Facile Method to Obtain Functionalised η6-Bound Arenes in Ru(II) and Os(II) Half-Sandwich Complexes.

Half-sandwich Ru(II)- and Os(II)-arene complexes have great potential for catalytic and biological applications. The possibility of fine-tuning their chemical reactivity by including modifications in the ligands around the metal adds to their many advantages. However, structural modifications at the η6-bound arene have had significant synthetic limitations, particularly in the design of Os(II)-tethered complexes. For the first time, we have employed a practical C(sp3)-C(sp2) coupling to obtain 28 new Ru(II) and Os(II) η6-arene half-sandwich complexes with a wide variety of arene functionalities, including those that enable the formation of tether rings, such as quinoline, and coumarin. The introduction of novel functional groups at the arene in Ru(II)- and Os(II) half-sandwich complexes can broaden the synthetic scope of this type of organometallic complexes, and help to take full advantage of their structural diversity, for example, in intracellular catalysis.

Synthesis and Characterization of a Luminescent Cyclic Poly(ethylene oxide)-Polypyridyl Ruthenium Complex.

We report the synthesis of a macrocyclic poly(ethylene oxide) (PEO) connected by one [Ru(bpy)3]2+ unit (where bpy = 2,2'-bipyridine), a photoactive metal complex that provides photosensitivity and potential biomedical applications to this polymer structure. The PEO chain provides biocompatibility, water solubility, and topological play. The macrocycles were successfully synthesized by copper-free click cycloaddition between a bifunctional dibenzocyclooctyne (DBCO)-PEO precursor and 4,4'-diazido-2,2'-bipyridine, followed by complexation with [Ru(bpy)2Cl2]. The cyclic product accumulated efficiently in MCF7 cancer cells and exhibited a longer fluorescence lifetime than its linear analogue, likely due to differences in the accessibility of the ligand-centered/intraligand states of Ru polypyridyls in both topologies.

Reversible Chromism of Tethered Ruthenium(II) Complexes in the Solid State.

Tethered ruthenium(II) complexes [Ru(η6:κ1-arene:N)Cl2] (where arene:N is 2-aminobiphenyl (1) and 2-benzylpyridine (2)) can convert into their open-tethered chlorido counterparts [Ru(η6-arene:NH)Cl3], 1·HCl and 2·HCl, at room temperature via solid-state reaction in the presence of HCl vapors. The reaction is accompanied by a change in color, is fully reversible, and crystallinity is maintained in both molecular materials. Organoruthenium tethers are presented as nonporous materials capable of capturing and releasing HCl reversibly in the crystalline solid state.

Flavin-Conjugated Pt(IV) Anticancer Agents.

In situ activation of Pt(IV) to Pt(II) species is a promising strategy to control the anticancer activity and overcome the off-target toxicity linked to classic platinum chemotherapeutic agents. Herein, we present the design and synthesis of two new asymmetric Pt(IV) derivatives of cisplatin and oxaliplatin (1·TARF and 2·TARF, respectively) bearing a covalently bonded 2',3',4',5'-tetraacetylriboflavin moiety (TARF). 1H and 195Pt NMR spectroscopy shows that 1·TARF and 2·TARF can be effectively activated into toxic Pt(II) species, when incubated with nicotinamide adenine dinucleotide, sodium ascorbate, and glutathione in the dark and under light irradiation. Density functional theory studies of the dark Pt(IV)-to-Pt(II) conversion of 2·TARF indicate that the process involves first hydride transfer from the donor to the flavin moiety of the complex, followed by electron transfer to the Pt(IV) center. When administered to MDA-MB-231 breast cancer cells preincubated with nontoxic amounts of ascorbate, 2·TARF displays enhanced toxicity (between 1 and 2 orders of magnitude), suggesting that the generation of oxaliplatin can selectively be triggered by redox activation. Such an effect is not observed when 2 and TARF are coadministered under the same conditions, demonstrating that covalent binding of the flavin to the Pt complex is pivotal.

Fast Hydrolysis and Strongly Basic Water Adducts Lead to Potent Os(II) Half-Sandwich Anticancer Complexes.

