Conjugation of a Ru(II) Arene Complex to Neomycin or to Guanidinoneomycin Leads to Compounds with Differential Cytotoxicities and Accumulation between Cancer and Normal Cells

A straightforward methodology for the synthesis of conjugates between a cytotoxic organometallic ruthenium(II) complex and amino- and guanidinoglycosides, as potential RNA-targeted anticancer compounds, is described. Under microwave irradiation, the imidazole ligand incorporated on the aminoglycoside moiety (neamine or neomycin) was found to replace one triphenylphosphine ligand from the ruthenium precursor [(η6-p-cym)RuCl(PPh3)2]+, allowing the assembly of the target conjugates. The guanidinylated analogue was easily prepared from the neomycin-ruthenium conjugate by reaction with N,N′-di-Boc-N″-triflylguanidine, a powerful guanidinylating reagent that was compatible with the integrity of the metal complex. All conjugates were purified by semipreparative high-performance liquid chromatography (HPLC) and characterized by electrospray ionization (ESI) and matrix-assisted laser desorptionionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and NMR spectroscopy. The cytotoxicity of the compounds was tested in MCF-7 (breast) and DU-145 (prostate) human cancer cells, as well as in the normal HEK293 (Human Embryonic Kidney) cell line, revealing a dependence on the nature of the glycoside moiety and the type of cell (cancer or healthy). Indeed, the neomycinruthenium conjugate (2) displayed moderate antiproliferative activity in both cancer cell lines (IC50 ≈ 80 μM), whereas the neamine conjugate (4) was inactive (IC50 ≈ 200 μM). However, the guanidinylated analogue of the neomycinruthenium conjugate (3) required much lower concentrations than the parent conjugate for equal effect (IC50 = 7.17 μM in DU-145 and IC50 = 11.33 μM in MCF-7). Although the same ranking in antiproliferative activity was found in the nontumorigenic cell line (3 2 > 4), IC50 values indicate that aminoglycoside-containing conjugates are about 2-fold more cytotoxic in normal cells (e.g., IC50 = 49.4 μM for 2) than in cancer cells, whereas an opposite tendency was found with the guanidinylated conjugate, since its cytotoxicity in the normal cell line (IC50 = 12.75 μM for 3) was similar or even lower than that found in MCF-7 and DU-145 cancer cell lines, respectively. Cell uptake studies performed by ICP-MS with conjugates 2 and 3 revealed that guanidinylation of the neomycin moiety had a positive effect on accumulation (about 3-fold higher in DU-145 and 4-fold higher in HEK293), which correlates well with the higher antiproliferative activity of 3. Interestingly, despite the slightly higher accumulation in the normal cell than in the cancer cell line (about 1.4-fold), guanidinoneomycinruthenium conjugate (3) was more cytotoxic to cancer cells (about 1.8-fold), whereas the opposite tendency applied for neomycinruthenium conjugate (2). Such differences in cytotoxic activity and cellular accumulation between cancer and normal cells open the way to the creation of more selective, less toxic anticancer metallodrugs by conjugating cytotoxic metal-based complexes such as ruthenium(II) arene derivatives to guanidinoglycosides.

Conjugation of a Ru(II) Arene Complex to Neomycin or to Guanidinoneomycin Leads to Compounds with Differential Cytotoxicities and Accumulation between Cancer and Normal Cells

A straightforward methodology for the synthesis of conjugates between a cytotoxic organometallic ruthenium(II) complex and amino- and guanidinoglycosides, as potential RNA-targeted anticancer compounds, is described. Under microwave irradiation, the imidazole ligand incorporated on the aminoglycoside moiety (neamine or neomycin) was found to replace one triphenylphosphine ligand from the ruthenium precursor [(η6-p-cym)RuCl(PPh3)2]+, allowing the assembly of the target conjugates. The guanidinylated analogue was easily prepared from the neomycin-ruthenium conjugate by reaction with N,N′-di-Boc-N″-triflylguanidine, a powerful guanidinylating reagent that was compatible with the integrity of the metal complex. All conjugates were purified by semipreparative high-performance liquid chromatography (HPLC) and characterized by electrospray ionization (ESI) and matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and NMR spectroscopy. The cytotoxicity of the compounds was tested in MCF-7 (breast) and DU-145 (prostate) human cancer cells, as well as in the normal HEK293 (Human Embryonic Kidney) cell line, revealing a dependence on the nature of the glycoside moiety and the type of cell (cancer or healthy). Indeed, the neomycin-ruthenium conjugate (2) displayed moderate antiproliferative activity in both cancer cell lines (IC50 ≈ 80 μM), whereas the neamine conjugate (4) was inactive (IC50 ≈ 200 μM). However, the guanidinylated analogue of the neomycin-ruthenium conjugate (3) required much lower concentrations than the parent conjugate for equal effect (IC50 = 7.17 μM in DU-145 and IC50 = 11.33 μM in MCF-7). Although the same ranking in antiproliferative activity was found in the nontumorigenic cell line (3 2 > 4), IC50 values indicate that aminoglycoside-containing conjugates are about 2-fold more cytotoxic in normal cells (e.g., IC50 = 49.4 μM for 2) than in cancer cells, whereas an opposite tendency was found with the guanidinylated conjugate, since its cytotoxicity in the normal cell line (IC50 = 12.75 μM for 3) was similar or even lower than that found in MCF-7 and DU-145 cancer cell lines, respectively. Cell uptake studies performed by ICP-MS with conjugates 2 and 3 revealed that guanidinylation of the neomycin moiety had a positive effect on accumulation (about 3-fold higher in DU-145 and 4-fold higher in HEK293), which correlates well with the higher antiproliferative activity of 3. Interestingly, despite the slightly higher accumulation in the normal cell than in the cancer cell line (about 1.4-fold), guanidinoneomycin-ruthenium conjugate (3) was more cytotoxic to cancer cells (about 1.8-fold), whereas the opposite tendency applied for neomycin-ruthenium conjugate (2). Such differences in cytotoxic activity and cellular accumulation between cancer and normal cells open the way to the creation of more selective, less toxic anticancer metallodrugs by conjugating cytotoxic metal-based complexes such as ruthenium(II) arene derivatives to guanidinoglycosides.

