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Strongly luminescent iridium(III) complexes, [Ir(C,N) 2 (S,S)] + (1) and [Ir(C,N) 2 (O,O)] (2), containing C,N (phenylquinoline), O,O (diketonate), or S,S (dithione) chelating ligands, have been characterized by X-ray crystallography and DFT calculations. Their long phosphorescence lifetimes in living cancer cells give rise to high quantum yields for the generation of 1 O 2 , with large 2-photon absorption cross-sections. 2 is nontoxic to cells, but potently cytotoxic to cancer cells upon brief irradiation with low doses of visible light, and potent at sub-micromolar doses towards 3D multicellular tumor spheroids with 2-photon red light. Photoactivation causes oxidative damage to specific histidine residues in the key proteins in aldose reductase and heat-shock protein-70 within living cancer cells. The oxidative stress induced by iridium photosensitizers during photoactivation can increase the levels of enzymes involved in the glycolytic pathway., (© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Two oxidovanadium(IV) complexes carrying Schiff base ligands obtained from the condensation of 4,5-dichlorobenzene-1,2-diamine and salicylaldehyde derivatives were synthesised and characterised, including their X-ray crystallographic structures. They were evaluated as dipeptidyl peptidase IV (DPP-IV) inhibitors for the treatment of type 2 diabetes. These compounds were moderate inhibitors of DPP-IV, with IC 50 values of ca. 40μM. In vivo tests showed that complexes 1 and 2 could lower significantly the level of glucose in the blood of alloxan-diabetic mice at doses of 22.5mgV·kg -1 and 29.6mgV·kg -1 , respectively. Moreover, molecular modeling studies suggested that the oxidovanadium complexes 1 and 2 could fit well into the active-site cleft of the kinase domain of DPP-IV. To the best of our knowledge, this is the first report of vanadium complexes capable of inhibiting DPP-IV., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The lectin DLasiL was isolated from seeds of the Dioclea lasiocarpa collected from the northeast coast of Brazil and characterized for the first time by mass spectrometry, DNA sequencing, inductively coupled plasma-mass spectrometry, electron paramagnetic resonance, and fluorescence spectroscopy. The structure of DLasiL lectin obtained by homology modelling suggested strong conservation of the dinuclear Ca/Mn and sugar-binding sites, and dependence of the solvent accessibility of tryptophan-88 on the oligomerisation state of the protein. DLasiL showed highly potent (low nanomolar) antiproliferative activity against several human carcinoma cell lines including A2780 (ovarian), A549 (lung), MCF-7 (breast) and PC3 (prostate), and was as, or more, potent than the lectins ConBr (Canavalia brasiliensis), ConM (Canavalia maritima) and DSclerL (Dioclea sclerocarpa) against A2780 and PC3 cells. Interestingly, DLasiL lectin caused a G2/M arrest in A2780 cells after 24h exposure, activating caspase 9 and delaying the on-set of apoptosis. Confocal microscopy showed that fluorescently-labelled DLasiL localized around the nuclei of A2780 cells at lectin doses of 0.5-2× IC 50 and gave rise to enlarged nuclei and spreading of the cells at high doses. These data reveal the interesting antiproliferative activity of DLasiL lectin, and suggest that further investigations to explore the potential of DLasiL as a new anticancer agent are warranted., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

We explore the efficacy of a hyphenated photonic crystal fibre microflow reactor - high-resolution mass spectrometer system as a method for screening the activity of potential new photoactivatable drugs. The use of light to activate drugs is an area of current development as it offers the possibility of reduced side effects due to improved spatial and temporal targeting and novel mechanisms of anticancer activity. The di-nuclear ruthenium complex [{(η 6 -indan)RuCl} 2 (μ-2,3-dpp)](PF 6 ) 2 , previously studied by Magennis et al. ( Inorg. Chem. , 2007, 46 , 5059) is used as a model drug to compare the system to standard irradiation techniques. The photodecomposition pathways using blue light radiation are the same for PCF and conventional cuvette methods. Reactions in the presence of small biomolecules 5'-guanosine monophosphate (5'-GMP), 5'-adenosine monophosphate (5'-AMP), l-cysteine (l-Cys) and glutathione (γ-l-glutamyl-l-cysteinyl-glycine, GSH) were studied. The complex was found to bind to nucleobases in the dark and this binding increased upon irradiation with 488 nm light, forming the adducts [(η 6 -indan)Ru 2 (μ-2,3-dpp) + 5'-GMP] 2+ and [(η 6 -indan)Ru + (5'-AMP)] + . These findings are consistent with studies using conventional methods. The dinuclear complex also binds strongly to GSH after irradiation, a possible explanation for its lack of potency in cell line testing. The use of the PCF-MS system dramatically reduced the sample volume required and reduced the irradiation time by four orders of magnitude from 14 hours to 12 seconds. However, the reduced sample volume also results in a reduced MS signal intensity. The dead time of the combined system is 15 min, limited by the intrinsic dead volume of the HR-MS.

Transition metal-containing proteins and enzymes are critical for the maintenance of cellular function and metal-based (metallo)drugs are commonly used for the treatment of many diseases, such as cancer. Detection and characterisation of metallodrug targets is crucial for improving drug-design and therapeutic efficacy. Due to the unique isotopic ratios of many metal species, and the complexity of proteomic samples, standard MS data analysis of these species is unsuitable for accurate assignment. Herein a new method for differentiating metal-containing species within complex LCMS data is presented based upon the Smart Numerical Annotation Procedure (SNAP). SNAP-LC accounts for the change in isotopic envelopes for analytes containing non-standard species, such as metals, and will accurately identify, record, and display the particular spectra within extended LCMS runs that contain target species, and produce accurate lists of matched peaks, greatly assisting the identification and assignment of modified species and tailored to the metals of interest. Analysis of metallated species obtained from tryptic digests of common blood proteins after reactions with three candidate metallodrugs is presented as proof-of-concept examples and demonstrates the effectiveness of SNAP-LC for the fast and accurate elucidation of metallodrug targets.

A photoactivatable dopamine-conjugated platinum(IV) anticancer complex (Pt-DA) has been incorporated into G-quadruplex G 4 K + borate hydrogels by using borate ester linkages (Pt-G 4 K + B hydrogel). These were characterized by 11 B NMR, attenuated total reflection Fourier transform infrared spectroscopy, circular dichroism, scanning electron microscopy and transmission electron microscopy. Microscopy investigations revealed the transformation of an extended fiber assembly into discrete flakes after incorporation of Pt-DA. Pt-DA showed photocytotoxicity against cisplatin-resistant A2780Cis human ovarian cancer cells (IC 50 74 μM, blue light) with a photocytotoxic index <2, whereas Pt-G 4 K + B hydrogels exhibited more potent photocytotoxicity (IC 50 3 μM, blue light) with a photocytotoxic index >5. Most notably, Pt-DA and Pt-G 4 K + B hydrogels show selective phototoxicity for cancer cells versus normal fibroblast cells (MRC5).

