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The organoruthenium complex [(eta(6)-hmb)Ru(en)(Cl)][PF6] (hmb is hexamethylbenzene, en is ethylenediamine) undergoes facile aquation and then reacts with KSCN in unbuffered solution to give the S-coordinated thiocyanato product [(eta(6)-hmb)Ru(en)(S-SCN)]+ which slowly converts to the thermodynamically favored N-bound complex [(eta(6)-hmb)Ru(en)(N-NCS)]+ (1+). Complex 1 was synthesized and characterized by X-ray crystallography and mass spectrometry. Despite its lack of hydrolysis over 24 h, complex 1 exhibits moderate cytotoxicity (IC(50) 24 microM) towards the human ovarian cancer cell line A2780, comparable with that of the chlorido analogue which is thought to be activated (towards potential target DNA) via a rapid aquation (Wang et. al. in Proc Natl Acad Sci USA 102:18269-18274, 2005). Detailed kinetic studies suggest that complex 1 binds to guanosine 5'-monophosphate (GMP) through direct N7 substitution of the N-bound SCN ligand. In the presence of a high concentration of chloride (104 mM), however, complex 1 may bind partly to GMP via Cl substitution. Show less

A series of half-sandwich arene-ruthenium complexes of the type [(eta(6)-p-cymene) Ru(thiosemicarbazone)Cl](+) have been synthesized and their biological activity investigated. The first structurally characterized arene-ruthenium half-sandwich complex with a thiosemicarbazone ligand is reported. Show less

The light-protected reaction of [(eta(6)-p-cymene)Ru(II)Cl(2)](2) with 1-(2-hydroxyethyl)piperazine in dry methanol, followed by addition of excess NH(4)PF(6), afforded the complex [(eta(6)-p-cymene)Ru(II)(NH(3))(2)Cl](PF(6)) () in 47% yield. Attempts to use the same protocol for the synthesis of [(eta(6)-p-cymene)Os(II)(NH(3))(2)Cl](PF(6)) led to the isolation of the binuclear triply methoxido-bridged arene-osmium compound [{(eta(6)-p-cymene)Os}(2)(mu-OCH(3))(3)](PF(6)) (). Both compounds were characterised by X-ray crystallography and (1)H NMR spectroscopy, and the ruthenium complex also by spectroscopic techniques (IR and UV-vis spectroscopies). The antiproliferative activity of complex in vitro was studied in A549 (non-small cell lung carcinoma), CH1 (ovarian carcinoma), and SW480 (colon carcinoma) cells and compared to that of [(eta(6)-p-cymene)Ru(II)(en)Cl](PF(6)) (). In contrast to the latter compound, is only modestly cytotoxic in all three cell lines (IC(50): 293-542 muM), probably due to the instability of the diammine ruthenium complex in aqueous solution. Show less

[RuCl(3).nH(2)O] and Na(trans-[RuCl(4)(DMSO)(2)]) were reacted with 1-pyrrolidinedithiocarbamate (PDT), its S-methyl ester (PDTM), and N,N-dimethylcarbamodithioic acid methyl ester (DMDTM) in water or methanol in order to obtain the corresponding Ru(III) derivatives. Once isolated and purified, the complexes were characterized by means of elemental analysis, conductivity measurements, FT-IR and (1)H NMR spectroscopy, ion electrospray mass spectrometry (ESI-MS), and thermal analyses. The crystal structure of mer-[Ru(DMDTM)(DMSO)Cl(3)] has been also determined by X-ray crystallography. In vitro cytotoxic activity of all the synthesized complexes was eventually evaluated on some selected human tumor cell lines. Show less

