RESUMEN
N,N'-Dialkylpiperazine-2,3-dithiones (R2pipdt) were recognized as a class of hexa-atomic cyclic dithiooxamide ligands with peculiar charge-transfer donor properties toward soft electron-acceptors such as noble metal cations and diiodine. The latter interaction is nowadays better described as halogen bonding. In the reaction with diiodine, R2pipdt unexpectedly provides the corresponding triiodide salts, differently from the other dithiooxamides, which instead typically achieve ligand·nI2 halogen-bonded adducts. In this paper, we report a combined experimental and theoretical study that allows elucidation of the nature of the cited products and the reasons behind the unpredictable behavior of these ligands. Specifically, low-temperature single-crystal X-ray diffraction measurements on a series of synthetically obtained R2pipdt (R = Me, iPr, Bz)/I3 salts, complemented by neutron diffraction experiments, were able to experimentally highlight the formation of [R2pipdtH]+ cations with a -S-H bond on the dithionic moiety. Differently, with R = Ph, a benzothiazolylium cation, resulting from an intramolecular condensation reaction of the ligand, is obtained. Based on density functional theory (DFT) calculations, a reasonable reaction mechanism where diiodine plays the fundamental role of promoting a halogen-bonding-mediated radical reaction has been proposed. In addition, the comparison of combined experimental and computational results with the corresponding reactions of N,N'-dialkylperhydrodiazepine-2,3-dithione (R2dazdt, a hepta-atomic cyclic dithiooxamide), which provide neutral halogen-bonded adducts, pointed out that the difference in the torsion angle of the free ligands represents the structural key factor in determining the different reactivities of the two systems.
RESUMEN
BACKGROUND: The risk of colorectal cancer (CRC) among subjects with a positive faecal immunochemical test (FIT) who do not undergo a colonoscopy is unknown. We estimated whether non-compliance with colonoscopy after a positive FIT is associated with increased CRC incidence and mortality. METHODS: The FIT-based CRC screening programme in the Veneto region (Italy) invited persons aged 50 to 69 years with a positive FIT (>20 µg Hb/g faeces) for diagnostic colonoscopy at an endoscopic referral centre. In this retrospective cohort study, we compared the 10-year cumulative CRC incidence and mortality among FIT positives who completed a diagnostic colonoscopy within the programme (compliers) and those who did not (non-compliers), using the Kaplan-Meier estimator and Cox-Aalen models. RESULTS: Some 88 013 patients who were FIT positive complied with colonoscopy (males: 56.1%; aged 50-59 years: 49.1%) while 23 410 did not (males: 54.6%; aged 50-59 years: 44.9%).The 10-year cumulative incidence of CRC was 44.7 per 1000 (95% CI, 43.1 to 46.3) among colonoscopy compliers and 54.3 per 1000 (95% CI, 49.9 to 58.7) in non-compliers, while the cumulative mortality for CRC was 6.8 per 1000 (95% CI, 5.9 to 7.6) and 16.0 per 1000 (95% CI, 13.1 to 18.9), respectively. The risk of dying of CRC among non-compliers was 103% higher than among compliers (adjusted HR, 2.03; 95% CI, 1.68 to 2.44). CONCLUSION: The excess risk of CRC death among those not completing colonoscopy after a positive faecal occult blood test should prompt screening programmes to adopt effective interventions to increase compliance in this high-risk population.