Apicomplexan parasites cause some of the most devastating human diseases, including malaria, toxoplasmosis, and cryptosporidiosis. New drug discovery is imperative in light of increased resistance. In this digest article, we briefly explore some of the recent and promising developments in new drug discovery against two apicomplexan parasites, Cryptosporidium and Toxoplasma., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A variety of transition metal complexes exhibit anticancer activity, but their target sites in cells need to be identified and mechanisms of action elucidated. Here, it was found that the sub-cellular distribution of [Os(η 6 -p-cym)(Azpy-NMe 2 )I] + (p-cym=p-cymene, Azpy-NMe 2 =2-(p-[dimethylamino]phenylazo)pyridine) (1), a promising drug candidate, can be mapped in human ovarian cancer cells at pharmacological concentrations using a synchrotron X-ray fluorescence nanoprobe (SXRFN). SXRFN data for Os, Zn, Ca, and P, as well as TEM and ICP analysis of mitochondrial fractions suggest localization of Os in mitochondria and not in the nucleus, accompanied by mobilization of Ca from the endoplasmic reticulum, a signaling event for cell death. These data are consistent with the ability of 1 to induce rapid bursts of reactive oxygen species and especially superoxide formed in the first step of O 2 reduction in mitochondria. Such metabolic targeting differs from the action of Pt drugs, offering promise for combatting Pt resistance, which is a current clinical problem., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The family of iodido Os II arene phenylazopyridine complexes [Os(η 6 -p-cym)(5-R 1 -pyridylazo-4-R 2 -phenyl))I] + (where p-cym=para-cymene) exhibit potent sub-micromolar antiproliferative activity towards human cancer cells and are active in vivo. Their chemical behavior is distinct from that of cisplatin: they do not readily hydrolyze, nor bind to DNA bases. We report here a mechanism by which they are activated in cancer cells, involving release of the I - ligand in the presence of glutathione (GSH). The X-ray crystal structures of two active complexes are reported, 1-I (R 1 =OEt, R 2 =H) and 2-I (R 1 =H, R 2 =NMe 2 ). They were labelled with the radionuclide 131 I (β - /γ emitter, t 1/2 8.02 d), and their activity in MCF-7 human breast cancer cells was studied. 1-[ 131 I] and 2-[ 131 I] exhibit good stability in both phosphate-buffered saline and blood serum. In contrast, once taken up by MCF-7 cells, the iodide ligand is rapidly pumped out. Intriguingly, GSH catalyzes their hydrolysis. The resulting hydroxido complexes can form thiolato and sulfenato adducts with GSH, and react with H 2 O 2 generating hydroxyl radicals. These findings shed new light on the mechanism of action of these organo-osmium complexes., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The novel photoactive ruthenium(ii) complex cis -[Ru(bpy) 2 (INH) 2 ][PF 6 ] 2 ( 1 ·2PF 6 , INH = isoniazid) was designed to incorporate the anti-tuberculosis drug, isoniazid, that could be released from the Ru(ii) cage by photoactivation with visible light. In aqueous solution, 1 rapidly released two equivalents of isoniazid and formed the photoproduct cis -[Ru(bpy) 2 (H 2 O) 2 ] 2+ upon irradiation with 465 nm blue light. We screened for activity against bacteria containing the three major classes of cell envelope: Gram-positive Bacillus subtilis , Gram-negative Escherichia coli , and Mycobacterium smegmatis in vitro using blue and multi-colored LED multi-well arrays. Complex 1 is inactive in the dark, but when photoactivated is 5.5× more potent towards M. smegmatis compared to the clinical drug isoniazid alone. Complementary pump-probe spectroscopy measurements along with density functional theory calculations reveal that the mono-aqua product is formed in <500 ps, likely facilitated by a 3 MC state. Importantly, complex 1 is highly selective in killing mycobacteria versus normal human cells, towards which it is relatively non-toxic. This work suggests that photoactivatable prodrugs such as 1 are potentially powerful new agents in combatting the global problem of antibiotic resistance.

Guanine bases in DNA are targets for some Ru-arene anticancer complexes. We have investigated the structure of the novel di-ruthenated d(GpG) adduct Ru 2 -GpG (where Ru = {(η 6 -biphenyl)-Ru(en)} 2+ (1')) in aqueous solution. 2D NMR results indicate that there are two conformers, supported by modeling studies. The major conformer I is a novel double-hamburger-like structure with a "head-to-head" (HH) base arrangement involving hydrophobic interactions between neighboring arene rings, the first example of a HH d(GpG) adduct constructed by weak interactions. Hence there are significant differences compared to Pt-d(GpG) adducts formed by cisplatin. There is no obviously rigid bending for the major conformer I. The minor conformer II of Ru 2 -GpG has a back-to-back structure, with two ruthenated guanine bases flipped away from each other. 19-23 base-pair oligodeoxyribonucleotides containing central TGGT sequences di-ruthenated by 1 show no directional bending, only slightly distorted di-ruthenated duplexes, consistent with the NMR data for conformer I. The structural differences and similarities of d(GpG) residues which are di-ruthenated or cross-linked by platination are discussed in the context of the biological activity of these metal complexes.

We report the synthesis and characterisation of the nitroxide spin-labelled photoactivatable Pt(iv) prodrug trans,trans,trans-[Pt(N3)2(OH)(OCOCH2CH2CONH-TEMPO)(Py)2] (Pt-TEMPO, where TEMPO = 2,2,6,6-tetramethylpiperidine 1-oxyl). Irradiation with blue visible light gave rise to Pt(ii) and azidyl as well as nitroxyl radicals. Pt-TEMPO exhibited low toxicity in the dark, but on photoactivation was as active towards human ovarian cancer cells as the clinical photosensitizer chlorpromazine and much more active than the anticancer drug cisplatin under the conditions used.