Complexes of the formula [Os(η6-arene)(C,N-phenylpyridine)Z] (where Z is chlorido or a tethered oxygen) undergo very fast Os-Z hydrolysis (<5 min), and the high basicity of the coordinated water molecule of the aqua adducts (Os-OH2; pKa > 8) very much contrasts with previously reported Os-aqua adducts bearing NN- and NO-chelating ligands (pKa < 6). The Os-Cl bond is unreactive in pure DMSO, yet the complexes readily form DMSO adducts upon aquation when dimethyl sulfoxide is present. Such a peculiar aqueous behavior is directly related to the negatively charged CN ligand. Potent Os-CN compounds (but not their Os-NN analogues) are particularly reactive; they bind to cysteine in vitro and decrease the activity of thioredoxin reductase (TrxR) in living cancer cells. By revealing some interesting structure-activity relationship on Os-CN vs Os-NN complexes, we start uncovering the molecular rationale for the successful biological applications of osmium(II) half-sandwich compounds.

Photoactive Platinum(II) Azopyridine Complexes.

Platinum(II) complexes containing the strong π-acceptor N,N-chelating ligand phenylazopyridine (Ph-azpy) [Pt(p-R-Ph-azpy)X2 ], R = H, NMe2 or OH, X = Cl or N3 , have been synthesized and characterized to explore the effects of monodentate ligands and phenyl substituents on their absorption spectra and photoactivation. Time-dependent density functional theory calculations showed that the complexes have a low-lying unoccupied orbital with strong σ-antibonding character toward the majority of the coordination bonds. The UV-visible absorption bands were assigned as mainly ligand-centered or metal-to-ligand charge-transfer transitions, with strong contributions from the chlorido and azido groups. In complexes with substituted Ph-azpy ligands, σ-donation from NMe2 and OH/O- groups results in a redshift of the main absorption bands compared with unsubstituted Ph-azpy complexes. The diazido complexes are photoactive in solution upon irradiation with either UVA or visible light for R = H or NMe2 , or UVA only when R = OH/O- . Intriguingly, the phenolate group of the latter complex undergoes very slow protonation in solution. Biological screening was limited by poor solubility; however, initial tests showed that the phenolato diazido complex is rapidly taken up into the nuclei of HaCaT keratinocytes, which are stained intensely blue, and its cytotoxicity is increased upon irradiation with UVA light.

Osmium(ii) tethered half-sandwich complexes: pH-dependent aqueous speciation and transfer hydrogenation in cells.

Aquation is often acknowledged as a necessary step for metallodrug activity inside the cell. Hemilabile ligands can be used for reversible metallodrug activation. We report a new family of osmium(ii) arene complexes of formula [Os(η6-C6H5(CH2)3OH)(XY)Cl]+/0 (1-13) bearing the hemilabile η6-bound arene 3-phenylpropanol, where XY is a neutral N,N or an anionic N,O- bidentate chelating ligand. Os-Cl bond cleavage in water leads to the formation of the hydroxido/aqua adduct, Os-OH(H). In spite of being considered inert, the hydroxido adduct unexpectedly triggers rapid tether ring formation by attachment of the pendant alcohol-oxygen to the osmium centre, resulting in the alkoxy tethered complex [Os(η6-arene-O-κ1)(XY)] n+. Complexes 1C-13C of formula [Os(η6:κ1-C6H5(CH2)3OH/O)(XY)]+ are fully characterised, including the X-ray structure of cation 3C. Tether-ring formation is reversible and pH dependent. Osmium complexes bearing picolinate N,O-chelates (9-12) catalyse the hydrogenation of pyruvate to lactate. Intracellular lactate production upon co-incubation of complex 11 (XY = 4-Me-picolinate) with formate has been quantified inside MDA-MB-231 and MCF7 breast cancer cells. The tether Os-arene complexes presented here can be exploited for the intracellular conversion of metabolites that are essential in the intricate metabolism of the cancer cell.

Activation of the Ir-N(pyridine) Bond in Half-Sandwich Tethered Iridium(III) Complexes.

