1,721,009 research outputs found
FATTY ACID BINDING PROTEINS (FABPs): SPECTROSCOPIC INTERACTION STUDIES WITH MEMBRANE MIMETICS AND LIPID-FUNCTIONALIZED DRUGS
No full textLe “fatty acid binding proteins” (FABPs) rappresentano una classe di proteine citosoliche note per essere coinvolte nel meccanismo di trasporto e nell’omeostasi dei lipidi. Queste piccole biomolecole sono infatti responsabili del trasporto di molecole idrofobiche e anfipatiche per via citoplasmatica attraverso la cellula con conseguente liberazione del carico in prossimità della membrana cellulare o di altri componenti cellulari. Nella famiglia delle FABPs, una particolare classe di proteine nota come “bile acid binding proteins” (BABPs) è responsabile del trasporto intracellulare di acidi biliari negli epatociti ed enterociti. Il meccanismo di ricircolo degli acidi biliari tra l’intestino e il fegato è chiamato “circolazione enteroepatica” e assicura il recupero di queste molecole per il successivo riutilizzo. L’alterazione del trasporto intracellulare degli acidi biliari è strettamente collegata a patologie colestatiche con compromissione del flusso biliare e possibilità di sviluppo di forme tumorali a livello epatico. Uno studio approfondito del ruolo delle BABPs nel trasporto intracellulare e dei meccanismi di caricamento e rilascio degli acidi biliari in prossimità delle membrane cellulari, risulta pertanto necessario. Sebbene, in analogia con altre FABPs, l’interazione delle BABPs con la membrana preveda una diretta “collisione”, gli equilibri tra proteina libera e legata alla membrana rimangono poco caratterizzati.
Nella prima parte del progetto studi condotti mediante utilizzo della Risonanza Magnetica Nucleare (NMR) hanno permesso di ottenere informazioni sui dettagli dell’interazione di BABP con sistemi mimetici di membrana. L’impossibilità di una diretta osservazione del complesso proteina-membrana attraverso NMR in soluzione ha inoltre richiesto metodi più avanzati per l’indagine del cosiddetto “stato invisibile”.
La conoscenza delle caratteristiche strutturali e di legame degli addotti tra le FABPs e molecole idrofobiche è inoltre alla base dello sviluppo in Risonanza Magnetica per Immagine (MRI) di una nuova classe di agenti di contrasto specifici per il fegato. Oggigiorno, infatti, un crescente interesse è rivolto allo studio di agenti di contrasto tessuto specifici e ad alta rilassività grazie all’interazione con macromolecole. Nella seconda parte del progetto l’interazione tra una proteina di trasporto intracellulare “human-liver FABP” e due differenti potenziali agenti di contrasto funzionalizzati rispettivamente con un acido grasso a catena lunga (AAZTAC17) e un acido biliare (B22626), è stata caratterizzata al fine di aumentare la specificità dell’interazione e la sensibilità di questi potenziali agenti di contrasto. L’affinità di legame delle due molecole per la proteina è stata determinata attraverso misure di rilassometria mentre la localizzazione del sito d’interazione è avvenuta attraverso esperimenti NMR sfruttando le proprietà paramagnetiche di rilassamento del Gd chelate nel complesso. Questi risultati si inseriscono in ambito medico come studi preliminari e potranno servire per lo sviluppo e l’utilizzo in diagnostica di una nuova generazione di agenti di contrasto a base di gadolinio.The fatty acid binding proteins (FABPs) are a class of cytosolic proteins known to participate in lipid transport and homoeostasis. These relatively small biomolecules are responsible for the translocation of hydrophobic or amphiphilic molecules across the cell, delivering their cargo to the cell membrane or to other cellular components. Some members of the FABP family, called bile acid binding proteins (BABPs), are responsible for the translocation of bile acid (BA) in the enterocytes and in the hepatocytes. This transport is achieved mainly through a protein mediated mechanism that involves BABPs as intracellular carriers. Bile acids undergo a recycling pathway between the intestine and the liver, called “enterohepatic circulation”, which assure the recovery of these molecules and their subsequent reutilization. Alterations of intracellular BA transport are linked to cholestatic diseases and BA accumulation leads to liver damage and may promote the development of liver tumors. A complete understanding of the functional role of BABPs necessitates a detailed description of the mechanisms of ligand uptake from and release to the cell membranes. These mechanisms possibly involve a direct collision of the protein with the membrane, in analogy with other FABP proteins. However, the binding equilibria describing the partitioning of these proteins between free and membrane-bound states remain poorly characterized. In the first part of the project the details the mechanism of interaction of apo BABP with the membrane mimetic systems were investigated via NMR spectroscopy. Despite the system under study prevents a direct investigation of the lipid- bound protein state by solution NMR we applied advance NMR methods for the investigation on the so-called NMR invisible “dark state” of the liposome bound protein. An application