Dinuclear trihydroxido-bridged osmium-arene complexes are inert and biologically inactive, but we show here that linking dihydroxido-bridged Os(II) -arene fragments by a bridging di-imine to form a metallacycle framework results in strong antiproliferative activity towards cancer cells and distinctive knotting of DNA. The shortened spacer length reduces biological activity and stability in solution towards decomposition to biologically inactive dimers. Significant differences in behavior toward plasmid DNA condensation are correlated with biological activity., (© 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Metallonitrosyl complexes are promising as nitric oxide (NO) donors for the treatment of cardiovascular, endothelial, and pathogenic diseases, as well as cancer. Recently, the reduced form of NO(-) (protonated as HNO, nitroxyl, azanone, isoelectronic with O2) has also emerged as a candidate for therapeutic applications including treatment of acute heart failure and alcoholism. Here, we show that HNO is a product of the reaction of the Ru(II) complex [Ru(bpy)2(SO3)(NO)](+) (1) with glutathione or N-acetyl-L-cysteine, using met-myoglobin and carboxy-PTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) as trapping agents. Characteristic absorption spectroscopic profiles for HNO reactions with met-myoglobin were obtained, as well as EPR evidence from carboxy-PTIO experiments. Importantly, the product HNO counteracted NO-induced as well as hypoxia-induced stabilization of the tumor-suppressor HIF-1α in cancer cells. The functional disruption of neovascularization by HNO produced by this metallonitrosyl complex was demonstrated in an in vitro angiogenesis model. This behavior is consistent with HNO biochemistry and contrasts with NO-mediated stabilization of HIF-1α. Together, these results demonstrate for the first time thiol-dependent production of HNO by a ruthenium complex and subsequent destabilization of HIF-1α. This work suggests that the complex warrants further investigation as a promising antiangiogenesis agent for the treatment of cancer.

7-(4-(Decanoyl)piperazin-1-yl)-ciprofloxacin, CipA, (1) which is an analogue of the antibiotic ciprofloxacin, and its ruthenium(II) complex [Ru(η(6)-p-cymene)(CipA-H)Cl], (2) have been synthesised and the x-ray crystal structures of 1·1.3H2O·0.6CH3OH and 2·CH3OH·0.5H2O determined. The complex adopts a typical pseudo-octahedral 'piano-stool' geometry, with Ru(II) π-bonded to the p-cymene ring and σ-bonded to a chloride and two oxygen atoms of the chelated fluoroquinolone ligand. The complex is highly cytotoxic in the low μM range and is as potent as the clinical drug cisplatin against the human cancer cell lines A2780, A549, HCT116, and PC3. It is also highly cytotoxic against cisplatin- and oxaliplatin-resistant cell lines suggesting a different mechanism of action. The complex also retained low μM cytotoxicity against the human colon cancer cell line HCT116p53 in which the tumour suppressor p53 had been knocked out, suggesting that the potent anti-proliferative properties associated with this complex are independent of the status of p53 (in contrast to cisplatin). The complex also retained moderate anti-bacterial activity in two Escherichia coli, a laboratory strain and a clinical isolate resistant to first, second and third generation β-lactam antibiotics., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

We report DNA cleavage by ruthenium(II) arene anticancer complex [(η(6)-p-terp)Ru(II)(en)Cl](+) (p-terp=para-terphenyl, en=1,2-diaminoethane, complex 1) after its photoactivation by UVA and visible light, and the toxic effects of photoactivated 1 in cancer cells. It was shown in our previous work (T. Bugarcic et al., J. Med. Chem. 51 (2008) 5310-5319) that this complex exhibits promising toxic effects in several human tumor cell lines and concomitantly its DNA binding mode involves combined intercalative and monofunctional (coordination) binding modes. We demonstrate in the present work that when photoactivated by UVA or visible light, 1 efficiently photocleaves DNA, also in hypoxic media. Studies of the mechanism underlying DNA cleavage by photoactivated 1 reveal that the photocleavage reaction does not involve generation of reactive oxygen species (ROS), although contribution of singlet oxygen ((1)O2) to the DNA photocleavage process cannot be entirely excluded. Notably, the mechanism of DNA photocleavage by 1 appears to involve a direct modification of mainly those guanine residues to which 1 is coordinatively bound. As some tumors are oxygen-deficient and cytotoxic effects of photoactivated ruthenium compounds containing {Ru(η(6)-arene)}(2+) do not require the presence of oxygen, this class of ruthenium complexes may be considered potential candidate agents for improved photodynamic anticancer chemotherapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We report a detailed study of a promising photoactivatable metal-based anticancer prodrug candidate, trans,trans,trans-[Pt(N3)2(OH)2(py)2] (C1; py = pyridine), using vibrational spectroscopic techniques. Attenuated total reflection Fourier transform infrared (ATR-FTIR), Raman, and synchrotron radiation far-IR (SR-FIR) spectroscopies were applied to obtain highly resolved ligand and Pt-ligand vibrations for C1 and its precursors (trans-[Pt(N3)2(py)2] (C2) and trans-[PtCl2(py)2] (C3)). Distinct IR- and Raman-active vibrational modes were assigned with the aid of density functional theory calculations, and trends in the frequency shifts as a function of changing Pt coordination environment were determined and detailed for the first time. The data provide the ligand and Pt-ligand (azide, hydroxide, pyridine) vibrational signatures for C1 in the mid- and far-IR region, which will provide a basis for the better understanding of the interaction of C1 with biomolecules.

The rapidly growing area of catalytic ruthenium chemistry has provided new complexes with potential as organometallic anticancer agents with novel mechanisms of action. Here we report the anticancer activity of four neutral organometallic Ru(II) arene N-tosyl-1,2-diphenylethane-1,2-diamine (TsDPEN) tethered transfer hydrogenation catalysts. The enantiomers (R,R)-[Ru(η(6)-C6H5(CH2)3-TsDPEN-N-Me)Cl] (8) and (S,S)-[Ru(η(6)-C6H5(CH2)3-TsDPEN-N-Me)Cl] (8a) exhibited higher potency than cisplatin against A2780 human ovarian cancer cells. When the N-methyl was replaced by N-H, i.e. to give (R,R)-[Ru(η(6)-Ph(CH2)3-TsDPEN-NH)Cl] (7) and (S,S)-[Ru(η(6)-Ph(CH2)3-TsDPEN-NH)Cl] (7a), respectively, anticancer activity decreased >5-fold. Their antiproliferative activity appears to be linked to their ability to accumulate in cells, and their mechanism of action might involve inhibition of tubulin polymerisation. This appears to be the first report of the potent anticancer activity of tethered Ru(II) arene complexes, and the structure-activity relationship suggests that the N-methyl substituents are important for potency. In the National Cancer Institute 60-cancer-cell-line screen, complexes 8 and 8a exhibited higher activity than cisplatin towards a broad range of cancer cell lines. Intriguingly, in contrast to their potent anticancer properties, complexes 8/8a are poor catalysts for asymmetric transfer hydrogenation, whereas complexes 7/7a are effective asymmetric hydrogenation catalysts.