We present four new organometallic half-sandwich iridium(III) complexes of formula [Ir(η5:κ1-C5Me4CH2py)(N,N)](PF6)2, bearing a N,N-chelating ligand [ethylenediamine (en), 1; 1,3-diaminopropane (dap), 2; 2,2'-bipyridine (bipy), 3; 1,10-phenanthroline (phen), 4]; and a derivatized cyclopentadienyl ligand, C5Me4CH2C5H4N, which forms an additional five-membered chelate. The latter is hemilabile, and the Ir-N(py) bond can be reversibly cleaved by various stimuli. The four complexes are unreactive toward hydrolysis at pH 7. Interestingly, 1 and 2 react with hydrochloric acid and formate, and speciation between closed and open tether complexes can be followed by 1H NMR spectroscopy. Complex 1 binds to nucleobase guanine (9-ethylguanine, 9-EtG), yet interaction to calf-thymus DNA was not observed. New X-ray structures of closed tether complexes 1-4 and open tether complexes [Ir(η5-C5Me4CH2pyH)(en)Cl](PF6)2 (1·HCl) and [Ir(η5-C5Me4CH2py)(en)H]PF6 (1·hyd) have been determined. Hydride capture is efficient for 1 and 2. The kinetics of Ir-H bond formation and hydride transfer in a model organic molecule have been investigated, revealing a strong dependence on the temperature. Coincubation of complex 1 with nontoxic concentrations of sodium formate decreases the IC50 value in MCF7 breast cancer cells, indicating the possibility of intracellular activation of the Ir-N(py) tether bond to generate cytotoxic activity via iridium-mediated transfer hydrogenation.

Caracterización de la enfermedad cardiaca en pacientes embarazadas y desenlaces hospitalarios materno-fetales / Characterisation of heart disease in pregnant patients and mother-newborn hospital outcomes

Resumen Introducción: la enfermedad cardiaca durante el embarazo puede llevar a deterioro clínico e incluso a la muerte de la madre o el feto. En nuestro medio hay pocos datos al respecto. Materiales y métodos: estudio observacional, analítico, de cohorte retrospectiva, de gestantes con enfermedad cardiaca, en el que se incluyeron pacientes con cardiopatía congénita o adquirida, o arritmias, que requirieran hospitalización o intervención urgente por manifestación de síntomas. Se excluyeron pacientes con insuficiencias valvulares leves o moderadas, o estenosis leves, y pacientes sin estudio ecocardiográfico o sin información del parto. Se determinaron eventos cardiacos primarios y secundarios, así como eventos obstétricos y neonatales. Resultados: se incluyeron 104 pacientes con igual número de embarazos. La evaluación por Cardiología fue en promedio a las 32 semanas. La fracción de expulsión promedio fue del 61% y el 23,1% tenía dilatación del ventrículo derecho. El 26,9% de las pacientes tenían alguna intervención cardiovascular previa. Las cardiopatías congénitas fueron el diagnóstico más frecuente (51,9%), seguido por enfermedad valvular (25,9%), arritmias (15,4%) y disfunción ventricular izquierda (4,8%). Los eventos cardiacos primarios se presentaron en 13,5% de las pacientes, en tanto que los secundarios en el 14,4%. La cesárea por indicación cardiaca fue sólo en el 21,2%. Los eventos neonatales ocurrieron en el 36,5%; y los eventos obstétricos en el 14,4%. Conclusiones: pese al alto riesgo y las etiologías complejas, las embarazadas con enfermedad cardiaca reciben evaluación tardía por cardiología, lo que puede explicar las altas tasas de eventos cardiacos maternos y neonatales. Se requieren grupos con experiencia para el manejo de estas pacientes.

