatin-resistant SKOV3 cell lines) have been assessed and discussed.

Synthesis and proteasome inhibition of N-allyl vinyl ester-based peptides.

Inhibition of the proteasome, the multicatalytic protease complex responsible for the turnover of many cellular proteins, represents an attractive target in the development of new drug therapies, proteasome inhibitors being potentially useful tools for the treatment of pathologies such as cancer, as well as inflammatory, immune and neurodegenerative diseases. Based on our previous development of a new class of inhibitors bearing a C-terminal VE cluster able to interact with catalytic threonine, we report herein the synthesis and activity of new VE-based peptide analogs bearing an additional allyl pharmacophore unit at the C- or N-terminal position of the pseudotripeptide sequence. In the new series, the structural modification carried out to the prototype determine a decrease of proteasome inhibition.

First exfoliated Ru-Ru-Au organometallic polymer with layered structure.

A new water soluble heterometallic polymeric complex [{(PTA)2CpRu-µ-CN-1κC:2κ2N-RuCp(PTA)2}-µ-{Au(CN)4}4]n·2H2O (1) is synthesized and characterized by single crystal X-ray diffraction. This complex self-assembles forming 3D polymeric structures with large scale hexagonal conformation. They also organize as 3D stacks of polymer sandwiches that can be exfoliated providing mono heterometallic-3D layers, as shown by electron microscopy. Regarding the polymer dynamics, quasi-elastic neutron scattering shows a transition from vibrational Debye-Waller behaviour to a more dynamically active state as a result of the loss of structural water molecules.

Novel Ruthenium-Silver PTA-Based Polymers and Their Behavior in Water.

New coordination polymers based on two metal-containing moieties Ru-Ag are synthesized: Na[RuCpX(PTA)-µ-(PTA)-1κP:2κ2N-AgX2]∞ (X = Cl (1), Br (2), I (3)). Characterization is performed by NMR, UV-visible and FT-IR spectroscopy, optical-electron microscopy, and elemental analyses (C, H, N, S). Light scattering is employed to characterize the colloidal particles growth by polymer self-assembling. These structures are stable over a broad range of pH and exhibit thermally-driven swelling, thus resembling a typical thermosensitive hydrogel.

Good isomerization of 2-cyclohexenol by two Ru(ii) complexes, synthesis and characterization of a reaction intermediate.

The catalytic activities of [RuClCp(PTA)2] (1) and [RuCp(PTA)2(H2O-κO)]OTf (2) were assessed for the redox isomerization of the cyclic allylic alcohol 2-cyclohexenol into cyclohexanone in water and biphasic media. Complex 2 showed unprecedented good TONs for the studied conversion both in water (TON = 647) and in the biphase of cyclohexene/H2O (TON = 3420) while 1 showed a lower but also good activity (water TON = 95, biphasic TON = 100). The catalytic reaction intermediate [RuCp(PTA)2(η2-C6H9OH)]CF3SO3 (3) was synthesized and characterized using NMR.

Water driven formation of channels: unusual solid-state structural transformation of a heterometallic polymer.

The backbone hetero-organometallic polymer trans-{[RuCp(PTA)2-µ-CN-RuCp(PTA)2-µ-CoCl3]}n·(DMSO)n (1·DMSO) has been synthesized and transformed into cis-{[{RuCp(PTA)2-µ-CN-1κC:2κ2N-RuCp(PTA)2}-µ-CoCl3]}n·{[RuCp(PTA)2-µ-CN-1κC:2κ2N-RuCp(PTA)2]Cl}0.5n·(15H2O)n (2·15H2O) by addition of water to crystallization media (PTA = 1,3,5-triaza-7-phosphaadamantane). The new polymer 2·15H2O presents a nano-channeled molecular packing with pores filled by water molecules. The crystal structures of 1·DMSO and 2·15H2O and the transformation process are herein presented and discussed.

Self-Organization and Swelling of Ruthenium-Metal Coordination Polymers with PTA (Metal = Ag, Au, Co).

We present the internal structure and dynamics of novel coordination polymers based on two metal-containing moieties Ru-X (X: Ag, Au, Co), bridged through the phosphine PTA (3,5,7-triaza-phosphaadamantane). X-ray scattering gives the heterometallic polymer organization. Quasi-elastic neutron scattering measurements over a broad temperature range show a transition from vibrational Debye-Waller behavior to a more dynamically active state, but with rather localized motions, coinciding with the loss of structural water at around room temperature. Light scattering reveals that the polymers self-associate to form stable micro-particles in aqueous solution with a thermally driven volume transition. This is described by the Flory theory for polymers in solution, in which the polymer solvency is calculated as a function of the temperature. Polymer self-organization is further studied by small-angle neutron scattering and electron microscopy. A polymer parallel-plane model with gaps controlled by the environmental temperature is proposed.

Water and catalytic isomerization of linear allylic alcohols by [RuCp(H2O-κO)(PTA)2]+ (PTA = 1,3,5-triaza-7-phosphaadamantane).

A new water soluble complex [RuCp(H2O-κO)(PTA)2]+ (1) (PTA = 1,3,5-triaza-7-phosphaadamantane) has been synthesized and fully characterized by NMR and IR. The crystal structure of 1(CF3SO3)·3.5H2O was characterized by single crystal X-ray determination. The catalytic activity of this complex was evaluated for the isomerisation of linear allylic alcohols from 3-buten-2-ol to 1-octen-3-ol into the correspondent ketones under both an inert atmosphere and in air, using as solvents: water, the substrate, mixtures of water/substrate, MeOH and mixtures of MeOH/water. An isomerization experiment on a mixture of all the studied allylic alcohols was also carried out.

Enhancement of the antiproliferative activity of [RuCp(PPh3)2(dmoPTA-1κP)]+via its coordination to one {CoCl2} unit: synthesis, crystal structure and properties of [RuCp(PPh3)2-µ-dmoPTA-1κP:2κ2N,N'-CoCl2](OTf)·0.25H2O.

Synthesis, characterization and the antiproliferative activity of a new bimetallic complex [RuCp(PPh3)2-µ-dmoPTA-1κP:2k2N,N'-CoCl2]OTf·0.25H2O are described. The stability of the complex was studied under air and N2 atmospheres and in CDCl3, DMSO, water and the cell culture medium, at room temperature and 40 °C. The complex showed an enhanced antiproliferative activity (up to six-fold) when compared with its parent complex [RuCp(PPh3)2(HdmoPTA)]2+ against human lung, cervix, breast, and colon solid tumor cell lines.

Study of the interaction of water with the aqua-soluble dimeric complex [RuCp(PTA)2-µ-CN-1κC:2κ(2)N-RuCp(PTA)2](CF3SO3) (PTA = 1,3,5-triaza-7-phosphaadamantane) by neutron and X-ray diffraction in solution.

The study of an aqueous solution of [RuCp(PTA)2-µ-CN-1κC:2κ(2)N-RuCp(PTA)2](CF3SO3) by neutron and X-ray diffraction revealed surprising details as to how the water molecules interact with the complex and affect its properties. The present communication demonstrates the applicability of sophisticated scattering techniques in combination with theoretical calculations to the study of coordination compounds in aqueous solution.