The fabrication of precious metal (ruthenium, osmium, gold, and iridium) nanocrystals from single atoms has been studied in real-time. The dynamics of the first stage of the metal nanocrystallisation on a doped (B,S)-graphitic surface are identified, captured, and reported.

Novel half-sandwich hydrosulfidoiridium(III) complexes [(η(5)-Cp*)Ir(phen)(SH)]PF6 (1), [(η(5)-Cp*)Ir(bpy)(SH)]PF6 (2), [(η(5)-Cp(biph))Ir(phen)(SH)]PF6 (3), and [(η(5)-Cp(biph))Ir(bpy)(SH)]PF6 (4) were prepared from the chlorido complexes by dechlorination and treatment with excess NaSH·xH2O; phen = 1,10-phenanthroline, bpy = 2,2'-bipyridine, Cp* = 1,2,3,4,5-pentamethylcyclopentadienyl, and Cp(biph) = 1,2,3,4-tetramethyl-5-biphenylcyclopentadienyl. Complexes 1-4 were characterized by various techniques including electrospray ionization mass spectrometry, NMR spectroscopy (δ(SH) ca. -2 ppm), and a single-crystal X-ray analysis. Complex [(η(5)-Cp*)Ir(phen)(SH)]BPh4 (1') shows a typical piano-stool geometry with Ir-S bond length of 2.388(2) Å. Cp(biph) complexes 3 (IC50 = 0.98 μM) and 4 (IC50 = 0.61 μM) showed significantly higher (p < 0.005) in vitro antiproliferative activity against A2780 human ovarian cancer cells, as compared with their Cp* analogues 1 (IC50 = 49.5 μM) and 2 (IC50 = 48.4 μM), and potency similar to the anticancer drug cisplatin. The complexes were relatively stable in aqueous solution toward hydrolysis and reactions with reduced glutathione (GSH), 9-ethylguanine, or 9-methyladenine. Interestingly, GSH was readily oxidized to glutathione disulfide in the presence of Cp(biph) complexes 3 and 4, as judged by (1)H NMR, perhaps indicative of a possible redox-linked mechanism of action.

Our appreciation of the scholarly ideas and thinking of Bob Williams is illustrated here by a few of the areas in which he inspired us. His journey to bring inorganic chemistry to life began with an early interest in analytical chemistry, rationalising the relative stabilities of metal coordination complexes (The Irving-Williams Series), and elucidating the organometallic redox chemistry of vitamin B12. He (and Vallee) recognised that metal ions are in energised (entatic) states in proteins and enzymes, which themselves are dynamic structures of rods and springs. He played a key role in helping Rosenberg to pave the road toward the clinic for the anticancer drug cisplatin. He believed that evolution is not just dependent on DNA, but also on the metallome. Organisms and the environment are one system: does DNA code directly for all the essential elements of life?

We present a new approach to investigate how the photodynamics of an octahedral ruthenium(II) complex activated through two-photon absorption (TPA) differ from the equivalent complex activated through one-photon absorption (OPA). We photoactivated a Ru(II) polypyridyl complex containing bioactive monodentate ligands in the photodynamic therapy window (620-1000 nm) by using TPA and used transient UV/Vis absorption spectroscopy to elucidate its reaction pathways. Density functional calculations allowed us to identify the nature of the initially populated states and kinetic analysis recovers a photoactivation lifetime of approximately 100 ps. The dynamics displayed following TPA or OPA are identical, showing that TPA prodrug design may use knowledge gathered from the more numerous and easily conducted OPA studies., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We have synthesised osmium nanoparticles of defined size (1.5-50 nm) on a B- and S-doped turbostratic graphitic structure by electron-beam irradiation of an organometallic osmium complex encapsulated in self-spreading polymer micelles, and characterised them by transmission electron microscopy (TEM), high-resolution TEM (HRTEM), and atomic force microscopy (AFM) on the same grid. Oxidation of the osmium nanoparticles after exposure to air was detected by X-ray photoelectron spectroscopy (XPS).

Surprisingly, the anticancer activity of half-sandwich Ru arene complexes [(η(6)-arene)Ru(en)Cl](+) appears to be promoted and not inhibited by binding to the intracellular thiol glutathione. Labilization of the Ru-S bond allowing DNA binding appeared to be initiated by oxygenation of the thiolate ligand, although oxidation by itself did not seem to weaken the Ru-S bond. In this study, we have investigated the solvation and acidic perturbations of mono (sulfenato) and bis (sulfinato) oxidized species of [(η(6)-arene)Ru(en) (SR)](+) complex in the presence of Brønsted and Lewis acids. Sulfur K-edge X-ray absorption spectroscopy together with density functional theory calculations show that solvation and acidic perturbation of sulfenato species produce a significant decrease in the S3p character of the Ru-S bond (Ru4dσ* ← S1s charge donation). Also there is a drastic fall in the overall ligand charge donation to the metal center in both sulfenato and sulfinato species. Our investigation clearly shows that mono oxidized sulfenato species are most susceptible to ligand exchange, hence providing a possible pathway for in vivo activation and biological activity.

