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International audience; Three new DEPMPO-based spin traps have been designed and synthesized for improved superoxide detection, each carrying a cyclodextrin (CD) moiety but with a different alkyl chain on the phosphorus atom or with a long spacer arm. EPR spectroscopy allowed us to estimate the half-life of the superoxide spin adducts which is close to the value previously reported for CD-DEPMPO (t(1/2) approximate to 50-55 min under the conditions investigated). The spectra are typical of superoxide adducts (almost no features of the HO center dot adduct that usually forms with time for other nitrone spin traps such as DMPO) and we show that at 250 mu M, the new spin trap enables the reliable detection of superoxide by 1 scan at the position opposite to the corresponding spin trap without the CD moiety. The resistance of the spin adducts to a reduction process has been evaluated, and the superoxide spin adducts are sensitive to ascorbate and glutathione (GSH), but not to glutathione peroxidase/GSH, reflecting the exposed nature of the nitroxide moiety to the bulk solvent. To understand these results, 2D-ROESY NMR studies and molecular dynamics pointed to a shallow or surface self-inclusion of the nitrone spin traps and of nitroxide spin adducts presumably due to the high flexibility of the permethyl-beta-CD rim.

International audience; The dinitroxide bis(TEMPO) bisketal (bTbk) was shown to crystallize into open frameworks whose structures were determined by single-crystal X-ray diffraction. We show that bTbk can be used as a supramolecular building block for the hosting of a plethora of guests inside the 1D channels of its paramagnetic framework, including other radicals such as TEMPO or 2-azaadamantane-N-oxyl. C60 and C70 were also found to be easily included in this open framework during its crystallization. This resulted in well-defined, nanostructured assemblies of composite radical crystals (bTbk/toluene/C60 or C70) or (bTbk/toluene/TEMPO) by a very simple dissolution/crystallization process with tunable guest content. Selective C60 extraction was also demonstrated directly from fullerene soot.

International audience; 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.

The base-induced cyclization of ( E )-2-aryl-1-[2-(benzylsulfonyl)phenyl]-1-nitroethenes to polysubstituted thiochroman S , S -dioxides exhibits a diastereoselectivity that can be oriented towards a selected isomer by means of appropriate adjustments of the experimental conditions. The interest of such a result also rests on the promising pharmacological activity of the products, whose structure encompasses different well-acknowledged pharmacophores. A conformational 1 H NMR investigation, backed by molecular-mechanics calculations, has also been accomplished.

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., National Institutes of Health (U.S.) (EB002804), National Institutes of Health (U.S.) (EB002026), National Institutes of Health (U.S.) (EB009866), National Institutes of Health (U.S.) (EB001965), National Institutes of Health (U.S.) (EB001035), Sixth Framework Programme (European Commission) (EU-Design Study Bio-DNP), Deutsche Forschungsgemeinschaft (postdoctoral fellowship), Naito Foundation

(1 E ,3 Z )-1-Aryl-4-methanesulfonyl-2-nitro-1,3-butadienes ( 8 ), derived from the initial ring-opening of 3-nitrothiophene ( 5 ), have been found to undergo a facile base-induced cyclization leading to thiopyran S , S -dioxides ( 9 ), thus furnishing a further example of effective ring-enlargement from 5- to 6-membered sulfur heterocycles. Compounds 9 are obtained as single racemic mixtures in satisfactory yields; they still contain a nitrovinylic moiety, which can be exploited for further modifications targeted to new derivatives endowed with either synthetic or pharmacological potentialities e.g., in the field of L-type Ca 2+ -channel blockers.