Asunto(s)
Colonoscopía , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Cooperación del Paciente , Anciano , Detección Precoz del Cáncer , Heces , Femenino , Humanos , Incidencia , Italia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
The development of highly sensitive, portable and low-cost sensors for the evaluation of ethanol content in liquid is particularly important in several monitoring processes, from the food industry to the pharmaceutical industry. In this respect, we report the optimization of two sensing approaches based on electrical impedance spectroscopy (EIS) and complementary double split ring resonators (CDSRRs) for the detection of ethanol in water. Miniaturized EIS sensors were realized with interdigitated electrodes, and the ethanol sensing was carried out in liquid solutions without any functionalization of the electrodes. Impedance fitting analysis, with an equivalent circuit over a frequency range from 100 Hz to 1 MHz, was performed to estimate the electric parameters, which allowed us to evaluate the amount of ethanol in water solutions. On the other hand, complementary double split ring resonators (CDSRRs) were optimized by adjusting the device geometry to achieve higher quality factors while operating at a low fundamental frequency despite the small size (useful for compact electronic packaging). Both sensors were found to be efficient for the detection of low amounts of ethanol in water, even in the presence of salts. In particular, EIS sensors proved to be effective in performing a broadband evaluation of ethanol concentration and are convenient when low cost is the priority. On the other end, the employment of split ring resonators allowed us to achieve a very low limit of detection of 0.2 v/v%, and provides specific advantages in the case of known environments where they can enable fast real-time single-frequency measurements.
Asunto(s)
Espectroscopía Dieléctrica , Agua , Espectroscopía Dieléctrica/métodos , Impedancia Eléctrica , Electrodos , EtanolRESUMEN
OBJECTIVES: to evaluate if the country of origin affects participation and outcomes of cervical cancer screening. DESIGN: retrospective cohort study. SETTING AND PARTICIPANTS: all Italian and foreign women resident in the Veneto region (North-Eastern Italy) who were born between 1986 and 1992 and who had been invited for the first time through the screening programme between 2011 and 2017 were identified and included in the survey. MAIN OUTCOME MEASURES: participation to screening was calculated along with the detection of Cervical Intraepithelial Neoplasia (CIN) grade 2 or 3 and of carcinoma, by citizenship. RESULTS: 96,105 (77.5%) Italians and 27,958 (22.5%) foreign women were included. Overall, the adjusted participation was 53.3%, with large differences among the geographical study areas. The value was highest for Italian women (56.4%), while women with other citizenships showed lower attendance: 45.5% for Eastern Europe, 44.8% for Sub Saharan Africa, 40.0% for Northern Africa, 38.5% for Central and Southern America, and 36.5% for Asia. The detection of CIN2+ was higher for women from Central and Southern America (23.0) or from Eastern Europe (17.9), while it was lower for those from Italy (11.9), Northern Africa (7.5), Sub-Saharan Africa (6.6), and from Asia (2.5) (p<0.001). CONCLUSIONS: cervical screening programmes should identify and face the barriers to participation of foreign women. This is particularly important for women from geographic areas with a high prevalence of disease, such as Central and Southern America and Eastern Europe.
Asunto(s)
Emigrantes e Inmigrantes , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Detección Precoz del Cáncer , Femenino , Humanos , Italia/epidemiología , Tamizaje Masivo , Infecciones por Papillomavirus/epidemiología , Estudios Retrospectivos , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/epidemiologíaRESUMEN
A simple and efficient approach for the synthesis of 2-spirocyclopropyl-indolin-3-ones is herein described. The method involves a diasteroselective cyclopropanation of aza-aurones with tosylhydrazones, selected as versatile carbene sources, and represents a remarkable synthetic alternative to get access to this class of C2-spiropseudoindoxyl scaffolds. The reactions proceed in the presence of a base and catalytic amounts of benzyl triethylammonium chloride and well-tolerate a broad range of substituents on both aza-aurones and tosylhydrazones to afford a series of C2-spirocyclopropanated derivatives in high yields. In addition, selected functional group transformations of the final products were explored demonstrating the synthetic potential of these indole-based derivatives.