Federalismo e forme di governo. L´inopportunità delle differenziazioni di modello

La legge costituzionale 1/1999 per le Regioni ordinarie (e la successiva 2/2001 per le Speciali) ha rappresentato un punto di svolta fondamentale del regionalismo italiano. Essa ha stabilito il principio dell’elezione popolare diretta del Presidente della Regione, a cui si collega un premio di maggioranza nel Consiglio regionale secondo il cosiddetto modello neo-parlamentare. Qualsiasi interruzione del rapporto fiduciario per dimissioni del Presidente o approvazione di una mozione di sfiducia porterebbe a nuove elezioni, cosa che rappresenta un serissimo deterrente alle crisi. La riforma prevedeva anche la possibilità per le Regioni di derogare col proprio Statuto a tali scelte tornando all’elezione consiliare e a sostituzioni della maggioranza. Nonostante alcuni tentativi di sfuggire alla regola del governo di legislatura utilizzando tale deroga in modo esplicito o surrettizio, seguendo vecchi retaggi assemblearisti, l’elezione diretta si è imposta ovunque, garantendo a tutte le Regioni analoghi e inediti standards di governabilità.

Normal forms for rational difference equations with applications to the global periodicity problem

We propose a classification and derive the associated normal forms for rational difference equations with complex coefficients. As an application, we study the global periodicity problem for second order rational difference equations with complex coefficients. We find new necessary conditions as well as some new examples of globally periodic equations.

Polynomial and linearized normal forms for almost periodic differential systems

"Vegeu el resum a l'inici del document del fitxer adjunt."

La figura di Nikola Tesla (1856-1943) in Tajna Nikole Tesle (1980)

Nikola Tesla è considerato, dai divulgatori scientifici che di lui si occupano, una figura chiave nella storia della scienza moderna e contemporanea, per l’importanza che hanno avuto le sue ricerche nello sviluppo di tecnologie del XX e XXI secolo. La sua attuale scarsa fama nel piano accademico contrasta con un’abbondante presenza di un Nikola Tesla come personaggio di finzione nelle arti popolari. Questa ricezione ambigua di Tesla potrebbe essere di fatto relazionata con il carattere utopico e visionario delle sue speranze nella scienza come mezzo di conoscenza per il miglioramento della società umana. Questo breve saggio si propone di analizzare come venga presentato il personaggio di Nikola Tesla nel lungometraggio jugoslavo Tajna Nikole Tesle, contribuendo così alla comprensione di come la narrativa di finzione possa sfruttare l’immagine di uno scienziato relativamente agli interessi politici legati a specifici contesti socio-storici.

Un análisis descriptivo de la traducción de los dialectos geográficos y sociales italianos al castellano: el caso de Il cane di terracotta de Andrea Camilleri

El éxito internacional de Andrea Camilleri, escritor siciliano cuyas novelas están caracterizadas por la presencia del dialecto, ha fomentado el debate sobre la posibilidad de traducir textos caracterizados por la presencia de variación lingüística. Esta cuestión ha sido tratada de forma marginal por la traductología y, a menudo, los estudiosos han abogado por la supresión de las marcas dialectales en las traducciones. Un análisis del sistema lingüístico italiano y de su literatura, sin embargo, no puede prescindir del estudio de los dialectos y de las variedades regionales, cuya presencia es todavía muy fuerte. El presente trabajo se centra en un análisis descriptivo, de tipo cualitativo y cuantitativo, de las réplicas de tres personajes de la novela de Camilleri Il cane di terracotta en la versión original y en su traducción al castellano. Este estudio, suportado por la descripción del marco teórico en el que se inscribe el tema de la variación lingüística, nos permite, en primer lugar, evaluar el peso de la presencia de marcas de dialecto geográfico y social en el texto original y trazar la compleja relación existente entre lengua nacional, dialectos y variedades regionales en Italia. En segundo lugar, a través del análisis de la versión en castellano podremos verificar si existe una supresión considerable de las marcas dialectales en la traducción

Interferència dels trastorns de personalitat en la capacitat parental. Comparació entre població normal i diagnosticada

En aquesta investigació, hem comparat tres mostres (amb diagnòstic de transtorn de la personalitat, amb trets disfuncionals de la personalitat i sans) per tal de valorar quina disposa d’un funcionament parental més acurat. Dels resultats obtinguts, malgrat el petit tamany de la mostra, podem afirmar que els progenitors sans obtenen millors resultats que els altres dos, i que els que disposen de trets disfuncionals tenen un funcionament més adequats que els que tenen un diagnòstic.