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

[reaction: see text] In prosecution of previous work on the thermal cyclization of 1-aryl-4-methanesulfonyl-2-nitro-3-phenylsulfonyl-1,3-butadienes (7), the 3-unsubstituted derivatives 8, deriving from the initial ring opening of 3-nitrothiophene (2), have been likewise found herein to undergo cyclization, followed by aromatization, in analogous mild experimental conditions, leading to the ring-fused homo- or heteroaromatic nitro derivatives 10. The concerted electrocyclic nature of the process is strongly supported by the outcome of tests based on the variation of the polarity of the solvent or of the electron density on the aryl of 8. Thus, the successful application of the process to the non-phenylsulfonyl-activated 8 significantly widens the scope of a synthetically valuable overall ring-opening/ring-closing procedure from nitrothiophenes. Support to the recently renewed interest in thermal 6pi electrocyclizations as a tool for the construction of the benzene ring is furthermore provided.

International audience; 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.

International audience; The dinitroxide biradical bTbk 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.

International audience; Toluene and 1-chloronaphthalene immobilization was observed when perturbing stimuli such asagitation or ultrasound are applied during the cooling of a hot supersaturated solution of therigid 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 immobilizationprocess.

International audience; We have investigated the properties of a series of dinitroxides as polarizing agents for SS NMR/DNP applications. Our results clearly establish that an orthogonal relative orientation of electron g tensors is a crucial requirement to obtain high enhancement DNP factors. Moreover, the ratio of the proton Larmor frequency over the e(-)-e(-) dipolar coupling (omega(H)/omega(D)) influences the efficiency of the cross effect (CE) mechanism, thus the \textless Ree \textgreater distance between the unpaired electrons must be adapted to omega(H).

The absolute configuration of a recently synthesized racemate of 2,2′-dinitro-2,2′-biaziridine (2a), a possible catalyst for asymmetric synthesis, has been determined by vibrational circular dichroism (VCD) spectroscopy in the mid-IR region and DFT calculations. Electronic circular dichroism (ECD) spectra have been obtained and Time-Dependent DFT (TD-DFT) calculations have been performed and found to be in agreement with the conclusions from VCD and DFT. A detailed conformational analysis, for approximately 300 geometries, has been carried out, allowing us to find evidence for the most populated conformers chiefly contributing to VCD and ECD spectra. The proposed absolute configuration and prevalent conformers are in correspondence with an equal configuration of the nitrogen atoms of the two aziridine rings.

(+/-)-2,2'-Dinitro-2,2'-biaziridines were obtained by a direct aza-MIRC (Michael initiated ring closure) reaction on (E,E)-1,4-dialkyl-2,3-dinitro-l,3-butadienes under very mild conditions. The reactions occur with high stereoselectivity as shown by the enantioselective HPLC analyses performed on the crude mixtures. Ring enlargement to 3,3'-bi(1,2,4-oxadiazole) derivatives was easily obtained by a simple treatment with sodium iodide in DMSO, with an unforeseen regioselective aziridine C-C cleavage.

Rate constants, k A,R , for the rearrangement of the ( Z )-phenylhydrazones ( 1a – e ) of a series of 5-alkyl-3-benzoyl-1,2,4-oxadiazoles substituted at C(5) with linear alkyl chains of different length (from C 4 up to C 12 ) into the relevant 4-acylamino-2,5-diphenyl-1,2,3-triazoles ( 2a – e ) have been measured in dioxan/water in the base-catalyzed region (pS + 10.5–12.6). For each substrate log k A,R are linearly related to pS + . The significant decrease of the slopes of these straight lines (from 0.96 down to 0.78) upon increasing the length of the linear alkyl chain at C(5) and that of the reactivity (down to 14–26%) upon increasing the substrate concentration suggest a decrease of the polarity of the ‘actual’ reaction medium and provide indirect evidence of the tendency of the substrates ( Z )- 1a – e to self-assemble. To confirm the above outcome direct evidence of the formation of self-assemblies in solution were obtained from 1 H NMR and spectrofluorimetry measurements while ESI-MS experiments point out the presence of aggregated substrates also in the gas phase.

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.

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 50 mM 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 12.5 mM 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%.