The antiproliferative properties of a group of 13 structurally diverse gold(III) compounds, including six mononuclear gold(III) complexes, five dinuclear oxo-bridged gold(III) complexes, and two organogold(III) compounds, toward several human tumor cell lines were evaluated in vitro using a systematic screening strategy. Initially all compounds were tested against a panel of 12 human tumor cell lines, and the best performers were tested against a larger 36-cell-line panel. Very pronounced antiproliferative properties were highlighted in most cases, with cytotoxic potencies commonly falling in the low micromolar--and even nanomolar--range. Overall, good-to-excellent tumor selectivity was established for at least seven compounds, making them particularly attractive for further pharmacological evaluation. Compare analysis suggested that the observed antiproliferative effects are caused by a variety of molecular mechanisms, in most cases "DNA-independent," and completely different from those of platinum drugs. Remarkably, some new biomolecular systems such as histone deacetylase, protein kinase C/staurosporine, mammalian target of rapamycin/rapamycin, and cyclin-dependent kinases were proposed for the first time as likely biochemical targets for the gold(III) species investigated. The results conclusively qualify gold(III) compounds as a promising class of cytotoxic agents, of outstanding interest for cancer treatment, while providing initial insight into their modes of action. Show less

A number of new ruthenium compounds have been synthesised, isolated and characterised, which exhibit excellent cytotoxicity against a number of different human tumour cell lines including a defined cisplatin resistant cell line and colon cancer cell lines. Addition of hydrophobic groups to the ruthenium molecules has a positive effect on the cytotoxicity values. Evidence is provided that, after incubation of a ruthenium compound with a 46 mer oligonucleotide duplex and subsequent nuclease treatment, ruthenium is bound to a guanine residue. Show less

The new Ru(II) chloroquine complexes [Ru(eta(6)-arene)(CQ)Cl2] (CQ = chloroquine; arene = p-cymene 1, benzene 2), [Ru(eta(6)-p-cymene)(CQ)(H2O)2][BF4]2 (3), [Ru(eta(6)-p-cymene)(CQ)(en)][PF6]2 (en = ethylenediamine) (4), and [Ru(eta(6)-p-cymene)(eta(6)-CQDP)][BF4]2 (5, CQDP = chloroquine diphosphate) have been synthesized and characterized by use of a combination of NMR and FTIR spectroscopy with DFT calculations. Each complex is formed as a single coordination isomer: In 1-4, chloroquine binds to ruthenium in the eta(1)-N mode through the quinoline nitrogen atom, whereas in 5 an unprecedented eta(6) bonding through the carbocyclic ring is observed. 1, 2, 3, and 5 are active against CQ-resistant (Dd2, K1, and W2) and CQ-sensitive (FcB1, PFB, F32, and 3D7) malaria parasites (Plasmodium falciparum); importantly, the potency of these complexes against resistant parasites is consistently higher than that of the standard drug chloroquine diphosphate. 1 and 5 also inhibit the growth of colon cancer cells, independently of the p53 status and of liposarcoma tumor cell lines with the latter showing increased sensitivity, especially to 1 (IC50 8 microM); this is significant because this type of tumor does not respond to currently employed chemotherapies. Show less

Two new ligands maip (1a), paip (1b) with their ruthenium (II) complexes [Ru(bpy)(2)(maip)](ClO(4))(2) (2a) and [Ru(bpy)(2)(paip)](ClO(4))(2) (2b) have been synthesized and characterized. The results show that complexes 2a and 2b interact with DNA through intercalative mode. The cytotoxicity of these compounds has been evaluated by MTT assay. The experiments on antioxidant activity show that these compounds exhibit good antioxidant activity against hydroxyl radical (OH). Show less

Organometallic ruthenium-arene compounds bearing a maltol ligand have been shown to be nearly inactive in in vitro anticancer assays, presumably due to the formation of dimeric Ru(II) species in aqueous solutions. In an attempt to stabilize such complexes, [Ru(eta(6)-p-cymene)(XY)Cl] (XY=pyrones or thiopyrones) complexes with different substitution pattern of the (thio)pyrone ligands have been synthesized, their structures characterized spectroscopically, and their aquation behavior investigated as well as their tumor-inhibiting potency. The aquation behavior of pyrone systems with electron-donating substituents and of thiopyrone complexes was found to be significantly different from that of the maltol-type complex reported previously. However, the formation of the dimer can be excluded as the primary reason for the inactivity of the complex because some of the stable compounds are not active in cancer cell lines either. In contrast, studies of their reactivity towards amino acids demonstrate different reactivities of the pyrone and thiopyrone complexes, and the higher stability of the latter probably renders them active against human tumor cells. Show less