Estudi comparatiu de detecció de Virus del Papiloma Humà entre pell psoriàsica i pell normal.

Existeix un debat continu sobre la rellevància del Virus del papiloma humà (VPH) en l’etiopatogènia de la psoriasi. S’ha reportat un elevat percentatge de detecció de VPH en pacients psoriàsics, sobretot el VPH5 i 36, suggerint que podrien correspondre a l’antigen causal de la cascada inmunològica. El propòsit de l’estudi és utilitzar un mètode ampli per a la detecció d’ADN tant de beta com gamma-papilomavirus en 30 biòpsies de pell psoriàsica i 30 biòpsies de pell sana. Avaluarem si els VPH són detectats de forma més freqüent en pell psoriàsica en comparació amb pell sana, i quins són els VPH específics més sobreexpresats.

Meaning of the λ parameter of skew–normal and log–skew normal distributions in fluid geochemistry

The literature related to skew–normal distributions has grown rapidly in recent yearsbut at the moment few applications concern the description of natural phenomena withthis type of probability models, as well as the interpretation of their parameters. Theskew–normal distributions family represents an extension of the normal family to whicha parameter (λ) has been added to regulate the skewness. The development of this theoreticalfield has followed the general tendency in Statistics towards more flexible methodsto represent features of the data, as adequately as possible, and to reduce unrealisticassumptions as the normality that underlies most methods of univariate and multivariateanalysis. In this paper an investigation on the shape of the frequency distribution of thelogratio ln(Cl−/Na+) whose components are related to waters composition for 26 wells,has been performed. Samples have been collected around the active center of Vulcanoisland (Aeolian archipelago, southern Italy) from 1977 up to now at time intervals ofabout six months. Data of the logratio have been tentatively modeled by evaluating theperformance of the skew–normal model for each well. Values of the λ parameter havebeen compared by considering temperature and spatial position of the sampling points.Preliminary results indicate that changes in λ values can be related to the nature ofenvironmental processes affecting the data

Al di là del fiume - attraverso il fiume: il basso corso del Ter in Catalogna

La ricerca prende in considerazione dal punto di vista dell’architettura e dell’urbanistica la relazione tra la città e il fiume che la attraversa o la lambisce; l’insediamento umano viene analizzato nel contesto del bacino idrografico al quale appartiene. La ricerca è stata sviluppata in seno alla tesi dottorale ora in fase di elaborazione presso il Departamento de Urbanismo y Ordenación del Territorio dell’Universidad Politecnica de Catalunya. La tesi ha come caso studio il tratto basso del fiume Ter in Catalogna. Nella discussione sul paesaggio urbano contemporaneo oggi la riflessione è centrata sulla città che si territorializza; la dimensione urbana interferisce con gran parte della superficie della terra facendo sfumare le tradizionali distinzioni tra urbano e non-urbano, tra spazio costruito e spazio aperto. In questo contesto, quale termine di conciliazione tra la dinamica naturale e la costruzione storica dei luoghi prodotta dall’intervento umano, il fiume si rivela uno strumento essenziale di analisi e progetto. L’obiettivo di questa ricerca è suggerire un’approssimazione al progetto della città che si sviluppa lungo il corso fluviale costruendo strumenti per la riflessione “attraverso il fiume”. Partendo dall’ipotesi che la città si insedia lungo un corso d’acqua secondo una sintassi territoriale stabilita dalla geografía e dalla geomorfologia del fiume stesso, il fine è fornire strumenti per il processo di recupero degli spazi fluviali in contesti urbanizzati. Il fiume diviene componente geografica chiave degli insediamenti dispersi e risorsa per costruirne l’abitabilità.

Normal forms, stability and splitting of invariant manifolds I. Gevrey Hamiltonians

In this paper, we give a new construction of resonant normal forms with a small remainder for near-integrable Hamiltonians at a quasi-periodic frequency. The construction is based on the special case of a periodic frequency, a Diophantine result concerning the approximation of a vector by independent periodic vectors and a technique of composition of periodic averaging. It enables us to deal with non-analytic Hamiltonians, and in this first part we will focus on Gevrey Hamiltonians and derive normal forms with an exponentially small remainder. This extends a result which was known for analytic Hamiltonians, and only in the periodic case for Gevrey Hamiltonians. As applications, we obtain an exponentially large upper bound on the stability time for the evolution of the action variables and an exponentially small upper bound on the splitting of invariant manifolds for hyperbolic tori, generalizing corresponding results for analytic Hamiltonians.