RESUMEN
Hepatocellular carcinoma (HCC) is a highly lethal cancer, and although a few drugs are available for treatment, therapeutic effectiveness is still unsatisfactory. New drugs are urgently needed for hepatocellular carcinoma (HCC) patients. In this context, reliable preclinical assays are of paramount importance to screen the effectiveness of new drugs and, in particular, measure their effects on HCC cell proliferation. However, cell proliferation measurement is a time-consuming and operator-dependent procedure. The aim of this study was to validate an engineered miniaturized on-chip platform for real-time, non-destructive cell proliferation assays and drug screening. The effectiveness of Sorafenib, the first-line drug mainly used for patients with advanced HCC, was tested in parallel, comparing the gold standard 96-well-plate assay and our new lab-on-chip platform. Results from the lab-on-chip are consistent in intra-assay replicates and comparable to the output of standard crystal violet proliferation assays for assessing Sorafenib effectiveness on HCC cell proliferation. The miniaturized platform presents several advantages in terms of lesser reagents consumption, operator time, and costs, as well as overcoming a number of technical and operator-dependent pitfalls. Moreover, the number of cells required is lower, a relevant issue when primary cell cultures are used. In conclusion, the availability of inexpensive on-chip assays can speed up drug development, especially by using patient-derived samples to take into account disease heterogeneity and patient-specific characteristics.
Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Proliferación Celular , Evaluación Preclínica de Medicamentos/métodos , Dispositivos Laboratorio en un Chip , Neoplasias Hepáticas/tratamiento farmacológico , Sorafenib/farmacología , Antineoplásicos/farmacología , Carcinoma Hepatocelular/fisiopatología , Fibroblastos/efectos de los fármacos , Fibroblastos/fisiología , Humanos , Neoplasias Hepáticas/fisiopatologíaRESUMEN
The synthesis of cyclohepta[b]indole derivatives through the dearomative (4 + 3) cycloaddition reaction of 2-vinylindoles or 4H-furo[3,2-b]indoles with in situ generated oxyallyl cations is reported. Oxyallyl cations are generated from α-bromoketones in the presence of a base and a perfluorinated solvent. Cyclohepta[b]indole scaffolds are obtained under mild reaction conditions, in the absence of expensive catalysts, starting from simple reagents, in good to excellent yields and with complete diasteroselectivity. Preliminary expansion of the scope to 3-vinylindoles and to aza-oxyallyl cations is reported.
RESUMEN
Merging the ability of cationic gold(I) catalysts to activate unsaturated π-systems with the electrophiles-driven ring-opening reactions of furans, we describe a new approach to synthesize 2-spiroindolin-3-ones from 4 H-furo[3,2- b]indoles. The reaction occurs through a cascade sequence involving addition of a gold-activated allene to the furan moiety of the starting furoindole followed by a ring-opening/ring-closing event affording 2-spirocyclopentane-1,2-dihydro-3 H-indolin-3-ones in moderate to good yields.
RESUMEN
N-Palmitoyl-ethanolamine (PEA) is an anti-inflammatory component of egg yolk that is usually employed for the prevention of respiratory apparatus virus infection and then frequently used for its efficient anti-inflammatory and analgesic effects in experimental models of visceral, neuropathic, and inflammatory diseases. Nevertheless, data of its use in animal or human therapy are still scarce and further studies are needed. Herein, we report the biological evaluation of a small library of N-palmitoyl-ethanolamine analogues or derivatives, characterized by a protected acid function (either as palmitoyl amides or hexadecyl esters), useful to decrease their hydrolysis rate in vitro and prolong their biological activity. Two of these compounds-namely phenyl-carbamic acid hexadecyl ester (4) and 2-methyl-pentadecanoic acid (4-nitro-phenyl)-amide (5)-have shown good anti-inflammatory and antioxidant properties, without affecting the viability of J774A.1 macrophages. Finally, crystals suitable for X-ray analysis of compound 4 have been obtained, and its solved crystal structure is here reported. Our outcomes may be helpful for a rational drug design based on new PEA analogues/derivatives with improved biological properties.
Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Etanolaminas/química , Etanolaminas/farmacología , Modelos Moleculares , Ácidos Palmíticos/química , Ácidos Palmíticos/farmacología , Amidas , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Estructura Molecular , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The antipodal introduction of two bromine atoms on the 2,12 ß-pyrrolic position of 5,10,15,20-tetra(3,5-di-tert-butylphenyl)porphyrin was successfully achieved by a light-induced reaction of the substrate with excess NBS. Complexation with Ni(II) of the major regioisomer led to good quality crystals, suitable for X-ray structure determination with unprecedented probability levels. The regiospecific character of the synthetic procedure and the exactness of the bromine atom position assignment were thus confirmed, suggesting an unexpected electrophilic aromatic substitution pathway rather than a free-radical halogenation process. A QTAIM topological analysis on the DFT-optimized wave function of the monosubstituted free-base porphyrin intermediate carrying a bromine atom in C2 ß-pyrrolic position confirmed the largest negative charge for the C12 carbon atom in antipodal position, in agreement with the proposed electrophilic aromatic substitution mechanism.