Three Ru(II) polypyridyl complexes with potential high DNA-binding ability have been designed and synthesized by extending the conjugated plane of the intercalative ligand and introducing electropositive pendants to the ancillary ligand. Spectral titration, DNA thermal denaturation, viscosity experiments, and quantum chemistry calculations were performed, and the complexes were found to intercalate into DNA base pairs with very high affinity even at high salt concentrations. Benefiting from their high DNA-binding ability, the complexes can effectively inhibit the DNA transcription activity by blocking the binding of T7 RNA polymerase to the template DNA. As efficient transcription inhibitors, the complexes demonstrated high in vitro antitumor activity against four selected tumor cell lines. Show less

Neutral and cationic organometallic ruthenium(II) piano stool complexes of the type [(eta(6)-cymene)RuCl(X)(Y)] (complexes R1-R8) has been synthesized and characterized. In cationic complexes, X, Y is either a eta(2) phosphorus ligand such as 1,1-bis(diphenylphosphino)methane (DPPM) and 1,2-bis(diphenylphosphino)ethane (DPPE) or partially oxidized ligands such as 1,2-bis(diphenylphosphino)methane monooxide (DPPMO) and 1,2-bis(diphenylphosphino)ethane monooxide (DPPEO) which are strong hydrogen bond acceptors. In neutral complexes, X is chloride and Y is a monodentate phosphorous donor. Complexes with DPPM and DPPMO ligands ([(eta(6)-cymene)Ru(eta(2)-DPPM)Cl]PF(6) (R2), [(eta(6)-cymene)Ru(eta(2)-DPPMO)Cl]PF(6) (R3), [(eta(6)-cymene)Ru(eta(1)-DPPM)Cl(2)] (R5) and [(eta(6)-cymene)Ru(eta(1)-DPPMO)Cl(2)] (R6) show good cytotoxicity. Growth inhibition study of several human cancer cell lines by these complexes has been carried out. Mechanistic studies for R5 and R6 show that inhibition of cancer cell growth involves both cell cycle arrest and apoptosis induction. Using an apoptosis PCR array, we identified the sets of anti-apoptotic genes that were down regulated and pro-apoptotic genes that were up regulated. These complexes were also found to be potent metastasis inhibitors as they prevented cell invasion through matrigel. The complexes were shown to bind DNA in a non intercalative fashion and cause unwinding of plasmid DNA in cell-free medium by competitive ethidium bromide binding, viscosity measurements, thermal denaturation and gel mobility shift assays. Show less

The synthesis and characterization of ruthenium(II) arene complexes of the general formula [(eta(6)-arene)Ru(XY)Z](+), where arene = p-cymene (p-cym), hexamethylbenzene (hmb), or biphenyl (bip), XY = o-phenylenediamine (o-pda), o-benzoquinonediimine (o-bqdi), or 4,5-dimethyl-o-phenylenediamine (dmpda), and Z = Cl, Br, or I, are reported (complexes 1-6). In addition, the X-ray crystal structures of [(eta(6)-p-cym)Ru(o-pda)Cl]PF(6) (1) and [(eta(6)-hmb)Ru(o-bqdi)Cl]PF(6) (3PF(6)) are described. The Ru-N distances in 3PF(6) are significantly shorter [2.033(4) and 2.025(4) A] compared to those in 1 [2.141(2) and 2.156(2) A]. All of the imine complexes (3-5) exhibit a characteristic broad (1)H NMR NH resonance at ca. delta 14-15. Complex 1 undergoes concomitant ligand-based oxidation and hydrolysis (38% after 24 h) in water. The oxidation also occurs in methanol. The iodido complex [(eta(6)-p-cym)Ru(o-bqdi)I]I (4) did not undergo hydrolysis, whereas the chlorido complex 3 showed relatively fast hydrolysis (t(1/2) = 7.5 min). Density functional theory calculations showed that the total bonding energy of 9-EtG in [(eta(6)-p-cym)Ru(o-pda)(9-EtG-N7)](2+) (1EtG) is 23.8 kJ/mol lower than that in [(eta(6)-p-cym)Ru(o-bqdi)(9-EtG-N7)](2+) (3EtG). The greater bonding energy is related to the contribution from strong hydrogen bonding between the NH proton of the chelating ligand and O6 of 9-EtG (1.69 A). A loss of cytotoxic activity was observed upon oxidation of the amine ligand to an imine (e.g., IC(50) = 11 microM for 1 and IC(50) > 100 microM for 3, against A2780 ovarian cancer cells). The relationship between the cytotoxic activity and the solution and solid state structures of the imine and amine complexes is discussed. Show less