On the grounds of previous encouraging results on the antitumor activity of (1 E ,3 E )-1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene ( 1 ), we have designed and synthesized two new molecules [(1 E ,3 E )-1,4-bis(4-carboxy-1-naphthyl)-2,3-dinitro-1,3-butadiene ( 2 ) and methyl (2 Z ,4 E )-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate ( 3 )] characterized by a common naphthylnitrobutadiene array but with different structural properties, with the aim of approaching to some structure–activity correlation. When 2 and 3 were analyzed in vitro for their inhibition of cell proliferation and pro-apoptotic properties, the carboxyderivative 2 did not furnish appreciable results. In contrast, 3 (which contains only one of the two naphthylnitroethenyl moieties of the original compound 1 ) showed remarkable activities in the range of micromolar concentrations (in six over eight cell lines its IC 50 s are in the 1–3 μM range), with a significant improvement compared to 1 . In particular, 3 proved able to bind to DNA, to upregulate p53, to block cells in the G2/M phase of their cycle, and to induce apoptosis. Thus, very interestingly, the performance of 3 with respect to 1 shows that a single 1-(1-naphthyl)-2-nitroethene moiety is able to ensure better (on four out of eight of the cell lines tested) or comparable levels of activity. This result suggests that the ‘molecular-simplification strategy’ could furnish a useful instrument for future design in our antitumor research.

Our interesting results on the antiproliferative (in vitro) and antitumour (in vivo) activities of (1E,3E)-1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene (1-Naph-DNB) have more recently induced us to design and synthesize some new 1,4-diaryl-2,3-dinitro-1,3-butadienes characterized by a common arylnitrobutadiene array but with different geometric and/or functional properties. This task was undertaken with the aim to obtain new compounds with an enhanced antiproliferative activity and, possibly, a different specificity with respect to the original (lead) compound. (1E,3E)-1,4-Bis(2-naphthyl)-2,3-dinitro-1,3-butadiene (2-Naph-DNB) is one of the molecules so obtained, a structural isomer of 1-Naph-DNB provided with a different spatial arrangement. When analyzed in vitro for its inhibition of cell proliferation 2-Naph-DNB showed a remarkable activity in the range of micromolar concentrations, with significant differences, with respect to 1-Naph-DNB, against some cell lines. Furthermore, it was able to significantly trigger apoptosis, to up-regulate p53, to block cells in the G2/M phase of the cell cycle and, finally, to slightly bind to DNA forming interstrand cross-links (ISCL). 2-Naph-DNB was then analyzed for its toxic activity in vivo in CD1 mice. This allowed the determination of toxicity parameters such as the lethal doses (LD) and the maximal tolerated dose (MTD) together with the definition of the spectrum of tissue alterations due to its administration i.v. Altogether our data suggest that the idea of modifying the geometry of the lead compound 1-Naph-DNB deserves further investigation aimed at synthesizing new molecules with similar chemical functionalities but with different spatial requirements, hopefully characterized by still enhanced activities in terms of inhibition of cell proliferation and apoptosis.

4-Alkyl-2-nitrothiophenes [10: R = CH3, CH(OH)CH3, CH(OCH3)CH3] react with secondary aliphatic amines, in the presence of AgNO3, to give 3-alkyl-2-amino-5-nitrothiophenes (12) through an oxidative nucleophilic substitution of hydrogen (ONSH) of synthetic interest. This behavior is in striking contrast with that of the parent 2-nitrothiophene (6), which was found to undergo ring-opening in analogous reaction conditions. A possible rationale for the crucial effect of alkyl groups is suggested, grounded also on a study of the corresponding Meisenheimer-like adducts.

A study of the behaviour of some electron-rich 2-methyleneindolines (1–3) with different electron-poor reagents (formation of new carbon–carbon and nitrogen–carbon bonds) has furnished interesting results from both synthetic and the mechanistic viewpoints. Enamines 1–3 have been reacted with the β-nitroenamines 4–7 (reaction CeCl3·7H2O promoted), giving the polymethine dyes 14–23. The same bases 1–3 have been nitroalkylated with the nitroolefins 8–10, furnishing the indolines 24–32, and the diastereoselectivity of the reaction has been thoroughly investigated. The most unexpected results derived from the first example of reaction of Fischer's bases with 1,2-diaza-1,3-butadienes. In fact, with 11–13, the ‘unknown’ indoline spirodihydropyrroles 33–40 were formed. Their structures were unambiguously assigned, and we determined, as an example, that of 33 by X-ray analysis.