Abstract Introduction: Heart disease during pregnancy can lead to a clinical deterioration, and even to the death of the mother or the child. There is lack of data as regards this in the scientific literature. Material and methods: A retrospective, observational, and analytical study was conducted on a cohort of pregnant women with heart disease. The study included patients with congenital or acquired heart disease or arrhythmias that required hospital admission or urgent treatment due to onset of symptoms. Patients with mild or moderate valve insufficiency, as well as those with no ultrasound data or information about their delivery, were excluded. Primary and secondary cardiac events, as well as obstetric and neonatal events were recorded. Results: The study included 104 patients with an equal number of pregnancies. The evaluation by Cardiology was at 32 weeks on average. The mean ejection fraction was 61%, and 23.1% had enlargement of the right ventricle. More than one-quarter (26.9%) of the patients had some previous cardiovascular treatment. Congenital heart disease was the most common diagnosis (51.9%), followed by valve disease (25.9%), arrhythmias (15.4%), and left ventricular dysfunction (4.8%). Primary cardiac events were observed in 13.5% of the patients, whilst 14.4% had secondary events. Caesarean section due to a cardiac indication was only performed in 21.2%. Neonatal events were recorded in 36.5%, with obstetric events in 14.4%. Conclusions: Despite the high risk and aetiological complexity, pregnant women with heart disease were assessed at a late stage by cardiology. This may explain the high rates of maternal and neonatal events. Groups with experience are required to manage these patients.

Risk factors for cardiac, obstetric, and neonatal complications in patients with heart disease during pregnancy.

Objective: Heart disease in pregnancy can cause clinical deterioration and maternal-fetal death. It is essential to evaluate risk factors related to complications. Methodology: This was a observational, analytical retrospective cohort study with a non-probabilistic convenience sample of pregnant women with congenital or acquired heart disease, corrected or not, or arrhythmias requiring urgent intervention. Patients with mild or moderate valvular regurgitation, mild valvular stenosis, patients without echocardiography or without delivery information were excluded from the study. The outcome was a composite of cardiac, obstetric, and neonatal events. Univariate and multivariate analyzes were performed with logistic regression model and discriminatory capacity with area under the curve and independent analysis of the modified World Health Organization (mWHO) risk classification (mWHO). Results: A total of 104 patients with an average age of 25 ± 6.5 years presented cardiac events in 13.5%, obstetric in 14.42%, and neonatal in 28.85%. The univariate analysis found an association with New York Heart Association functional status, hypertensive disorders of pregnancy, cesarean delivery, gestational age < 27 weeks, hypoxemia, and mWHO risk. In multivariate only cesarean delivery (odds ratio [OR], 2.68; 95% confidence interval [CI], 1.05-6.86) and gestational age at delivery (OR, 0.39; 95% CI, 0.22-0.67) maintain association with outcomes. The area under the curve for the mWHO risk is 0.75. Conclusions: There is a high rate of adverse events in patients with heart disease during pregnancy. Gestational age and cesarean delivery behaved as predictors of adverse maternal-fetal outcomes. The mWHO risk classification had an acceptable prediction of adverse outcomes.

Objetivo: La enfermedad cardíaca en el embarazo puede ocasionar deterioro clínico y muerte maternofetal. Es indispensable evaluar factores de riesgo relacionados con complicaciones. Método: Estudio observacional y analítico de cohorte retrospectivo con muestra no probabilística por conveniencia de embarazadas con cardiopatía congénita o adquirida, corregida o no, o arritmias que requerían intervención urgente. Se excluyó a pacientes con insuficiencias valvulares leves o moderadas, estenosis valvulares leves, pacientes sin ecocardiografía o sin información del parto. El desenlace fue un compuesto de episodios cardíacos, obstétricos y neonatales. Se realizó análisis univariado y multivariado con modelo de regresión logística y capacidad diferenciadora con área bajo la curva y análisis independiente de la clasificación de riesgo de la OMS modificada (OMSm). Resultados: 104 pacientes con edad promedio de 25 ± 6.5 años presentaron episodios cardíacos en 13.5%, obstétricos en 14.42% y neonatales en 28.85%. El análisis univariado encontró una relación con el estado funcional de la NYHA, trastornos hipertensivos del embarazo, parto por cesárea, edad gestacional < 27 semanas, hipoxemia y riesgo de la OMSm. En el multivariado sólo el parto por cesárea (OR, 2.68; IC 95%, 1.05-6.86) y la edad gestacional al momento del parto (OR, 0.39; IC 95%, 0.22-0.67) mantienen nexo con los desenlaces. El área bajo la curva para el riesgo de la OMSm es de 0.75. Conclusiones: Hay una elevada tasa de efectos adversos en pacientes con enfermedad cardíaca durante el embarazo. La edad gestacional y el parto por cesárea se comportaron como predictores de resultados adversos maternofetales. La clasificación de riesgo de la OMSm tuvo una predicción aceptable de desenlaces adversos.