of the acquired knowledge on FABPs/lipid interactions has been recently proposed for the development of hepatospecific contrast agents (CAs) for magnetic resonance imaging (MRI). About one-third of MRI clinical scans are carried out in the presence of gadolinium-agents because they add relevant physiological information to the superb anatomical resolution attainable with this technique. There is a growing interest in the development of CAs displaying high tissue specificity and high intrinsic relaxivity obtained with slowly-tumbling molecules binding. In the second part of the project two lipid-functionalized Gd-chelates (AAZTAC17 and B22626) were investigated here for targeting to human liver-fatty acid binding protein (hL-FABP) as a means to increase sensitivity and specificity of intracellular-directed MRI probes. The former consists of a long aliphatic chain bound to the AAZTA coordination cage, the latter has a bile acid-like body linked to the basic unit of DTPA which chelates Gd. The binding affinities of the two selected series of Gd(III) chelates molecules to a liver cytosolic fatty acid transporter, have been determined through relaxivity measurements while the interaction modes and localisation of binding site were characterized performing NMR experiments in solution exploiting the relaxation properties of Gd complexes. These preliminary studies will serve in a medicinal chemistry approach to the design of new Gd-based contrast agents for MRI
Molecular conformations and pi-hydrogen bonds in anti- and syn- binuclear Rh(I) complexes of as-indacene-diide: a computational study
No full textAb initio calculations are employed to interpret the different conformations in mono- and bi-nuclear Rh(I) derivatives of as-indacene, observed by X-ray crystallography. In particular, we discuss the quite unusual COD (1,5-cyclooctadiene) group orientation in the homo-bimetallic complex anti-{2,7-dimethyl-as-indacene-diide-[Rh(COD)]2}, which is related to the metal hapticity and is stabilised by the presence of π-hydrogen bonds between olefin protons of COD and the π-electron cloud of the six-membered ring of the bridging ligand. Finally, the structure of syn-{2,7-dimethyl-as-indacene-diide-[Rh(COD)]2} is treated where mainly steric constraints appear to control the spatial disposition of the ancillary ligands. Second-order perturbative natural bond orbital (NBO) analysis provides a meaningful picture of non-covalent intramolecular C–H⋯C(π) interactions
Metal stabilized carbanions XIII. The mechanism of migration of the Cr(CO)3 unit from the eta6-membered to the eta5-membered ring in indenyl anions
No full textThe potassium salts of eta-6-indenyl-, eta-6-(1-phenyl)indenyl-, and eta-6-(1,3-diphenyl)indenyl-Cr(CO)3 anions have been prepared in THF solution at -30-degrees-C and fully characterized by H-1 NMR spectroscopy. At higher temperatures, the Cr(CO)3 group migrates from the benzo- to the cylopentadienyl-ring, the migration being slowest for the 1,3-diphenyl-substituted species. A kinetic study indicates that an intra-molecular pathway through an eta-3 intermediate is preferred
Synthesis and characterization of η6-Cr(CO)3-indenyl-η3-rhodium-η4-C8H12: an η3:η6 co-ordination for the indenyl ligand
No full textDeprotonation of indene–tricarbonylchromium with KH in tetrahydrofuran at –40 °C gives the η6-tricarbonylchromium–indenyl anion which reacts with [Rh(CI)COD]2(COD = cyclo-octa-1,5-diene) to form [η6-Cr(CO)3-indenyl-η3-rhodium-η4- COD]; the same bimetallic complex is obtained by reaction of the rhodium dimer with the isomeric η5-indenyl-tricarbonylchromium anion
Electronic communication in heterobinuclear organometallic complexes through unsaturated hydrocarbon bridges
No full textMuch of the interest about the construction of model compounds suitable for investigating the phenomena associated with the interaction of two or more metal centers, the so-called cooperative effect, has been concentrated on homobimetallic complexes and less attention has been paid to the class of heterobimetallic derivatives. This review will feature experimental detection and the effects of the electronic communication in heterobinuclear organometallic complexes through unsaturated hydrocarbon bridges. The described systems are classified according to the nature of the bridging ligand, in three main groups: (i) carbon sigma-bonded molecular wires; (ii) fulvalene and fulvalene-like bridges; (iii) fused delocalized polycyclic bridges. In this contribution, we discuss the flexibility of heterobimetallic complexes, and more in general of asymmetric bimetallic species, in terms of tailoring the cooperative effects, i.e. of controlling and tuning the reactivity of one metal center by acting on the adjacent one. Satisfactory quantitative estimate of the degree of metal to metal communication through the bridging ligand is obtained in illustrative examples combining efficient electrochemical and spectroscopic techniques with consolidated theories. A review with almost 350 references
Structural effects in the reductive activation of (Indenyl)RhL2 complexes: the reduction of the anti and syn isomers of Cr(CO)3-Indenyl-Rh(cod).