A photoactivatable platinum(IV) complex, trans,trans,trans-[Pt(N3 )2 (OH)(succ)(py)2 ] (succ=succinylate, py=pyridine), has been conjugated to guanidinoneomycin to study the effect of this guanidinum-rich compound on the photoactivation, intracellular accumulation and phototoxicity of the pro-drug. Surprisingly, trifluoroacetic acid treatment causes the replacement of an azido ligand and the axial hydroxide ligand by trifluoroacetate, as shown by NMR spectroscopy, MS and X-ray crystallography. Photoactivation of the platinum-guanidinoneomycin conjugate in the presence of 5'-guanosine monophosphate (5'-GMP) led to the formation of trans-[Pt(N3 )(py)2 (5'-GMP)](+) , as does the parent platinum(IV) complex. Binding of the platinum(II) photoproduct {PtN3 (py)2 }(+) to guanine nucleobases in a short single-stranded oligonucleotide was also observed. Finally, cellular uptake studies showed that guanidinoneomycin conjugation improved the intracellular accumulation of the platinum(IV) pro-drug in two cancer cell lines, particularly in SK-MEL-28 cells. Notably, the higher phototoxicity of the conjugate in SK-MEL-28 cells than in DU-145 cells suggests a degree of selectivity towards the malignant melanoma cell line., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Organometallic complexes have the potential to behave as catalytic drugs. We investigate here Rh(III) complexes of general formula [(Cp(x))Rh(N,N')(Cl)], where N,N' is ethylenediamine (en), 2,2'-bipyridine (bpy), 1,10-phenanthroline (phen) or N-(2-aminoethyl)-4-(trifluoromethyl)benzenesulfonamide (TfEn), and Cp(x) is pentamethylcyclopentadienyl (Cp*), 1-phenyl-2,3,4,5-tetramethylcyclopentadienyl (Cp(xPh)) or 1-biphenyl-2,3,4,5-tetramethyl cyclopentadienyl (Cp(xPhPh)). These complexes can reduce NAD(+) to NADH using formate as a hydride source under biologically-relevant conditions. The catalytic activity decreased in the order of N,N-chelated ligand bpy > phen > en with Cp* as the η(5)-donor. The en complexes (1-3) became more active with extension to the Cp(X) ring, whereas the activity of the phen (7-9) and bpy (4-6) compounds decreased. [Cp*Rh(bpy)Cl](+) (4) showed the highest catalytic activity, with a TOF of 37.4±2h(-1). Fast hydrolysis of the chlorido complexes 1-10 was observed by (1)H NMR (<10min at 310K). The pKa* values for the aqua adducts were determined to be ca. 8-10. Complexes 1-9 also catalysed the reduction of pyruvate to lactate using formate as the hydride donor. The efficiency of the transfer hydrogenation reactions was highly dependent on the nature of the chelating ligand and the Cp(x) ring. Competition reactions between NAD(+) and pyruvate for reduction by formate catalysed by 4 showed a preference for reduction of NAD(+). The antiproliferative activity of complex 3 towards A2780 human ovarian cancer cells increased by up to 50% when administered in combination with non-toxic doses of formate, suggesting that transfer hydrogenation can induce reductive stress in cancer cells., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Combination with redox modulators can potentiate the anticancer activity and maximize the selectivity of organometallic complexes with redox-based mechanisms of action. We show that nontoxic doses of l-buthionine sulfoximine increase the selectivity of organo-Os complex FY26 for human ovarian cancer cells versus normal lung fibroblasts to 63-fold. This increase is not due to changes in the mechanism of action of FY26 but to the decreased response of cancer cells to oxidative stress.

Understanding the mechanism of action of anti-cancer agents is of paramount importance for drug development. NMR spectroscopy can provide insights into the kinetics and thermodynamics of the binding of metallodrugs to biomolecules. NMR is most sensitive for highly abundant I=1/2 nuclei with large magnetic moments. Polarization transfer can enhance NMR signals of insensitive nuclei at physiologically-relevant concentrations. This paper reviews NMR methods for speciation of precious metal anti-cancer complexes, including platinum-group and gold-based anti-cancer agents. Examples of NMR studies involving interactions with DNA and proteins in particular are highlighted., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We deposited Os atoms on S- and Se-doped boronic graphenic surfaces by electron bombardment of micelles containing 16e complexes [Os(p-cymene)(1,2-dicarba-closo-dodecarborane-1,2-diselenate/dithiolate)] encapsulated in a triblock copolymer. The surfaces were characterized by energy-dispersive X-ray (EDX) analysis and electron energy loss spectroscopy of energy filtered TEM (EFTEM). Os atoms moved ca. 26× faster on the B/Se surface compared to the B/S surface (233 ± 34 pm·s(-1) versus 8.9 ± 1.9 pm·s(-1)). Os atoms formed dimers with an average Os-Os distance of 0.284 ± 0.077 nm on the B/Se surface and 0.243 ± 0.059 nm on B/S, close to that in metallic Os. The Os2 molecules moved 0.83× and 0.65× more slowly than single Os atoms on B/S and B/Se surfaces, respectively, and again markedly faster (ca. 20×) on the B/Se surface (151 ± 45 pm·s(-1) versus 7.4 ± 2.8 pm·s(-1)). Os atom motion did not follow Brownian motion and appears to involve anchoring sites, probably S and Se atoms. The ability to control the atomic motion of metal atoms and molecules on surfaces has potential for exploitation in nanodevices of the future.

The organometallic "half-sandwich" compound [Os(η(6)-p-cymene)(4-(2-pyridylazo)-N,N-dimethylaniline)I]PF6 is 49× more potent than the clinical drug cisplatin in the 809 cancer cell lines that we screened and is a candidate drug for cancer therapy. We investigate the mechanism of action of compound 1 in A2780 epithelial ovarian cancer cells. Whole-transcriptome sequencing identified three missense mutations in the mitochondrial genome of this cell line, coding for ND5, a subunit of complex I (NADH dehydrogenase) in the electron transport chain. ND5 is a proton pump, helping to maintain the coupling gradient in mitochondria. The identified mutations correspond to known protein variants (p.I257V, p.N447S, and p.L517P), not reported previously in epithelial ovarian cancer. Time-series RNA sequencing suggested that osmium-exposed A2780 cells undergo a metabolic shunt from glycolysis to oxidative phosphorylation, where defective machinery, associated with mutations in complex I, could enhance activity. Downstream events, measured by time-series reverse-phase protein microarrays, high-content imaging, and flow cytometry, showed a dramatic increase in mitochondrially produced reactive oxygen species (ROS) and subsequent DNA damage with up-regulation of ATM, p53, and p21 proteins. In contrast to platinum drugs, exposure to this organo-osmium compound does not cause significant apoptosis within a 72-h period, highlighting a different mechanism of action. Superoxide production in ovarian, lung, colon, breast, and prostate cancer cells exposed to three other structurally related organo-Os(II) compounds correlated with their antiproliferative activity. DNA damage caused indirectly, through selective ROS generation, may provide a more targeted approach to cancer therapy and a concept for next-generation metal-based anticancer drugs that combat platinum resistance.