Risk factors for cardiac, obstetric, and neonatal complications in patients with heart disease during pregnancy / Factores de riesgo para complicaciones cardíacas, obstétricas y neonatales en pacientes con enfermedad cardíaca durante el embarazo

Abstract Objective: Heart disease in pregnancy can cause clinical deterioration and maternal-fetal death. It is essential to evaluate risk factors related to complications. Methodology: This was a observational, analytical retrospective cohort study with a non-probabilistic convenience sample of pregnant women with congenital or acquired heart disease, corrected or not, or arrhythmias requiring urgent intervention. Patients with mild or moderate valvular regurgitation, mild valvular stenosis, patients without echocardiography or without delivery information were excluded from the study. The outcome was a composite of cardiac, obstetric, and neonatal events. Univariate and multivariate analyzes were performed with logistic regression model and discriminatory capacity with area under the curve and independent analysis of the modified World Health Organization (mWHO) risk classification (mWHO). Results: A total of 104 patients with an average age of 25 ± 6.5 years presented cardiac events in 13.5%, obstetric in 14.42%, and neonatal in 28.85%. The univariate analysis found an association with New York Heart Association functional status, hypertensive disorders of pregnancy, cesarean delivery, gestational age < 27 weeks, hypoxemia, and mWHO risk. In multivariate only cesarean delivery (odds ratio [OR], 2.68; 95% confidence interval [CI], 1.05-6.86) and gestational age at delivery (OR, 0.39; 95% CI, 0.22-0.67) maintain association with outcomes. The area under the curve for the mWHO risk is 0.75. Conclusions: There is a high rate of adverse events in patients with heart disease during pregnancy. Gestational age and cesarean delivery behaved as predictors of adverse maternal-fetal outcomes. The mWHO risk classification had an acceptable prediction of adverse outcomes.

Resumen Objetivo: La enfermedad cardíaca en el embarazo puede ocasionar deterioro clínico y muerte maternofetal. Es indispensable evaluar factores de riesgo relacionados con complicaciones. Método: Estudio observacional y analítico de cohorte retrospectivo con muestra no probabilística por conveniencia de embarazadas con cardiopatía congénita o adquirida, corregida o no, o arritmias que requerían intervención urgente. Se excluyó a pacientes con insuficiencias valvulares leves o moderadas, estenosis valvulares leves, pacientes sin ecocardiografía o sin información del parto. El desenlace fue un compuesto de episodios cardíacos, obstétricos y neonatales. Se realizó análisis univariado y multivariado con modelo de regresión logística y capacidad diferenciadora con área bajo la curva y análisis independiente de la clasificación de riesgo de la OMS modificada (OMSm). Resultados: 104 pacientes con edad promedio de 25 ± 6.5 años presentaron episodios cardíacos en 13.5%, obstétricos en 14.42% y neonatales en 28.85%. El análisis univariado encontró una relación con el estado funcional de la NYHA, trastornos hipertensivos del embarazo, parto por cesárea, edad gestacional < 27 semanas, hipoxemia y riesgo de la OMSm. En el multivariado sólo el parto por cesárea (OR, 2.68; IC 95%, 1.05-6.86) y la edad gestacional al momento del parto (OR, 0.39; IC 95%, 0.22-0.67) mantienen nexo con los desenlaces. El área bajo la curva para el riesgo de la OMSm es de 0.75. Conclusiones: Hay una elevada tasa de efectos adversos en pacientes con enfermedad cardíaca durante el embarazo. La edad gestacional y el parto por cesárea se comportaron como predictores de resultados adversos maternofetales. La clasificación de riesgo de la OMSm tuvo una predicción aceptable de desenlaces adversos.