[reaction: see text] In prosecution of previous work on the thermal cyclization of 1-aryl-4-methanesulfonyl-2-nitro-3-phenylsulfonyl-1,3-butadienes (7), the 3-unsubstituted derivatives 8, deriving from the initial ring opening of 3-nitrothiophene (2), have been likewise found herein to undergo cyclization, followed by aromatization, in analogous mild experimental conditions, leading to the ring-fused homo- or heteroaromatic nitro derivatives 10. The concerted electrocyclic nature of the process is strongly supported by the outcome of tests based on the variation of the polarity of the solvent or of the electron density on the aryl of 8. Thus, the successful application of the process to the non-phenylsulfonyl-activated 8 significantly widens the scope of a synthetically valuable overall ring-opening/ring-closing procedure from nitrothiophenes. Support to the recently renewed interest in thermal 6pi electrocyclizations as a tool for the construction of the benzene ring is furthermore provided.

Michael addition of lithium enolates of γ-butyrolactone 1 and α-methyl-γ-butyrolactone 1 ′ to ( E )-1-nitropropene 2 , ( E )-β-nitrostyrene 3 and ( E )-2-nitro-1-phenylpropene 4 is described. Reactions of the lithium enolate of 1 ′ with 2 and 4 occurred with high diasteroselectivity (80 and 92% d.e., respectively). Reactions of the zinc enolate of 1 ′ with two β-nitroenamines and two methylthio-substituted 1-amino-2-nitro-1,3-dienes were also examined. Catalytic reduction of the nitroalkylated and nitroalkenylated products allowed the achievement of functionalized γ-lactams and/or cyclic hydroxamic acids.

The (E)-2-aryl-1-[2-(methylthio)phenyl]-1-nitroethylenes 5 can easily be oxidized to the relevant sulfones 6 and effectively subjected to cyclization via an intramolecular Michael addition after metallation with lithium bis(trimethylsilyl)amide in THF. After quenching with ammonium chloride the 3-aryl-4-nitrothiochroman S,S-dioxides 2 are obtained as diastereomeric mixtures in good to excellent yields. Both yields and stereochemistry of the ring-closure step appear to be influenced by steric effects of the 3-aryl moiety. As sulfides 5 derive from an initial ring opening of 3-nitrobenzo[b]thiophene ( 1 ), the overall 1 to 2 process can be considered as an effective 5 to 6 ring enlargement of the sulfur heterocycle. A conformational 1H NMR and molecular-mechanics investigation on the isolated diastereomeric 2 has also been accomplished.

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.

By studying the rearrangement in dioxane/water of a series of (Z)-arylhydrazones of 5-amino-3- benzoyl-1,2,4-oxadiazole (1a-k) into the relevant (2-aryl-5-phenyl-2H-1,2,3-triazol-4-yl)ureas (2a-k) in a wide range of pS + (an operational scale of proton concentration in the mixed solvent used; dioxane/water, 1:1, v:v), the occurrence of three different reaction pathways (specific-acid- catalyzed, uncatalyzed, and general-base-catalyzed) for the relevant SNi process has been recently enlightened. The significantly different substituent effects on the three pathways cause some crossovers in the log kA,R versus pS + plots. Both the pS + value at which the crossover occurs and the width of the uncatalyzed pathway appear in turn substituent-dependent. Thus, thanks to the wide and complete range of substituents examined, the data obtained have been treated by using free-energy relationships. Interestingly enough, these results also furnish valuable information concerning the effects of "small" variations in chemical structures able to produce "large" reactivity variations in some way recalling what can occur in biological systems.