RESUMEN
The crystal and molecular structures of 134 pairs of diastereoisomers and of 279 racemic-homochiral pairs were retrieved from the Cambridge Structural Database. Lattice and intramolecular energies are calculated. Density differences between crystals of stereoisomers of all kind are mostly within 5%, as observed also for crystal polymorphs. Racemic crystals are predominantly, but not exclusively, more stable and more dense. Denser crystals are predominantly more stable, but there is no quantitative correlation between density and energy differences between partners in the chosen pairs. Second-order symmetry operators are neither ubiquitous in the racemic nor patently superior to first-order operators in promoting crystal cohesion. Thermodynamic, energetic factors in the final crystalline products are not enough to explain the (largely) predominant occurrence of racemic crystallization from racemic solution. At least for homogeneous nucleation, a probabilistic factor, from kinetics or from statistical predominance of mixed versus enantiopure aggregates, must be in action during the early separation of liquid-like particles, which are thought to be the precursors of crystal nucleation.
RESUMEN
We report the detection of high energy electrons of some hundreds of MeV, crossing a methylammonium lead bromide single crystal device with sensitivity down to a single electron. In the device, the released energy is close to the energy released by minimum-ionizing particles. This is the first demonstration of a perovskite-based device that can be used for tracking and counting minimum-ionizing charged particles. The device reaches single particle sensitivity with a low bias voltage of 5 V. It also shows a good linearity of the response as a function of the number of electrons in a dynamic range of approximately 104.
RESUMEN
The use of TDM in clinical practice to monitor the plasma levels of antibiotics administered to critically ill patients is a well-established approach that allows for optimization of the patient's response to drug therapy, considering the characteristics of the drug, the clinical and physiological status of the patient and any peculiar of the pathogen that caused the clinical picture. In our laboratory, we have developed a single LC-MS/MS analysis for dosing the serum concentration of an antibacterial panel composed of eight antibacterial and two selective inhibitors. The method presented used a certified material furnished by a commercial company and was internally validated using the EMA guidelines. The results have shown high sensitivity, precision, and accuracy, a lower matrix effect combined with simple sample preparation and a time-saving procedure. We have evaluated the recovery rate and matrix effect by testing serum samples without pathological index and serum pools obtained from haemolysed, icteric, or lipemic samples. The assay has shown a recovery range between 94% and 101%.
Asunto(s)
Antibacterianos , Monitoreo de Drogas , Cromatografía Líquida con Espectrometría de Masas , Humanos , Antibacterianos/sangre , Monitoreo de Drogas/métodos , Cromatografía Líquida con Espectrometría de Masas/métodos , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodosRESUMEN
BACKGROUND: Faecal immunochemical test (FIT)-based screening is effective in reducing colorectal cancer (CRC) incidence, but its sensitivity for proximal lesions remains low. OBJECTIVES: We compared age-adjusted CRC surgical resection rates across anatomic sites (proximal colon, distal colon, rectum), age groups and sex over 20 years in a large Italian population. We particularly focused on changes in trends following FIT-screening implementation in the target population (50-69 years). DESIGN: This retrospective study analysed data from the Veneto Region's administrative Hospital Discharge Dataset, involving over 54 000 patients aged 40-89 (43.4% female) who underwent CRC surgery between 2002 and 2021. RESULTS: Overall, surgery rates increased until 2007 (annual percentage changes: 2.5% in males, 2.9% in females) and then declined (-4.2% in males, -3.4% in females). This decline was steeper for distal and rectal cancers compared with proximal cancer, suggesting a shift towards more right-sided CRC surgery.In males, the prescreening increase in proximal surgery was reversed after screening implementation (slope change: -6%) while the prescreening decline accelerated for distal (-4%) and rectal (-3%) surgeries. In females, stable prescreening trends shifted downward for all sites (-5% for proximal, -8% for distal and -7% for rectal surgery). However, the change in trends between prescreening and postscreening periods was not different across anatomic sites for either sex (all slope change differences in pairwise comparisons were not statistically significant). CONCLUSION: The shift towards proximal surgery may not be entirely due to the FIT's low sensitivity but may reflect an underlying upward trend in proximal cancers independent of screening.
