Rhodium-Catalyzed Intermolecular [5+1] and [5+2] Cycloadditions Using 1,4-Enynes with an Electron-Donating Ester on the 3-Position.

Various 3-acyloxy-1,4-enynes could be employed in rhodium-catalyzed intermolecular [5+1] and [5+2] cycloadditions with CO or alkynes, respectively. The rate of these cycloadditions could be accelerated significantly by using 1,4-enynes with an electron-donating ester on the 3-position. The scope of rhodium-catalyzed [5+1] and [5+2] cycloadditions were examined by using 1,4-enynes bearing an electron-donating ester.

Rhodium-Catalyzed Stereoselective Intramolecular [5 + 2] Cycloaddition of 3-Acyloxy 1,4-Enyne and Alkene.

The first rhodium-catalyzed intramolecular [5 + 2] cycloaddition of 3-acyloxy 1,4-enyne and alkene was developed. The cycloaddition is highly diastereoselective in most cases. Various cis-fused bicyclo[5.3.0]decadienes were prepared stereoselectively. The chirality in the propargylic ester starting materials could be transferred to the bicyclic products with high efficiency. Electron-deficient phosphine ligand greatly facilitated the cycloaddition. Up to three new stereogenic centers could be generated. The resulting diene in the products could be hydrolyzed to enones, which allowed the introduction of more functional groups to the seven-membered ring.

Mechanism and Reactivity of Rh-Catalyzed Intermolecular [5+1] Cycloaddition of 3-Acyloxy-1,4-Enyne (ACE) and CO: A Computational Study.

The first theoretical study on the mechanism of [RhCl(CO)2]2-catalyzed [5 + 1] cycloadditions of 3-acyloxy-1,4-enyne (ACE) and CO has been performed using density functional theory (DFT) calculations. The effect of ester on reactivity of this reaction has been investigated. The computational results have revealed that the preferred catalytic cycle involves the sequential steps of 1,2-acyloxy migration, CO insertion, reductive elimination to form ketene intermediate, 6π-electroncyclization, and aromatization to afford the resorcinol product. The 1,2-acyloxy migration is found to be the rate-determining step of the catalytic cycle. The electron-rich p-dimethylaminobenzoate substrate promotes 1,2-acyloxy migration and significantly increases the reactivity by stabilizing the positive charge building up in the oxocyclic transition state.

Synthesis of Naturally Occurring Tropones and Tropolones.

Tropones and tropolones are an important class of seven-membered non-benzenoid aromatic compounds. They can be prepared directly by oxidation of seven-membered rings. They can also be derived from cyclization or cycloaddition of appropriate precursors followed by elimination or rearrangement. This review discusses the types of naturally occurring tropones and tropolones and outlines important methods developed for the synthesis of tropone and tropolone natural products.

3-Acyloxy-1,4-enyne: a New Five-carbon Synthon for Rhodium-Catalyzed (5+2) Cycloadditions.

Seven-membered rings are ubiquitous in natural products and pharmaceutical agents and their syntheses continue to stimulate the development of novel synthetic methods. The (5+2) cycloaddition is one of the most efficient ways to access seven-membered rings since the 2-carbon components (alkenes, alkynes, or allenes) are readily available. Prior to our study, however, there was only one type of transition metal-catalyzed (5+2) cycloaddition: the reaction between vinylcyclopropanes and alkenes, alkynes, or allenes. We recently developed a new type of transition metal-catalyzed (5+2) cycloaddition, where the 5-carbon building block is 3-acyloxy-1,4-enyne (ACE). Our recent progress on Rh-catalyzed intra- and intermolecular (5+2) cycloadditions of ACEs and alkynes is summarized in this article. Using chiral propargylic esters, bicyclic products were prepared in high optical purity by the intramolecular (5+2) cycloadditions. Monocyclic seven-membered rings were synthesized by intermolecular (5+2) cycloaddition of ACEs and alkynes. Kinetic studies indicated that the rate of this intermolecular cycloaddition was significantly accelerated when the acetate was replaced by dimethylaminobenzoate. DFT calculations suggested that novel metallacycles were generated by a Rh-promoted oxidative cycloaddition of 1,4-enynes accompanied by a 1,2-acyloxy migration of propargylic esters.

Transfer of chirality in the rhodium-catalyzed intramolecular [5+2] cycloaddition of 3-acyloxy-1,4-enynes (ACEs) and alkynes: synthesis of enantioenriched bicyclo[5.3.0]decatrienes.

Chiral bicycles: Enantioenriched bicyclo[5.3.0]decatrienes were prepared from readily available chiral 3-acyloxy-1,4-enynes (ACEs) for the first time. In most cases, the chirality of the ACEs could be transferred to the bicyclic products with high efficiency. Inversion of the configuration was observed, thus confirming the predictions of previous computational studies.