Risk factors for cardiac, obstetric and neonatal complications in patients with heart disease during pregnancy.

Objective: Heart disease in pregnancy can cause clinical deterioration and maternal-fetal death. It is essential to evaluate risk factors related to complications. Method: Observational, analytical retrospective cohort study with a non-probabilistic convenience sample of pregnant women with congenital or acquired heart disease, corrected or not, or arrhythmias requiring urgent intervention. Patients with mild or moderate valvular regurgitation, mild valvular stenosis, patients without echocardiography or without delivery information were excluded. The outcome was a composite of cardiac, obstetric and neonatal events. Univariate and multivariate analyzes were performed with logistic regression model and discriminatory capacity with area under the curve and independent analysis of the modified World Health Organization (mWHO) risk classification (mWHO). Results: 104 patients with an average age of 25 ± 6.5 years presented cardiac events in 13.5%, obstetric in 14.42% and neonatal in 28.85%. The univariate analysis found an association with New York Heart Association functional status, hypertensive disorders of pregnancy, cesarean delivery, gestational age <27 weeks, hypoxemia, and mWHO risk. In multivariate only cesarean delivery (odds ratio [OR], 2.68; 95% confidence interval [CI], 1.05-6.86) and gestational age at delivery (OR, 0.39; 95% CI, 0.22-0.67) maintain association with outcomes. The area under the curve for the mWHO risk is 0.75. Conclusions: There is a high rate of adverse events in patients with heart disease during pregnancy. Gestational age and cesarean delivery behaved as predictors of adverse maternal-fetal outcomes. The mWHO risk classification had an acceptable prediction of adverse outcomes.

Objetivo: La enfermedad cardíaca en el embarazo puede ocasionar deterioro clínico y muerte maternofetal. Es indispensable evaluar factores de riesgo relacionados con complicaciones. Método: Estudio observacional y analítico de cohorte retrospectivo con muestra no probabilística por conveniencia de embarazadas con cardiopatía congénita o adquirida, corregida o no, o arritmias que requerían intervención urgente. Se excluyó a pacientes con insuficiencias valvulares leves o moderadas, estenosis valvulares leves, pacientes sin ecocardiografía o sin información del parto. El desenlace fue un compuesto de episodios cardíacos, obstétricos y neonatales. Se realizó análisis univariado y multivariado con modelo de regresión logística y capacidad diferenciadora con área bajo la curva y análisis independiente de la clasificación de riesgo de la OMS modificada (OMSm). Resultados: 104 pacientes con edad promedio de 25 ± 6.5 años presentaron episodios cardíacos en 13.5%, obstétricos en 14.42% y neonatales en 28.85%. El análisis univariado encontró una relación con el estado funcional de la NYHA, trastornos hipertensivos del embarazo, parto por cesárea, edad gestacional < 27 semanas, hipoxemia y riesgo de la OMSm. En el multivariado sólo el parto por cesárea (OR, 2.68; IC 95%, 1.05-6.86) y la edad gestacional al momento del parto (OR, 0.39; IC 95%, 0.22-0.67) mantienen nexo con los desenlaces. El área bajo la curva para el riesgo de la OMSm es de 0.75. Conclusiones: Hay una elevada tasa de efectos adversos en pacientes con enfermedad cardíaca durante el embarazo. La edad gestacional y el parto por cesárea se comportaron como predictores de resultados adversos maternofetales. La clasificación de riesgo de la OMSm tuvo una predicción aceptable de desenlaces adversos.

Structurally Strained Half-Sandwich Iridium(III) Complexes As Highly Potent Anticancer Agents.

