Egon Rizzato

Dynamic Nuclear Polarization with a Rigid Biradical

A new polarizing agent with superior performance in dynamic nuclear polarization experiments is introduced, and utilizes two TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) moieties connected through a rigid spiro tether (see structure). The observed NMR signal intensities were enhanced by a factor of 1.4 compared to those of TOTAPOL, a previously described TEMPO-based biradical with a flexible tether.

Rigid Orthogonal bis-TEMPO Biradicals with Improved Solubility for Dynamic Nuclear Polarization

The synthesis and characterization of oxidized bis-thioketal-trispiro dinitroxide biradicals that orient the nitroxides in a rigid, approximately orthogonal geometry are reported. The biradicals show better performance as polarizing agents in dynamic nuclear polarization (DNP) NMR experiments as compared to biradicals lacking the constrained geometry. In addition, the biradicals display improved solubility in aqueous media due to the presence of polar sulfoxides. The results suggest that the orientation of the radicals is not dramatically affected by the oxidation state of the sulfur atoms in the biradical, and we conclude that a biradical polarizing agent containing a mixture of oxidation states can be used for improved solubility without a loss in performance.

Analysis of the recent antipsychotic aripiprazole in human plasma by capillary electrophoresis and high-performance liquid chromatography with diode array detection

Two methods, based on the use of capillary electrophoresis (CE) and high-performance liquid chromatography (HPLC), respectively, were developed for the analysis of the atypical antipsychotic aripiprazole in plasma of schizophrenic patients for therapeutic drug monitoring purposes. Good analytical performances were obtained with the CE method, using uncoated fused silica capillaries and a background electrolyte composed of 50mM phosphate buffer at pH 2.5. With 20 kV voltage, aripiprazole was detectable at 214 nm within 5 min. The second analytical method, based on HPLC with diode array detection, employed a C8 reversed-phase column and a mixture of a 12.5mM phosphate buffer, pH 3.5, containing triethylamine and acetonitrile as the mobile phase. Aripiprazole was detected at 254 nm and a complete chromatographic run lasted about 10 min. For both analytical methods loxapine was used as the internal standard and the same plasma sample pre-treatment by means of solid-phase extraction on cyano cartridges was carried out, with extraction yield values always higher than 91.3%. Linear responses for aripiprazole were obtained between 70 and 700 ng mL(-1) and precision assays (expressed as relative standard deviation values) were lower than 7.0%. After validation, both methods were successfully applied to human plasma samples drawn from schizophrenic patients undergoing therapy with Abilify tablets. Accuracy was satisfactory, with recovery value higher than 91.0%.

Mitochondria-Targeted Spin Traps: Synthesis, Superoxide Spin Trapping, and Mitochondrial Uptake

Development of reliable methods and site-specific detection of free radicals is an active area of research. Here, we describe the synthesis and radical-trapping properties of new derivatives of DEPMPO and DIPPMPO, bearing a mitochondria-targeting triphenylphosphonium cationic moiety or guanidinium cationic group. All of the spin traps prepared have been observed to efficiently trap superoxide radical anions in a cell-free system. The superoxide spin adducts exhibited similar spectral properties, indicating no significant differences in the geometry of the cyclic nitroxide moieties of the spin adducts. The superoxide adduct stability was measured and observed to be highest (t1/2 = 73 min) for DIPPMPO nitrone linked to triphenylphosphonium moiety via a short carbon chain (Mito-DIPPMPO). The experimental results and DFT quantum chemical calculations indicate that the cationic property of the triphenylphosphonium group may be responsible for increased superoxide trapping efficiency and adduct stability of Mito-DIPPMPO, as compared to the DIPPMPO spin trap. The studies of uptake of the synthesized traps into isolated mitochondria indicated the importance of both cationic and lipophilic properties, with the DEPMPO nitrone linked to the triphenylphosphonium moiety via a long carbon chain (Mito10-DEPMPO) exhibiting the highest mitochondrial uptake. We conclude that, of the synthesized traps, Mito-DIPPMPO and Mito10-DEPMPO are the best candidates for potential mitochondria-specific spin traps for use in biologically relevant systems.

Strategies for improving the water solubility of new antitumour nitronaphthylbutadiene derivatives

Different nitronaphthylbutadienes have been previously proved to have antitumour activity. The main drawback of these derivatives is their low water solubility. With the aim of facilitating the administration of these new drugs we have synthesized the hexyl (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate analogue (1-Naph-NHCB) which is demonstrated to be easily included into cyclodextrins and/or entrapped into liposomes. Its antitumour activity was revealed to be almost comparable with that of the previously studied methyl analogue ester (1-Naph-NMCB). On the other hand, in vitro studies with different cancer cell lines showed that the cytotoxic activity of both 1-Naph-NMCB and 1-Naph-NHCB were fully preserved and in some cases also enhanced when entrapped into liposomal carriers.

Perturbation induced formation of a 3D-network of microcrystals producing soft materials

Toluene and 1-chloronaphthalene immobilization was observed when perturbing stimuli such as agitation or ultrasound are applied during the cooling of a hot supersaturated solution of the rigid dinitroxide bTbk. X-Ray diffraction and cryo-SEM on gels and solid samples (crystal, powder) confirmed the pivotal role of clathrate type microcrystals in the solvent immobilization process.

Sensitivity of different resistant tumour cell lines to the two novel compounds (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate and (1E,3E)-1,4-bis(2-naphthyl)-2,3-dinitro-1,3-butadiene

The inhibition of cell proliferation by methyl (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate (1-Naph-NMCB) and (1E,3E)-1,4-bis(2-naphthyl)-2,3-dinitro-1,3-butadiene (2-Naph-DNB) has been studied in vitro against four cell lines selected for their resistance to doxorubicin, cisplatin, taxol and 5-fluorouracil. In previous experiments both compounds showed good in vitro antiproliferative, cytotoxic and pro-apoptotic activities against cell lines of different histologic origin. The results of the experiments presented here suggest that 1-Naph-NMCB is able to overcome all of the different mechanisms of resistance showed by the resistant cell lines used for our experiments. On the contrary, when we used the taxol-resistant A549-T12 cell line, characterized by a mechanism of resistance due to a mutation of the target site of taxol on microtubules, it displayed a partial but significant cross-resistance to 2-Naph-DNB. Although the actual mechanism of this cross-resistance has not yet been definitively elucidated, our results from immunostaining of microtubules suggest that it may be linked to the presence of a shared target site for taxol and 2-Naph-DNB on microtubules.

Organic multishell isostructural host-guest crystals: fullerenes C-60 inside a nitroxide open framework

The dinitroxide biradical crystallizes forming hexagonal open frameworks with one-dimensional corrugated channels filled with crystallization solvent. The large pockets constitutive of the channels allowed the inclusion of C(60) in the paramagnetic network. The rapidity and high fidelity of crystal growth were used to prepare isostructural multilayer host-guest crystals successively stained with C(60).

An Unprecedented “Reverse” 1,2-Migration of a Nitro Group within an α-Aryl-β-nitroethenyl Moiety Driven by Steric and Stereoelectronic Effects

Reference EPFL-ARTICLE-150326doi:10.2174/157017807781024165 URL: http://www.bentham.org/loc/contabs/loc4-4.htm#13 Record created on 2010-08-06, modified on 2017-05-12