[Azathioprine-induced hepatotoxicity in a patient with Crohn's disease]. / Hepatotoxicidad inducida por azatioprina en paciente con enfermedad de Crohn.

Immunosuppressive drugs are among the pharmacological groups with the most theoretical potential to induce adverse reactions, including hepatic reactions. We report the case of a 35-year-old patient with Crohn's disease treated with azathioprine for steroid dependence which, after a hepatic biopsy, was diagnosed with nodular regenerative hyperplasia secondary to this treatment.

Hepatotoxicidad inducida por azatioprina en paciente con enfermedad de Crohn / Azathioprine-induced hepatotoxicity in a patient with Crohn’s disease

Los inmunosupresores se encuentran entre los grupos farmacológicos con mayor potencial teórico de inducir reacciones adversas, entre ellas las hepáticas. Presentamos el caso de un paciente de 35 años con enfermedad de Crohn en tratamiento con azatioprina por corticodependencia al que se le diagnosticó tras realización de una biopsia hepática de hiperplasia nodular regenerativa secundaria a este tratamiento (AU)

Immunosuppressive drugs are among the pharmacological groups with the most theoretical potential to induce adverse reactions, including hepatic reactions. We report the case of a 35-year-old patient with Crohn’s disease treated with azathioprine for steroid dependence which, after a hepatic biopsy, was diagnosed with nodular regenerative hyperplasia secondary to this treatment (AU)

Effect of ester on rhodium-catalyzed intermolecular [5+2] cycloaddition of 3-acyloxy-1,4-enynes and alkynes.

We systematically examined the effect of different esters on the rhodium-catalyzed intermolecular [5+2] cycloaddition of 3-acyloxy-1,4-enynes and alkynes with a concomitant 1,2-acyloxy migration. Significant rate acceleration was observed for benzoate substrates bearing an electron-donating substituent. The cycloaddition can now be conducted under much more practical conditions for most terminal alkynes.

Arthroplasty infection by Priopionibacterium granulosum treated with reimplantation despite ongoing purulent-appearing fluid collection.

We present the first case of infection in a native or prosthetic joint by Propionibacterium granulosum in which a patient developed symptoms of prosthetic hip infection 5 years after primary surgery. The patient required multiple operative debridements to eradicate the infection and was successfully reimplanted despite an ongoing purulent-appearing, although sterile, fluid collection at the time of reimplantation. There is no clinical or laboratory evidence of infection at 3 years post-reimplantation, and the patient has a well-functioning total hip arthroplasty. P granulosum is a low-virulence but highly-inflammatory organism. It seems to produce a large fluid collection that may require multiple debridements. To our knowledge, there are no reported cases of native or prosthetic joint infection from P granulosum. We present the first case here.

Rhodium-catalyzed acyloxy migration of propargylic esters in cycloadditions, inspiration from the recent "gold rush".

Transition metal-catalyzed acyloxy migration of propargylic esters offers versatile entries to allene and vinyl carbene intermediates for various fascinating subsequent transformations. Most π-acidic metals (e.g. gold and platinum) are capable of facilitating these acyloxy migration events. However, very few of these processes involve redox chemistry, which are well-known for most other transition metals such as rhodium. The coupling of acyloxy migration of propargylic esters with oxidative addition, migratory insertion, and reductive elimination may lead to ample new opportunities for the design of new reactions. This tutorial review summarizes recent developments in Rh-catalyzed 1,3- and 1,2-acyloxy migration of propargylic esters in a number of cycloaddition reactions. Related Au- and Pt-catalyzed cycloadditions involving acyloxy migration are also discussed.

Catalytic enantioselective halolactonization of enynes and alkenes.

New organocatalysts have been developed for the enantioselective halolactonization of (Z)-1,3-enynes and 1,1-disubstituted alkenes. In the case of 1,3-enynes, the carboxylate nucleophile and halogen electrophile were added to the conjugated π-system from the same face. Up to 99% ee was achieved for the 1,4-syn-bromolactonization of conjugated (Z)-1,3-enynes. Based on the results from the enyne halolactonization, a second generation of catalysts was designed for simple olefins. Up to 91% ee was observed for chlorolactonization of 1,1-disubstituted alkenes. The catalysts developed for the enantioselective halolactonization of both enynes and alkenes are composed of a cinchona alkaloid skeleton tethered to a urea group.

Rhodium-catalyzed carbonylation of 3-acyloxy-1,4-enynes for the synthesis of cyclopentenones.

Functionalized cyclopentenones were synthesized by a Rh-catalyzed carbonylation of 3-acyloxy-1,4-enynes, derived from alkynes and α,ß-unsaturated aldehydes. The reaction involved a Saucy-Marbet 1,3-acyloxy migration of propargyl esters and a [4 + 1] cycloaddition of the resulting acyloxy substituted vinylallene with CO.