We show that the binding mode adopted by picolinamide derivatives in organometallic Os(II) and Ru(II) half-sandwich complexes can lead to contrasting cancer cell cytotoxicity. N-Phenyl picolinamide derivatives (XY) in Os(II) (1, 3-5, 7, 9) and Ru(II) (2, 6, 8, 10) complexes [(eta(6)-arene)(Os/Ru)(XY)Cl](n+), where arene = p-cymene (1-8, 10) or biphenyl (9), can act as N,N- or N,O-donors. Electron-withdrawing substituents on the phenyl ring resulted in N,N-coordination and electron-donating substituents in N,O-coordination. Dynamic interconversion between N,O and N,N configurations can occur in solution and is time- and temperature- (irreversible) as well as pH-dependent (reversible). The neutral N,N-coordinated compounds (1-5 and 9) hydrolyzed rapidly (t(1/2) > 4 > 1 > 9). In contrast, N,O-coordinated complexes 7 and 8 hydrolyzed slowly, did not bind to guanine or adenine, and were nontoxic. Show less

We have compared the organometallic arene complexes [(eta(6)-biphenyl)M(ethylenediamine)Cl](+) RM175 (M=Ru(II)) and its isostructural osmium(II) analogue AFAP51 (M=Os(II)) for their ability to induce cell detachment resistance from fibronectin, collagen IV and poly-l-lysine, and cell re-adhesion after treatment, their effects on cell migration and cell viability, on matrix metalloproteinases production, and on primary tumour growth of MCa mammary carcinoma, the effect of human serum albumin on their cytotoxicity. There are differences between ruthenium and osmium. The Os complex is up to 6x more potent than RM175 towards highly-invasive breast MDA-MB-231, human breast MCF-7 and human epithelial HBL-100 cancer cells, but whereas RM175 was active against MCa mammary carcinoma in vivo and caused metastasis reduction, AFAP51 was not. Intriguingly the presence of human serum albumin in the growth medium enhanced the cytotoxicity of both compounds. RM175 increased the resistance of MDA-MB-231 cells to detachment from substrates and both compounds inhibited the production of MMP-2. These data confirm the key role of ruthenium itself in anti-metastatic activity. It will be interesting to explore the activity of osmium arene complexes in other tumour models and the possibility of changing the non-arene ligands to tune the anticancer activity of osmium in vivo. Show less

In this review article, we summarize the current state of biophysical knowledge concerning the phase behavior and organization of cardiolipin (CL) and CL-containing phospholipid bilayer model membranes. We first briefly consider the occurrence and distribution of CL in biological membranes and its probable biological functions therein. We next consider the unique chemical structure of the CL molecule and how this structure may determine its distinctive physical properties. We then consider in some detail the thermotropic phase behavior and organization of CL and CL-containing lipid model membranes as revealed by a variety of biophysical techniques. We also attempt to relate the chemical properties of CL to its function in the biological membranes in which it occurs. Finally, we point out the requirement for additional biophysical studies of both lipid model and biological membranes in order to increase our currently limited understanding of the relationship between CL structure and physical properties and CL function in biological membranes. Show less