Asunto(s)
Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Masculino , Italia/epidemiología , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Detección Precoz del Cáncer/métodos , Detección Precoz del Cáncer/tendencias , Detección Precoz del Cáncer/estadística & datos numéricos , Neoplasias Colorrectales/cirugía , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Adulto , Anciano de 80 o más Años , Sangre Oculta , Tamizaje Masivo/métodos , Tamizaje Masivo/tendencias , Tamizaje Masivo/estadística & datos numéricos , IncidenciaRESUMEN
Objective: We investigated whether there are differences in cancer incidence by geographical area of origin in North-eastern Italy. Methods: We selected all incident cases recorded in the Veneto Tumour Registry in the period 2015-2019. Subjects were classified, based on the country of birth, in six geographical areas of origin (Italy, Highly Developed Countries-HDC, Eastern Europe, Asia, Africa, South-central America). Age-standardized incidence rates and incidence rate ratio (IRR) were calculated, for all cancer sites and for colorectal, liver, breast and cervical cancer separately. Results: We recorded 159,486 all-site cancer cases; 5.2% cases occurred in subjects born outside Italy, the majority from High Migratory Pressure Countries (HMPC) (74.3%). Incidence rates were significantly lower in subjects born in HMPC in both sexes. Immigrants, in particular born in Asia and Africa, showed lower rates of all site cancer incidence. The lowest IRR for colorectal cancer was observed in males from South-Central America (IRR 0.19, 95%CI 0.09-0.44) and in females from Asia (IRR 0.32, 95%CI 0.18-0.70). The IRR of breast cancer appeared significantly lower than Italian natives in all female populations, except for those coming from HDC. Females from Eastern Europe showed a higher IRR for cervical cancer (IRR 2.02, 95%CI 1.57-2.61). Conclusion: Cancer incidence was found lower in subjects born outside Italy, with differences in incidence patterns depending on geographical area of origin and the cancer type in question. Further studies, focused on the country of birth of the immigrant population, would help to identify specific risk factors influencing cancer incidence.
RESUMEN
Objective.Detectors that can provide accurate dosimetry for microbeam radiation therapy (MRT) must possess intrinsic radiation hardness, a high dynamic range, and a micron-scale spatial resolution. In this work we characterize hydrogenated amorphous silicon detectors for MRT dosimetry, presenting a novel combination of flexible, ultra-thin and radiation-hard features.Approach.Two detectors are explored: an n-type/intrinsic/p-type planar diode (NIP) and an NIP with an additional charge selective layer (NIP + CSC).Results.The sensitivity of the NIP + CSC detector was greater than the NIP detector for all measurement conditions. At 1 V and 0 kGy under the 3T Cu-Cu synchrotron broadbeam, the NIP + CSC detector sensitivity of (7.76 ± 0.01) pC cGy-1outperformed the NIP detector sensitivity of (3.55 ± 0.23) pC cGy-1by 219%. The energy dependence of both detectors matches closely to the attenuation coefficient ratio of silicon against water. Radiation damage measurements of both detectors out to 40 kGy revealed a higher radiation tolerance in the NIP detector compared to the NIP + CSC (17.2% and 33.5% degradations, respectively). Percentage depth dose profiles matched the PTW microDiamond detector's performance to within ±6% for all beam filtrations except in 3T Al-Al due to energy dependence. The 3T Cu-Cu microbeam field profile was reconstructed and returned microbeam width and peak-to-peak values of (51 ± 1)µm and (405 ± 5)µm, respectively. The peak-to-valley dose ratio was measured as a function of depth and agrees within error to the values obtained with the PTW microDiamond. X-ray beam induced charge mapping of the detector revealed minimal dose perturbations from extra-cameral materials.Significance.The detectors are comparable to commercially available dosimeters for quality assurance in MRT. With added benefits of being micron-sized and possessing a flexible water-equivalent substrate, these detectors are attractive candidates for quality assurance,in-vivodosimetry and in-line beam monitoring for MRT and FLASH therapy.