Rhodium-catalyzed intra- and intermolecular [5 + 2] cycloaddition of 3-acyloxy-1,4-enyne and alkyne with concomitant 1,2-acyloxy migration.

A new type of rhodium-catalyzed [5 + 2] cycloaddition was developed for the synthesis of seven-membered rings with diverse functionalities. The ring formation was accompanied by a 1,2-acyloxy migration event. The five- and two-carbon components of the cycloaddition are 3-acyloxy-1,4-enynes (ACEs) and alkynes, respectively. Cationic rhodium(I) catalysts worked most efficiently for the intramolecular cycloaddition, while only neutral rhodium(I) complexes could facilitate the intermolecular reaction. In both cases, electron-poor phosphite or phosphine ligands often improved the efficiency of the cycloadditions. The scope of ACEs and alkynes was investigated in both the intra- and intermolecular reactions. The resulting seven-membered-ring products have three double bonds that could be selectively functionalized.

Quantitative evaluation on [9°Y] DOTATOC PET and SPECT imaging by phantom acquisitions and clinical applications in locoregional and systemic treatments.

AIM: The aim of this paper was to compare [9°Y]-PET and SPECT imaging quantification for dosimetric applications in targeted radionuclide therapy. METHODS: Imaging studies were carried out by SPECT-CT and PET equipment performing phantom tests first. [9°Y]-SPECT and PET scans were compared in terms of sensitivity, minimum detectable activity concentration, recovery coefficients (RCs) and system spatial resolution (FWHM). Quantitative evaluations by PET and SPECT acquisitions were then assessed in patients who received therapeutic activity of [9°Y]-DOTATOC directly injected into the surgical cavity by locoregional route in glioma treatment and by systemic route in neuroendocrine tumour patients who underwent intravenous infusion. Finally 3D-dose distributions by SPECT and PET images were obtained. RESULTS: Sensitivity was proven to be about fivefold higher for SPECT than for PET. To obtain a good-quality PET imaging, the minimum detectable activity concentration was determined to be equal to 1 MBq/mL compared with 0.05 MBq/mL that was sufficient to assess adequate SPECT imaging. RCs were 100% for volume ≥ 25.5 mL for PET and ≥ 110 mL for SPECT. FWHM was 7 mm for PET and 19 mm for SPECT scans. With regard to locoregional therapy, excellent imaging was obtained with both PET and SPECT. On the contrary, systemic administration did not permit us to obtain suitable PET imaging. PET and SPECT images were affected by considerable noise, whose influence is much more important in the quantitative evaluation of dose volume histograms rather than in the visual interpretation of images. CONCLUSION: [9°Y]-activity quantification is feasible by SPECT and PET imaging. For clinical applications, SPECT-CT is the best technique for visualizing the radiopharmaceuticals following systemic infusion, while both SPECT and PET scans are effective in analyzing locoregional distribution. Nevertheless PET study demonstrates the best spatial definition.

Asymmetric aza-[3+3] annulation in the synthesis of indolizidines: an unexpected reversal of regiochemistry.

An enantioselective and diastereoselective aza-[3+3] annulation of pyrrolidine-based exo-cyclic vinylogous amides and urethanes with chiral vinyl iminium salts is described. This asymmetric annulation manifold is possible because of an unexpected regiochemical reversal whereby head-to-tail annulations dominated over the predicted head-to-head. It should find prevalent synthetic applications in the enantioselective synthesis of indolizidines.

[Virology, diagnostic tests, epidemiology and transmission mechanisms of hepatitis C virus infection]. / Virología, pruebas diagnósticas, epidemiología y mecanismos de transmisión del VHC.

The hepatitis C virus is a human virus, classified within a third type (Hepacivirus) of the Flaviviridae family. It is a spherical virus, of approximately 50 nm in diameter, with a glycoprotein covering that contains lipids, and its genome is a simple chain RNA molecule. It is characterised by a high degree of genomic heterogeneity, whose evolutionary consequence in the long term is the appearance of genetically different viral groups, genotypes and quasispecies. There are different diagnostic techniques for detecting hepatitis C virus infection. Serological assays: the detection of specific IgG against HCV by means of enzyme immunoassays is the most practical method for diagnosing infection by this virus. Supplementary immunblot tests are employed to confirm the specificity of the results of the EIA test. Molecular assays: qualitative and quantitative techniques have been developed for detecting RNA-HCV, based on the direct detection of the virions. The pathogeny of hepatitis C is not well understood. Its world prevalence is estimated at some 3%, which is why routine screening for its detection is not recommended. HCV transmission basically occurs through percutaneous exposure to infected blood, with higher rates observed in imprisoned persons, vagabonds, intravenous drug addicts, haemophiliacs and patients on haemodialysis. Although it can be transmitted sexually, it seems that this path is not very efficient, with a greater prevalence observed in persons with multiple sexual partners. Vertical transmission is estimated at some 2%, reaching 20% in cases of maternal coinfection with HIV.