We report the synthesis, characterization, and antiproliferative activity of 15 iridium(III) half-sandwich complexes of the type [(η 5 -Cp*)Ir(2-(R'-phenyl)-R-pyridine)Cl] bearing either an electron-donating (-OH, -CH 2 OH, -CH 3 ) or electron-withdrawing (-F, -CHO, -NO 2 ) group at various positions on the 2-phenylpyridine (2-PhPy) chelating ligand giving rise to six sets of structural isomers. The X-ray crystal structures of [(η 5 -Cp*)Ir(2-(2'-fluorophenyl)pyridine)Cl] ( 1 ) and [(η 5 -Cp*)Ir(2-(4'-fluorophenyl)pyridine)Cl] ( 2 ) exhibit the expected "piano-stool" configuration. DFT calculations showed that substituents caused only localized effects on the electrostatic potential surface of the chelating 2-PhPy ligand of the complexes. Hydrolysis of all complexes is rapid, but readily reversed by addition of NaCl. The complexes show preferential binding to 9-ethylguanine over 9-methyladenine and are active catalysts for the oxidation of NADH to NAD + . Antiproliferative activity experiments in A2780 ovarian, MCF-7 breast, A549 lung, and HCT116 colon cancer cell lines showed IC 50 values ranging from 1 to 89 μM, with the most potent complex, [(η 5 -Cp*)Ir(2-(2'-methylphenyl)pyridine)Cl] ( 13 ) (A2780 IC 50 = 1.18 μM), being 10× more active than the parent, [(η 5 -Cp*)Ir(2-phenylpyridine)Cl], and 2× more active than [(η 5 -Cp xPh )Ir(2-phenylpyridine)Cl]. Intriguingly, contrasting biological activities are observed between structural isomers despite exhibiting similar chemical reactivity. For pairs of structural isomers both the nature and position of the functional group can affect the hydrophobicity of the complex. An increase in hydrophobicity resulted in enhanced cellular-iridium accumulation in A2780 ovarian cells, which generally gave rise to an increase in potency. The structural isomers [(η 5 -Cp*)Ir(2-(4'-fluorophenyl)pyridine)Cl] ( 2 ) and [(η 5 -Cp*)Ir(2-phenyl-5-fluoropyridine)Cl] ( 4 ) preferentially localized in the cytosol > membrane and particulate > nucleus > cytoskeleton. This work highlights the strong dependence of biological behavior on the nature and position of the substituent on the chelating ligand and shows how this class of organometallic anticancer complexes can be fine-tuned to increase their potency without using extended cyclopentadienyl systems.

A new anticancer agent based on the conjugation of a photoactivatable Pt(IV) pro-drug to a cyclic RGD-containing peptide is described. Upon visible light irradiation, phototoxicity was induced preferentially in SK-MEL-28 melanoma cancer cells overexpressing αVβ3 integrin compared to control DU-145 human prostate carcinoma cells.

Asymmetric transfer hydrogenation (ATH) is an important process in organic synthesis for which the Noyori-type Ru(II) catalysts [(arene)Ru(Tsdiamine)] are now well established and widely used. We now demonstrate for the first time the catalytic activity of the osmium analogues. X-ray crystal structures of the 16-electron Os(II) catalysts are almost identical to those of Ru(II). Intriguingly the precursor complex was isolated as a dichlorido complex with a monodentate amine ligand. The Os(II) catalysts are readily synthesised (within 1 h) and exhibit excellent enantioselectivity in ATH reactions of ketones., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

X-ray crystal structures of human serum transferrin (77 kDa) with Yb(III) or Fe(III) bound to the C-lobe and malonate as the synergistic anion show that the large Yb(III) ion causes the expansion of the metal binding pocket while octahedral metal coordination geometry is preserved, an unusual geometry for a lanthanide ion.

Metal ions are known to act as catalytic centres in metallo-enzymes. On the other hand, low-molecular-weight metal complexes are widely used as catalysts in chemical systems. However, small catalysts do not have a large protein ligand to provide substrate selectivity and minimize catalyst poisoning. Despite the challenges that the lack of a protein ligand might pose, some success in the use of metal catalysts for biochemical transformations has been reported. Here, we present a brief overview of such reports, especially involving catalytic reactions in cells. Examples include C-C bond formation, deprotection and functional group modification, degradation of biomolecules, and redox modulation. We discuss four classes of catalytic redox modulators: photosensitizers, superoxide dismutase mimics, thiol oxidants, and transfer hydrogenation catalysts. Catalytic metallodrugs offer the prospect of low-dose therapy and a challenging new design strategy for future exploration., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Organometallic complexes are effective hydrogenation catalysts for organic reactions. For example, Noyori-type ruthenium complexes catalyse reduction of ketones by transfer of hydride from formate. Here we show that such catalytic reactions can be achieved in cancer cells, offering a new strategy for the design of safe metal-based anticancer drugs. The activity of ruthenium(II) sulfonamido ethyleneamine complexes towards human ovarian cancer cells is enhanced by up to 50 × in the presence of low non-toxic doses of formate. The extent of conversion of coenzyme NAD(+) to NADH in cells is dependent on formate concentration. This novel reductive stress mechanism of cell death does not involve apoptosis or perturbation of mitochondrial membrane potentials. In contrast, iridium cyclopentadienyl catalysts cause cancer cell death by oxidative stress. Organometallic complexes therefore have an extraordinary ability to modulate the redox status of cancer cells.

Which elements are essential for human life? Here we make an element-by-element journey through the periodic table and attempt to assess whether elements are essential or not, and if they are, whether there is a relevant code for them in the human genome. There are many difficulties such as the human biochemistry of several so-called essential elements is not well understood, and it is not clear how we should classify elements that are involved in the destruction of invading microorganisms, or elements which are essential for microorganisms with which we live in symbiosis. In general, genes do not code for the elements themselves, but for specific chemical species, i.e. for the element, its oxidation state, type and number of coordinated ligands, and the coordination geometry. Today, the biological periodic table is in a position somewhat similar to Mendeleev's chemical periodic table of 1869: there are gaps and we need to do more research to fill them. The periodic table also offers potential for novel therapeutic and diagnostic agents, based on not only essential elements, but also non-essential elements, and on radionuclides. Although the potential for inorganic chemistry in medicine was realized more than 2000 years ago, this area of research is still in its infancy. Future advances in the design of inorganic drugs require more knowledge of their mechanism of action, including target sites and metabolism. Temporal speciation of elements in their biological environments at the atomic level is a major challenge, for which new methods are urgently needed.

The Os(II) arene anticancer complex [(η(6)-bip)Os(en)Cl](+) (Os1-Cl; where bip = biphenyl, and en = ethylenediamine) binds strongly to DNA. Here we investigate reactions between Os1-Cl and the self-complementary 12-mer oligonucleotide 5'-TAGTAATTACTA-3' (DNA12) using ultra high resolution Fourier Transform-Ion Cyclotron Resonance Mass Spectrometry (FT-ICR MS). Identification of the specific sites of DNA osmiation with {(η(6)-bip)Os(en)}(2+) was made possible by the use of Electron Detachment Dissociation (EDD) which produced a wide range of assignable osmiated MS/MS fragments. In contrast, the more commonly used CAD and IRMPD techniques produced fragments which lose the bound osmium. These studies reveal that not only is guanine G3 a strong binding site for {(η(6)-bip)Os(en)}(2+) but, unexpectedly, so too is cytosine C10. Interestingly, the G3/C10 di-osmiated adduct of DNA12 also formed readily but did not undergo such facile fragmentation by EDD, perhaps due to folding induced by van der Waal's interactions of the bound osmium arene species. These new insights into osmium arene DNA adducts should prove valuable for the design of new organometallic drugs and contribute to understanding the lack of cross resistance of this organometallic anticancer complex with cisplatin.