Asunto(s)
Radiometría , Silicio , Silicio/química , Radiometría/instrumentación , Hidrógeno , Radioterapia/instrumentaciónRESUMEN
BACKGROUND: The increasing use of complex and high dose-rate treatments in radiation therapy necessitates advanced detectors to provide accurate dosimetry. Rather than relying on pre-treatment quality assurance (QA) measurements alone, many countries are now mandating the use of in vivo dosimetry, whereby a dosimeter is placed on the surface of the patient during treatment. Ideally, in vivo detectors should be flexible to conform to a patient's irregular surfaces. PURPOSE: This study aims to characterize a novel hydrogenated amorphous silicon (a-Si:H) radiation detector for the dosimetry of therapeutic x-ray beams. The detectors are flexible as they are fabricated directly on a flexible polyimide (Kapton) substrate. METHODS: The potential of this technology for application as a real-time flexible detector is investigated through a combined dosimetric and flexibility study. Measurements of fundamental dosimetric quantities were obtained including output factor (OF), dose rate dependence (DPP), energy dependence, percentage depth dose (PDD), and angular dependence. The response of the a-Si:H detectors investigated in this study are benchmarked directly against commercially available ionization chambers and solid-state diodes currently employed for QA practices. RESULTS: The a-Si:H detectors exhibit remarkable dose linearities in the direct detection of kV and MV therapeutic x-rays, with calibrated sensitivities ranging from (0.580 ± 0.002) pC/cGy to (19.36 ± 0.10) pC/cGy as a function of detector thickness, area, and applied bias. Regarding dosimetry, the a-Si:H detectors accurately obtained OF measurements that parallel commercially available detector solutions. The PDD response closely matched the expected profile as predicted via Geant4 simulations, a PTW Farmer ionization chamber and a PTW ROOS chamber. The most significant variation in the PDD performance was 5.67%, observed at a depth of 3 mm for detectors operated unbiased. With an external bias, the discrepancy in PDD response from reference data was confined to ± 2.92% for all depths (surface to 250 mm) in water-equivalent plastic. Very little angular dependence is displayed between irradiations at angles of 0° and 180°, with the most significant variation being a 7.71% decrease in collected charge at a 110° relative angle of incidence. Energy dependence and dose per pulse dependence are also reported, with results in agreement with the literature. Most notably, the flexibility of a-Si:H detectors was quantified for sample bending up to a radius of curvature of 7.98 mm, where the recorded photosensitivity degraded by (-4.9 ± 0.6)% of the initial device response when flat. It is essential to mention that this small bending radius is unlikely during in vivo patient dosimetry. In a more realistic scenario, with a bending radius of 15-20 mm, the variation in detector response remained within ± 4%. After substantial bending, the detector's photosensitivity when returned to a flat condition was (99.1 ± 0.5)% of the original response. CONCLUSIONS: This work successfully characterizes a flexible detector based on thin-film a-Si:H deposited on a Kapton substrate for applications in therapeutic x-ray dosimetry. The detectors exhibit dosimetric performances that parallel commercially available dosimeters, while also demonstrating excellent flexibility results.
Asunto(s)
Radiometría , Silicio , Radiometría/instrumentación , Hidrógeno , Dosimetría in Vivo , Terapia por Rayos X/instrumentación , HumanosRESUMEN
Deuterium labeling is a powerful way to gain mechanistic information in biology and chemistry. However, selectivity is hard to control experimentally, and labeled sites can be difficult to assign both in solution and in the solid state. Here we show that very selective high-deuterium contents can be achieved for the polyhydride ruthenium phosphine complex [RuH2(H2)2(PCyp3)2] (1) (PCyp3 = P(C5H9)3). The selectivity of the H/D exchange process is demonstrated by multinuclear NMR and neutron diffraction analyses. It has also been investigated through density functional theory (DFT) calculations. The reactions are performed under mild conditions at room temperature, and the extent of deuterium incorporation, involving selective C-H bond activation within the cyclopentyl rings of the phosphine ligands, can easily be tuned (solvent effects, D2 pressure). It is shown that D2 gas can inhibit the C-H/C-D exchange process.