Is carbohydrates-deficient transferrin the best test of the alcoholic etiology in acute pancreatitis?

AIM: To demonstrate if carbohydrates deficient transferrin (CDT) is the best marker to detect an excessive alcohol consumption as a cause of acute pancreatitis. MATERIAL AND METHODS: Prospective study of 60 patients consecutively admitted in our hospital. Acute pancreatitis were classified according to their different etiologies, alcoholic (11), probably alcoholic (4), biliary (25) and others (20). In all cases, we have compared CDT with classical quemical markers of alcohol abuse such as mean corpuscular volumen (MCV), gamma-glutamyltransferase (GGT) and aspartateaminotransferase (AST). Statistic correlations were done between the quantity of alcohol consumed and CDT, GGT, AST and MCV variables. RESULTS: Correlation between CDT and MCV with the excessive alcohol consumption was statistically significant. The acute pancreatitis caused by alcohol and the suspicious alcoholic group had a average CDT higher than the rest of the groups (p < 0.05). Taking a cut point with a CDT value of 20, the diagnosis capacity of the test to detect the alcoholic etiology was 82 and 92% of specificity. Taking a cut point with a MCV value higher than 95, sensibility was 67% and specificity was 82%. CONCLUSION: In our experience, the most efficient marker of the alcoholic etiology in acute pancreatitis was CDT.

¿La transferrina deficiente en carbohidratos es el mejor test de la etiología alcohólica en la pancreatitis aguda? / Is carbohydrates-deficient transferrin the best test of the alcoholic etiology in acute pancreatitis?

Objetivo: demostrar si el test de la transferrina deficiente en carbohidratos (CDT) es la mejor prueba para detectar la ingesta excesiva de alcohol como causa de la pancreatitis aguda. Material y métodos: estudio prospectivo de 60 pacientes con pancreatitis aguda ingresados consecutivamente en nuestro hospital. Las pancreatitis agudas se clasificaron según las diferentes etiologías en alcohólicas (11), probablemente alcohólicas (4), biliares (25), y otras (20). Comparamos en todos los casos la CDT con los marcadores bioquímicos clásicos de la toma excesiva de alcohol como son el volumen corpuscular medio (VCM), gammaglutamil-transpeptidasa (GGT) y aspartato-aminotransferasa (AST).Se realizaron las correlaciones estadísticas entre la cantidad de alcohol consumida y las variables CDT, GGT, AST y VCM.Resultados: la correlación entre la CDT y el VCM con la toma excesiva de alcohol fue estadísticamente significativa.Las pancreatitis agudas por el alcohol y el grupo de sospecha alcohólica tuvieron una CDT media mayor que los demás grupos (p<0,05). Tomando como punto de corte un valor de CDT de 20, la capacidad diagnóstica de la prueba para detectar la etiología alcohólica fue del 82 por ciento y 92 por ciento de especificidad. Tomando como punto de corte un VCM mayor de 95 la sensibilidad fue de un 67 por ciento y la especificidad de un 82 por ciento. Conclusión: en nuestra experiencia, el marcador más eficiente de la etiología alcohólica en las pancreatitis agudas fue la CDT (AU)

Role of nuclear medicine in the treatment of malignant gliomas: the locoregional radioimmunotherapy approach.

The high-grade malignant gliomas (anaplastic astrocytomas and glioblastoma) have a very bad prognosis since the available methods of treatment (surgery, radiotherapy and chemotherapy) are unable to control the progression of the disease for long. The use of specific monoclonal antibodies labelled with a suitable isotope (iodine-131 or yttrium-90) represents an effective approach to hamper tumour regrowth. Some authors have injected the antibodies intravenously, or have tried to increase the tumour/background ratio with the avidin/biotin system. In many cases the labelled monoclonal antibodies were injected directly into the tumoral bed after the operation. The authors' experiences concern a quite large locoregional radioimmunotherapy study which was performed by using antitenascin antibodies labelled initially with 131I and more recently with 90Y. The clinical results demonstrate the ability of this technique to control, for a long time, the growth of these tumours. The glioblastoma median survival was prolonged to 25 months (131I group) or 31 months (90Y group). The response rate (which comprises PR, CR and NED) was 47.1% (glioblastoma 131I group) or 40% ( glioblastoma 90Y group). In many cases a significant tumour shrinking effect was radiologically demonstrated. The use of 90Y proved more favourable in bulky lesions, and reduced the radioprotection problems.