Fibrils formed by human serum transferrin [(1-3 μM) apo-Tf, partially iron-saturated (Fe0.6 -Tf) and holo-Tf (Fe2 -Tf) forms], from dilute bicarbonate solutions, were deposited on formvar surfaces and studied by electron microscopy. We observed that possible bacterial contamination appears to give rise to long, pea-pod-like (PPL) structures for Fe2 -Tf, attributable to the formation of polyhydroxybutyrate (PHB) storage granules, under the nutrient-limiting conditions used. These PPL structures contained periodic nanomineralisation sites susceptible to uranyl stain. Extended incubation of transferrin solutions (about four days) gave rise to extensive transferrin fibril structures. Optical microscopy and AFM studies showed that red blood cells (RBCs) readily adhere to these fibrils. Moreover, the fibrils appear to penetrate RBC membranes and to induce rapid cell destruction (within about 5 h). It is speculated that in situations in vivo where transferrin fibrils can form, such interactions might have adverse physiological consequences, and further studies could aid the understanding of related pathological events., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Theranostic agents are emerging multifunctional molecules capable of simultaneous therapy and diagnosis of diseases. We found that platinum(II)-gadolinium(III) complexes with the formula [{Pt(NH3)2Cl}2GdL](NO3)2 possess such properties. The Gd center is stable in solution and the cytoplasm, whereas the Pt centers undergo ligand substitution in cancer cells. The Pt units interact with DNA and significantly promote the cellular uptake of Gd complexes. The cytotoxicity of the Pt-Gd complexes is comparable to that of cisplatin at high concentrations (≥0.1 mM), and their proton relaxivity is higher than that of the commercial magnetic resonance imaging (MRI) contrast agent Gd-DTPA. T1-weighted MRI on B6 mice demonstrated that these complexes can reveal the accumulation of platinum drugs in vivo. Their cytotoxicity and imaging capabilities make the Pt-Gd complexes promising theranostic agents for cancer treatment., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Tuberculosis has re-emerged as a worldwide threat, which has motivated the development of new drugs. The antituberculosis complex Na3[Fe(CN)5(isoniazid)] (IQG607) in particular is of interest on account of its ability to overcome resistance. IQG607 has the potential for redox-mediated-activation, in which an acylpyridine (isonicotinoyl) radical could be generated without assistance from the mycobacterial KatG enzyme. Here, we have investigated the reactivity of IQG607 toward hydrogen peroxide and superoxide, well-known intracellular oxidizing agents that could play a key role in the redox-mediated-activation of this compound. HPLC, NMR and electronic spectroscopy studies showed a very fast oxidation rate for bound isoniazid, over 460-fold faster than free isoniazid oxidation. A series of EPR spin traps were used for detection of isonicotinoyl and derived radicals bound to iron. This is the first report for an isonicotinoyl radical bound to a metal complex, supported by (14)N and (1)H hyperfine splittings for the POBN and PBN trapped radicals. POBN and PBN exhibited average hyperfine coupling constants of aN=15.6, aH=2.8 and aN=15.4, aH=4.7, respectively, which are in close agreement to the isonicotinoyl radical. Radical generation is thought to play a major role in the mechanism of action of isoniazid and this work provides strong evidence for its production within IQG607, which, along with biological and chemical oxidation data, support a redox-mediated activation mechanism. More generally the concept of redox activation of metallo prodrugs could be applied more widely for the design of therapeutic agents with novel mechanisms of action., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We report the synthesis and characterization of eight half-sandwich cyclopentadienyl Ir III pyridine complexes of the type [(η 5 -Cp xph )Ir(phpy)Z]PF 6 , in which Cp xph = C 5 Me 4 C 6 H 5 (tetramethyl(phenyl)cyclopentadienyl), phpy = 2-phenylpyridine as C ∧ N-chelating ligand, and Z = pyridine (py) or a pyridine derivative. Three X-ray crystal structures have been determined. The monodentate py ligands blocked hydrolysis; however, antiproliferative studies showed that all the Ir compounds are highly active toward A2780, A549, and MCF-7 human cancer cells. In general the introduction of an electron-donating group (e.g., Me, NMe 2 ) at specific positions on the pyridine ring resulted in increased antiproliferative activity, whereas electron-withdrawing groups (e.g., COMe, COOMe, CONEt 2 ) decreased anticancer activity. Complex 5 displayed the highest anticancer activity, exhibiting submicromolar potency toward a range of cancer cell lines in the National Cancer Institute NCI-60 screen, ca. 5 times more potent than the clinical platinum(II) drug cisplatin. DNA binding appears not to be the major mechanism of action. Although complexes [(η 5 -Cp xph )Ir(phpy)(py)] + ( 1 ) and [(η 5 -Cp xph )Ir(phpy)(4-NMe 2 -py)] + ( 5 ) did not cause cell apoptosis or cell cycle arrest after 24 h drug exposure in A2780 human ovarian cancer cells at IC 50 concentrations, they increased the level of reactive oxygen species (ROS) dramatically and led to a loss of mitochondrial membrane potential (ΔΨm), which appears to contribute to the anticancer activity. This class of organometallic Ir complexes has unusual features worthy of further exploration in the design of novel anticancer drugs.

Mechanistic insight into the photo-induced solvent substitution reaction of cis-[Ru(bipyridine)2(nicotinamide)2](2+) (1) is presented. Complex 1 is a photoactive species, designed to display high cytotoxicity following irradiation, for potential use in photodynamic therapy (photochemotherapy). In Ru(II) complexes of this type, efficient population of a dissociative triplet metal-centred ((3)MC) state is key to generating high quantum yields of a penta-coordinate intermediate (PCI) species, which in turn may form the target species: a mono-aqua photoproduct [Ru(bipyridine)2(nicotinamide)(H2O)](2+) (2). Following irradiation of 1, a thorough kinetic picture is derived from ultrafast UV/Vis transient absorption spectroscopy measurements, using a 'target analysis' approach, and provides both timescales and quantum yields for the key processes involved. We show that photoactivation of 1 to 2 occurs with a quantum yield ≥0.36, all within a timeframe of ~400 ps. Characterization of the excited states involved, particularly the nature of the PCI and how it undergoes a geometry relaxation to accommodate the water ligand, which is a keystone in the efficiency of the photoactivation of 1, is accomplished through state-of-the-art computation including complete active space self-consistent field methods and time-dependent density functional theory. Importantly, the conclusions here provide a detailed understanding of the initial stages involved in this photoactivation and the foundation required for designing more efficacious photochemotherapy drugs of this type.