RESUMEN
This paper presents the synthesis and structural characterization of the unprecedented tris-phosphido-bridged compounds Pt3(µ-PBu(t)2)3X3 (X = Cl, Br, I), having only 42 valence electrons, while up to now analogous clusters typically have 44e(-). The new species were obtained by an apparent bielectronic oxidation of the 44e(-) monohalides Pt3(µ-PBu(t)2)3(CO)2X with the corresponding dihalogen X2. Their X-ray structures are close to the D3h symmetry, similarly to the 44e(-) analogues with three terminal carbonyl ligands. The products were also obtained by electrochemical oxidation of the same monohalides in the presence of the corresponding halide. In a detailed study on the formation of Pt3(µ-PBu(t)2)3I3, the redox potentials indicated that I2 can only perform the first monoelectronic oxidation but is unsuited for the second one. Accordingly, the 43e(-) intermediate [Pt3(µ-PBu(t)2)3(CO)2I](+) was ascertained to play a key role. Another piece of information is that, together with the fully oxidized product Pt3(µ-PBu(t)2)3I3, the transient 44e(-) species [Pt3(µ-PBu(t)2)3(CO)3](+) is formed in the early steps of the reaction. In order to extract detailed information on the formation pathway, involving both terminal ligand substitutions and electron transfer processes, a DFT investigation has been performed and all the possible intermediates have been defined together with their associated energy costs. The profile highlights many important aspects, such as the formation of an appropriate couple of 43e(-) intermediates having different sets of terminal coligands, and suitable redox potentials for the transfer of one electron. Optimizations of 45e(-) associative intermediates in the ligand substitution reactions indicate their possible involvement in the redox process with reduction of the overall energy cost. Finally, according to MO arguments, the unique stability of the 42e(-) phosphido-bridged Pt3 clusters can be attributed to the simultaneous presence of three terminal halides.
RESUMEN
Current in-vitro 2D cultures and animal models present severe limitations in recapitulating human physiopathology with striking discrepancies in estimating drug efficacy and side effects when compared to human trials. For these reasons, microphysiological systems, organ-on-chip and multiorgans microdevices attracted considerable attention as novel tools for high-throughput and high-content research to achieve an improved understanding of diseases and to accelerate the drug development process towards more precise and eventually personalized standards. This review takes the form of a guide on this fast-growing field, providing useful introduction to major themes and indications for further readings. We start analyzing Organs-on-chips (OOC) technologies for testing the major drug administration routes: (1) oral/rectal route by intestine-on-a-chip, (2) inhalation by lung-on-a-chip, (3) transdermal by skin-on-a-chip and (4) intravenous through vascularization models, considering how drugs penetrate in the bloodstream and are conveyed to their targets. Then, we focus on OOC models for (other) specific organs and diseases: (1) neurodegenerative diseases with brain models and blood brain barriers, (2) tumor models including their vascularization, organoids/spheroids, engineering and screening of antitumor drugs, (3) liver/kidney on chips and multiorgan models for gastrointestinal diseases and metabolic assessment of drugs and (4) biomechanical systems recapitulating heart, muscles and bones structures and related diseases. Successively, we discuss technologies and materials for organ on chips, analyzing (1) microfluidic tools for organs-on-chips, (2) sensor integration for real-time monitoring, (3) materials and (4) cell lines for organs on chips. (Nano)delivery approaches for therapeutics and their on chip assessment are also described. Finally, we conclude with a critical discussion on current significance/relevance, trends, limitations, challenges and future prospects in terms of revolutionary impact on biomedical research, preclinical models and drug development.