Six complexes of formula [Ir(η5:κ1-C5Me4CH2py)(C,N)]PF6, where C5Me4CH2py is 2-((2,3,4,5-tetramethylcyclopentadienyl)methyl)pyridine, and C,N is 2-phenylpyridine (1), 7,8-benzoquinoline (2), 1-phenylisoquinoline (3), 2-(p-tolyl)pyridine (4), 4-chloro-2-phenylquinoline (5), or 2-(2,4-difluorophenyl)pyridine (6), have been synthesized. The cyclopentadienyl ligand bears a tethered pyridine that binds to the metal center, resulting in an Ir(η5:κ1-C5Me4CH2pyN) tether-ring structure, as confirmed by the X-ray crystal structures of 1, 2, 4, 5, and 6. Nontether versions of 1 and 2 were synthesized to aid unambiguous correlation between structure and activity. While nontether complexes are highly potent toward MCF7 cancer cells (similar to cisplatin), complexes bearing the tether-ring structure, 1-6, are exceptionally more potent (1-2 orders of magnitude). Additionally, 1-6 disrupt mitochondrial membrane potential (ΔΨm) and induce oxidative stress. Internalization studies strongly correlate intracellular accumulation and anticancer activity in tether and nontether complexes. We present a new class of organo-iridium drug candidates bearing a structural feature that results in a leap in anticancer potency.

Unambiguous Intracellular Localization and Quantification of a Potent Iridium Anticancer Compound by Correlative 3D Cryo X-Ray Imaging.

The iridium half-sandwich complex [Ir(η5 :κ1 -C5 Me4 CH2 py)(2-phenylpyridine)]PF6 is highly cytotoxic: 15-250× more potent than clinically used cisplatin in several cancer cell lines. We have developed a correlative 3D cryo X-ray imaging approach to specifically localize and quantify iridium within the whole hydrated cell at nanometer resolution. By means of cryo soft X-ray tomography (cryo-SXT), which provides the cellular ultrastructure at 50 nm resolution, and cryo hard X-ray fluorescence tomography (cryo-XRF), which provides the elemental sensitivity with a 70 nm step size, we have located the iridium anticancer agent exclusively in the mitochondria. Our methodology provides unique information on the intracellular fate of the metallodrug, without chemical fixation, labeling, or mechanical manipulation of the cells. This cryo-3D correlative imaging method can be applied to a number of biochemical processes for specific elemental localization within the native cellular landscape.

Reversible pH-Responsive Behavior of Ruthenium(II) Arene Complexes with Tethered Carboxylate.

Five complexes of formula [Ru(η6-C6H5CH2COOH)(XY)Cl]Cl/Na (XY = ethylenediamine (1), o-phenylenediamine (2), phenanthroline (3), and oxalato (4)) and [Ru(η6:κ1-C6H5CH2COO)(tmen)]Cl (tmen = N, N, N', N'-tetramethylethylenediamine, 5C) have been synthesized and fully characterized. Five new X-ray crystal structures ([Ru(η6-C6H5CH2COOH)(µ-Cl)Cl]2, 1, 3, 4, and 5C·PF6) have been determined, which are the first examples of ruthenium(II) structures with phenylacetic acid as arene ligand. Furthermore, 5C·PF6 is the first example of a five-membered tether ring with a Ru(η6:κ1-arene:O) bond. The tether ring in these complexes opens in acidic pH (<5) and closes reversibly in aqueous solution. The chlorido open-form undergoes aquation, and the aqua adduct can be observed (prior to ring closure) by NMR. The speciation has an attractive complexity in the pH range 0-12, showing interconversion of the three species (chlorido, aqua, and closed tether), dependent on the proton concentration and the nature of the XY chelating ligand. The closed tether version of 3, complex 3C, with σ-donor/π-acceptor phenanthroline as chelating ligand, opens up more readily (pH 4), while the tether ring in complex 5C hardly opens even at pH as low as 1. We have determined the p Ka of the pendant carboxylic group and that of the aqua adduct (ca. 3 and ca. 7, respectively), which can be finely tuned by the appropriate choice of XY. Complexes 1 and 2, which predominate in their inactive (closed-tether) form in intracellular conditions, show some cytotoxic activity (IC50 130 and 117 µM, respectively) in A2780 ovarian cancer cells. Complex 1 catalyzes the reduction through transfer hydrogenation of pyruvate to lactate and NAD+ to NADH in the presence of formate as H-source. Co-incubation with sodium formate decreases the IC50 value of 1 in A2780 cancer cells significantly.