The cellular mechanism of action of an iridium(III) half-sandwich complex [(η(5)-C5Me4C6H4C6H5)Ir(phen)Cl]PF6 (phen = phenanthroline) (1) is reported. Complex 1 was used to treat several cell lines, including cisplatin-sensitive, cisplatin-resistant (with intrinsic and acquired resistance) carcinoma cells with wild type p53 status as well as the cells with no intact p53 gene, and nontumorigenic cells. Complex 1 preferentially kills cancer cells over nontumorigenic cells and exhibits no cross-resistance with cisplatin. It appears to retain significant activity in human tumor cell lines that are refractory or poorly responsive to cisplatin, and in contrast to cisplatin it displays a high activity in human tumor cell lines that are characterized by both wild type and mutant p53 gene. The mechanism of cell killing was established through detailed cell-based assays. Complex 1 exhibits dual effects in killing cancer cells causing nuclear DNA damage and mitochondrial dysfunction involving ROS production simultaneously. Flow cytometric studies and impedance-based monitoring of cellular responses to 1 demonstrated that 1 acts more quickly than cisplatin to induce cell death and that 1 is a more effective apoptosis inducer than cisplatin in particular in early stages of treatment, when the apoptotic effects predominate over necrosis. Overall, our findings confirm that 1 and its iridium derivatives represent promising candidates for further pre-clinical studies and new additions to the growing family of nonplatinum metal-based anticancer complexes.

To further explore the binding chemistry of cisplatin (cis-Pt(NH3)2Cl2) to peptides and also establish mass spectrometry (MS) strategies to quickly assign the platinum-binding sites, a series of peptides with potential cisplatin binding sites (Met(S), His(N), Cys(S), disulfide, carboxyl groups of Asp and Glu, and amine groups of Arg and Lys, were reacted with cisplatin, then analyzed by electron capture dissociation (ECD) in a Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR MS). Radical-mediated side-chain losses from the charge-reduced Pt-binding species (such as CH3S(•) or CH3SH from Met, SH(•) from Cys, CO2 from Glu or Asp, and NH2(•) from amine groups) were found to be characteristic indicators for rapid and unambiguous localization of the Pt-binding sites to certain amino acid residues. The method was then successfully applied to interpret the top-down ECD spectrum of an inter-chain Pt-crosslinked insulin dimer, insulin + Pt(NH3)2 + insulin (>10 kDa). In addition, ion mobility MS shows that Pt binds to multiple sites in Substance P, generating multiple conformers, which can be partially localized by collisionally activated dissociation (CAD). Platinum(II) (Pt(II)) was found to coordinate to amine groups of Arg and Lys, but not to disulfide bonds under the conditions used. The coordination of Pt to Arg or Lys appears to arise from the migration of Pt(II) from Met(S) as shown by monitoring the reaction products at different pH values by ECD. No direct binding of cisplatin to amine groups was observed at pH 3 ~ 10 unless Met residues were present in the sequence, but noncovalent interactions between cisplatin hydrolysis and amination [Pt(NH3)4](2+) products and these peptides were found regardless of pH.

The lipophilicity of ten photoactivatable platinum(IV) diazido prodrugs of formula trans,trans,trans-[Pt(N3 )2 (OH)2 (R)(R')] (where R and R' are NH3 , methylamine, ethylamine, pyridine, 2-picoline, 3-picoline or thiazole) has been determined by their retention times on reversed-phase HPLC. The lipophilicity of the complexes shows a linear dependence on the lipophilicity (partition coefficient) of the ligands. Accumulation of platinum in A2780 human ovarian cancer cells after one hour drug exposure in the dark is compared with their cytotoxic potency on activation with UVA (365 nm) and to their lipophilicity. No correlation between lipophilicity and intracellular accumulation of platinum was observed, perhaps suggesting involvement of active transport and favoured influx of selected structures. Furthermore, no correlation between platinum accumulation and photocytotoxicity was observed in A2780 cancer cells, implying that the type of intracellular damage induced by these complexes plays a key role in their cytotoxic effects., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Metal nanocrystals offer new concepts for the design of nanodevices with a range of potential applications. Currently the formation of metal nanocrystals cannot be controlled at the level of individual atoms. Here we describe a new general method for the fabrication of multi-heteroatom-doped graphitic matrices decorated with very small, ångström-sized, three-dimensional (3D)-metal crystals of defined size. We irradiate boron-rich precious-metal-encapsulated self-spreading polymer micelles with electrons and produce, in real time, a doped graphitic support on which individual osmium atoms hop and migrate to form 3D-nanocrystals, as small as 15 Å in diameter, within 1 h. Crystal growth can be observed, quantified and controlled in real time. We also synthesize the first examples of mixed ruthenium-osmium 3D-nanocrystals. This technology not only allows the production of ångström-sized homo- and hetero-crystals, but also provides new experimental insight into the dynamics of nanocrystals and pathways for their assembly from single atoms.

The problems of acquired resistance associated with platinum drugs may be addressed by chemotherapeutics based on other transition metals as they offer the possibility of novel mechanisms of action. In this study, the cellular uptake and induction of apoptosis in A549 human non-small cell lung cancer cells of three promising osmium(II) arene complexes containing azopyridine ligands, [Os(η(6)-arene)(p-R-phenylazopyridine)X]PF6, where arene is p-cymene or biphenyl, R is OH or NMe2, and X is Cl or I, were investigated. These complexes showed time-dependent (4–48 h) potent anticancer activity with highest potency after 24 h (IC50 values ranging from 0.1 to 3.6 μM). Cellular uptake of the three compounds as quantified by ICP-MS, was independent of their logP values (hydrophobicity). Furthermore, maximum cell uptake was observed after 24 h, with evident cell efflux of the osmium after 48 and 72 h of exposure, which correlated with the corresponding IC50 values. The most active compound 2, [Os(η(6)-p-cymene)(NMe2-phenylazopyridine)I]PF6, was taken up by lung cancer cells predominately in a temperature-dependent manner indicating that energy-dependent mechanisms are important in the uptake of 2. Cell fractionation studies showed that all three compounds accumulated mainly in cellular membranes. Furthermore, compound 2 induced apoptosis and caused accumulation in the S-phase of the cell cycle. In addition, 2 induced cytochrome c release and alterations in mitochondrial membrane potential even after short exposure times, indicating that mitochondrial apoptotic pathways are involved. This study represents the first steps towards understanding the mode of action of this promising class of new osmium-based chemotherapeutics.