No full textThe electrochemical reduction of anti- and syn-[Cr(CO)(3)(indenyl)Rh(cod)] complexes (cod = cyclooctadiene) has been investigated, to evaluate, in each stereochemical situation, the effects of the contemporary presence of two metals coordinated to the indenyl ligand. In contrast to the reduction of monometallic [(indenyl)Rh(cod)], which gives rise to two well separated monoelectronic waves, the reduction of both bimetallic complexes occurs at more positive potentials in a single bielectronic and chemically reversible wave. These results indicate that an ECrevE mechanism is active, in which the chemical step following the first electron transfer is the reversible structural rearrangement of the 35-electron radical anion, which allows the second electron transfer to occur at a more positive potential than the first one. This structural rearrangement is more marked when the two metals are syn, which suggests the presence of an interaction between the two metals in this configuration. Side reactions correspond to the dissociation of the mono- and dianions; yet the dianions are surprisingly less frangible than the monoanions
On different chemical and catalytic behavior of (η-indenyl)-Rh(η4-COD) and Cr(CO)3(μ-η:η-indenyl)Rh(η4-COD) complexes
No full textCr(CO)3(μ-η:η-indenyl)Rh(η4-COD) displays higher reactivity than (indenyl)Rh(η4-COD) both as catalyst in cyclotrimerization reactions of alkynes and in ligand substitution reactions. These results can be explained on the basis of the coordinative flexibilty which arise from the simultaneous coordination of the two metals at the indenyl ligand. The reactivity is correlated to the slippage of chromium and rhodium from an unreactive η6-bonding mode to η4 and η3 ones, respectively
Low hapticity intermediates in the carbonylation of (eta5-2,6-dimethyl-5-hydro-s-indacenide)-Ir(eta4-COD)
No full textThe isomeric (eta(1)-5-hydro-2,6-dimethyl-s-indacenide)-Ir(eta(4)-COD)(CO)(2) and (eta(1)-7-hydro-2,6-dimethyl-s-indacenide)-Ir(eta(4)-COD)(CO)(2)) complexes are produced in a ii I ratio in the first step of the carbonylation reaction of (eta(5)-2,6-dimethyl-5-hydro-s-indacenide)-Ir(eta(4)-COD) at 233 K. At 243 K, in the presence of excess CO, they slowly convert into the isomeric (eta(1)-5-hydro-2,6-dimethyl-s-indacenide)-Ir[eta(2)-COD)(CO)(3)) and (eta(1)-7-hydro-2,6-dimethyl-s-indacenide]-Ir(eta(2)-COD)(CO)(3). The unprecedented eta(2)-coordination of COD towards iridium has been detected both by conventional variable temperature 1D H-1 NMR spectroscopy and by a single-temperature 2D EXSY experiment
103Rh NMR Chemical Shifts in Organometallic Complexes: A Combined Experimental and Density Functional Study
No full textExperimental 103Rh NMR chemical shifts of mono- and binuclear rhodium(I) complexes containing s- or as-hydroindacenide and indacenediide bridging ligands with different ancillary ligands (1,5-cyclooctadiene, ethylene, carbonyl) are presented. A protocol, based on density functional theory calculations, was established to determine 103Rh NMR shielding constants in order to rationalise the effects of electronic and structural variations on the spectroscopic signal, and to gain insight into the efficiency of this computational method when applied to organometallic systems. Scalar and spin–orbit relativistic effects based on the ZORA (zeroth order regular approximation) level have been taken into account and discussed. A good agreement was found for model compounds over a wide range of chemical shifts of rhodium (≈10 000 ppm). This allowed us to discuss the experimental and calculated δ(103Rh) in larger complexes and to relate it to their electronic structure
Chemical communication induced by intermolecular electron transfer in heterobimetallic ferrocenyl-indenyl-Cr(CO)3 complexes
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