Control of Reversible Activation Dynamics of [Ru{η6 :κ1 -C6 H5 (C6 H4 )NH2 }(XY)]n+ and the Effect of Chelating-Ligand Variation.

The potential use of organoruthenium complexes as anticancer drugs is well known. Herein, a family of activatable tethered ruthenium(II) arene complexes of general formula [Ru{η6 :κ1 -C6 H5 (C6 H4 )NH2 }(XY)]n+ (closed tether ring) bearing different chelating XY ligands (XY=aliphatic diamine, phenylenediamine, oxalato, bis(phosphino)ethane) is reported. The activation of these complexes (closed- to open-tether conversion) occurs in methanol and DMSO at different rates and to different reaction extents at equilibrium. Most importantly, RuII -complex activation (cleavage of the Ru-Ntether bond) occurs in aqueous solution at high proton concentration (upon Ntether protonation). The activation dynamics can be modulated by rational variation of the XY chelating ligand. The electron-donating capability and steric hindrance of XY have a direct impact on the reactivity of the Ru-N bond, and XY=N,N'-dimethyl-, N,N'-diethyl-, and N,N,N',N'-tetramethylethylenediamine afford complexes that are more prone to activation. Such activation in acidic media is fully reversible, and proton concentration also governs the deactivation rate, that is, tether-ring closure slows down with decreasing pH. Interaction of a closed-tether complex and its open-tether counterpart with 5'-guanosine monophosphate revealed selectivity of the active (open) complex towards interaction with nucleobases. This work presents ruthenium tether complexes as exceptional pH-dependent switches with potential applications in cancer research.

Thermal selectivity of intermolecular versus intramolecular reactions on surfaces.

On-surface synthesis is a promising strategy for engineering heteroatomic covalent nanoarchitectures with prospects in electronics, optoelectronics and photovoltaics. Here we report the thermal tunability of reaction pathways of a molecular precursor in order to select intramolecular versus intermolecular reactions, yielding monomeric or polymeric phthalocyanine derivatives, respectively. Deposition of tetra-aza-porphyrin species bearing ethyl termini on Au(111) held at room temperature results in a close-packed assembly. Upon annealing from room temperature to 275 °C, the molecular precursors undergo a series of covalent reactions via their ethyl termini, giving rise to phthalocyanine tapes. However, deposition of the tetra-aza-porphyrin derivatives on Au(111) held at 300 °C results in the formation and self-assembly of monomeric phthalocyanines. A systematic scanning tunnelling microscopy study of reaction intermediates, combined with density functional calculations, suggests a [2+2] cycloaddition as responsible for the initial linkage between molecular precursors, whereas the monomeric reaction is rationalized as an electrocyclic ring closure.

Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells.

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.

Cellular accumulation, lipophilicity and photocytotoxicity of diazido platinum(IV) anticancer complexes.

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.

The potent oxidant anticancer activity of organoiridium catalysts.

Platinum complexes are the most widely used anticancer drugs; however, new generations of agents are needed. The organoiridium(III) complex [(η(5) -Cp(xbiph) )Ir(phpy)(Cl)] (1-Cl), which contains π-bonded biphenyltetramethylcyclopentadienyl (Cp(xbiph) ) and C^N-chelated phenylpyridine (phpy) ligands, undergoes rapid hydrolysis of the chlorido ligand. In contrast, the pyridine complex [(η(5) -Cp(xbiph) )Ir(phpy)(py)](+) (1-py) aquates slowly, and is more potent (in nanomolar amounts) than both 1-Cl and cisplatin towards a wide range of cancer cells. The pyridine ligand protects 1-py from rapid reaction with intracellular glutathione. The high potency of 1-py correlates with its ability to increase substantially the level of reactive oxygen species (ROS) in cancer cells. The unprecedented ability of these iridium complexes to generate H2 O2 by catalytic hydride transfer from the coenzyme NADH to oxygen is demonstrated. Such organoiridium complexes are promising as a new generation of anticancer drugs for effective oxidant therapy.