AbstractNasopharyngeal carcinoma (NPC) is a common neoplasm in Southeastern Asia, and cisplatin‐containing regimens for combinational chemotherapy are widely used for treating locally recurrent or metastatic diseases. However, resistance to cisplatin is not infrequently seen and its associated side effects may be life‐threatening. In this report, another metallo‐pharmaceutical agent gold(III) porphyrin complex [Au(TPP)]Cl was investigated in comparison to cisplatin for its in vitro and in vivo anticancer effects. Through induction of the intrinsic apoptosis pathway, [Au(TPP)]Cl exhibited 100‐fold higher potency than cisplatin in killing NPC cells, including cisplatin‐sensitive and cisplatin‐resistant variants, and also an variant harboring the Epstein‐Barr virus. In addition, a safety concentration window was demonstrated, allowing [Au(TPP)]Cl to kill tumors with minimal cytotoxicity to noncancerous cells. More importantly, weekly intraperitoneal injection of 3 mg/kg [Au(TPP)]Cl was more effective than the same dose of cisplatin in inducing tumor apoptosis in vivo and remarkably inhibited tumor growth in animals without any noticeable side effect. [Au(TPP)]Cl therefore is a promising chemotherapeutic agent that deserves further development as a novel drug for the treatment of advanced NPC, in particular, for cases with cisplatin‐resistance. © 2008 Wiley‐Liss, Inc. Show less

The hydrolysis of oxaliplatin, a third generation anticancer drug, is expected to play an important role in the activation of this compound before it reaches DNA. The first and second hydrolysis corresponding to the addition of the first water molecule concomitant with the ring-opening, followed by addition of a second water and loss of the monodentate oxalato ligand, respectively, were studied combining density functional theory (DFT) with the conductor-like dielectric continuum model (CPCM) approach. The reaction was studied in neutral and acidic conditions, and all stationary points have been identified. The computed potential energy surfaces show that, for the neutral hydrolysis, the ring-opening reaction is the rate-limiting process, with an activation barrier of about 28 kcal/mol. For the acid degradation in water, according to experimental data, the reaction is expected to proceed in a faster biphasic process, and the rate-limiting process is the ligand detachment that occurs with a barriers of about 22 kcal/mol. According to the calculated results, we expect that the reaction is favored in acidic conditions and that the monoaquated complex should be the species reacting with DNA. Show less

In the present review we summarize different strategies to induce DNA compaction and decompaction. DNA compaction is achieved using different cationic co-solutes, such as trivalent ions, surfactant, and polycations. In addition, single-chained DNA compaction can also be achieved in solvents with low dielectric constants and by confinement. The decompaction strategies depend, naturally, on the method used for the compaction and can be accomplished by, for example, heparins, cyclodextrins, non-ionic or anionic surfactants. Show less

Although homo sapiens is equipped with subneocortical neuro-endocrine structures comparable to those of all mammals, there is no scientific curiosity about basic behaviours such as the maternal protective aggressive instinct or basic emotional states such as joy. A study of the fetus ejection reflex is an opportunity to present the rational control of the procreative drives as a by-product of human brain evolution, and to clarify the concepts of neocortical inhibitions and cultural conditioning. After referring to recent spectacular advances, we anticipate that in the near future several developing scientific disciplines will have the power to overcome the effects of thousands of years of socialisation of childbirth. Show less

Dying tumour cells can elicit a potent anticancer immune response by exposing the calreticulin (CRT)/ERp57 complex on the cell surface before the cells manifest any signs of apoptosis. Here, we enumerate elements of the pathway that mediates pre-apoptotic CRT/ERp57 exposure in response to several immunogenic anticancer agents. Early activation of the endoplasmic reticulum (ER)-sessile kinase PERK leads to phosphorylation of the translation initiation factor eIF2alpha, followed by partial activation of caspase-8 (but not caspase-3), caspase-8-mediated cleavage of the ER protein BAP31 and conformational activation of Bax and Bak. Finally, a pool of CRT that has transited the Golgi apparatus is secreted by SNARE-dependent exocytosis. Knock-in mutation of eIF2alpha (to make it non-phosphorylatable) or BAP31 (to render it uncleavable), depletion of PERK, caspase-8, BAP31, Bax, Bak or SNAREs abolished CRT/ERp57 exposure induced by anthracyclines, oxaliplatin and ultraviolet C light. Depletion of PERK, caspase-8 or SNAREs had no effect on cell death induced by anthracyclines, yet abolished the immunogenicity of cell death, which could be restored by absorbing recombinant CRT to the cell surface. Show less

Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is the primary transcription factor protecting cells from oxidative stress by regulating cytoprotective genes, including the antioxidant glutathione (GSH) pathway. GSH maintains cellular redox status and affects redox signaling, cell proliferation, and death. GSH homeostasis is regulated by de novo synthesis as well as GSH redox state; previous studies have demonstrated that Nrf2 regulates GSH homeostasis by affecting de novo synthesis. We report that Nrf2 modulates the GSH redox state by regulating glutathione reductase (GSR). In response to oxidants, lungs and embryonic fibroblasts (MEFs) from Nrf2-deficient (Nrf2(-/-)) mice showed lower levels of GSR mRNA, protein, and enzyme activity relative to wild type (Nrf2(+/+)). Nrf2(-/-) MEFs exhibited greater accumulation of glutathione disulfide and cytotoxicity compared to Nrf2(+/+) MEFs in response to t-butylhydroquinone, which was rescued by restoring GSR. Microinjection of glutathione disulfide induced greater apoptosis in Nrf2(-/-) MEFs compared to Nrf2(+/+) MEFs. In silico promoter analysis of the GSR gene revealed three putative antioxidant-response elements (ARE1, -44; ARE2, -813; ARE3, -1041). Reporter analysis, site-directed mutagenesis, and chromatin immunoprecipitation assays demonstrated binding of Nrf2 to two AREs distal to the transcription start site. Overall, Nrf2 is critical for maintaining the GSH redox state via transcriptional regulation of GSR and protecting cells against oxidative stress. Show less

AbstractA brief overview is given of platinum anticancer drugs in routine clinical use and under clinical development worldwide. Details of the binding of these drugs with nucleic acids, the preferred binding site, etc. are discussed as well. Using the mechanistic knowledge at the molecular level, in particular DNA binding, possibilities for new drugs are explored. A major part of the review deals with design, synthesis and biochemical/biophysical studies of such new compounds and their possible applications as cytostatic drugs. Special attention is given to the application of bifunctionality in such new compounds. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) Show less

Meridional rhodium(III) polypyridyl complexes of the type mer-[RhX(3)(DMSO)(pp)] (X=Cl, pp=phen 1, dpq 2, dppz 3; X=Br, pp=phen 4) represent a promising class of potent cytostatic agents for the treatment of lymphoma and leukemia. Exposure of their DMSO solutions to light leads to slow isomerization to mixtures of the mer and the generally less active fac isomers. As a result, the IC(50) values of 1 and 2 toward HT-29 cells increase from 0.19 and 0.069 microM on immediate use in the dark to 0.66 and 0.312 microM, respectively, after exposure of their DMSO stock solutions to light for 7 days. In striking contrast, the complexes mer-[IrX(3)(DMSO)(phen)] (X=Cl 7, Br 8) are significantly less cytotoxic than their facial Ir(III) polypyridyl counterparts: IC(50)=20.3 microM for 7 and 4.6 microM for fac-[IrCl(3)(DMSO)(phen)] 5 toward MCF-7 cells. The IC(50) values for the complexes fac-[IrX(3)(L)(pp)] 9-13 decrease in the orders: a) Cl>Br for X and b) H(2)O>DMSO for L. Specific apoptotic cell death by DNA fragmentation was detected for leukemia (NALM-6) and lymphoma (BJAB) cells after incubation with 2, 3, and 11 (X=Br, L=H(2)O, pp=phen) for 72 h. Loss of the mitochondrial membrane potential in lymphoma cells indicates that apoptosis is mediated via the intrinsic mitochondrial pathway. LDH release assays after 1 or 3 h demonstrate that necrotic damage is negligible. Show less