On the rearrangements of biologically-relevant vinyl allene oxides to cis-cyclopentenones, ketols, and Favorskii-type carboxylic acids.

In addition to stereodefined cis-cyclopentenones, the rearrangement of naturally-occurring vinyl allene oxides can provide ketols, cyclopropylcarbinols, and Favorskii-type bis-(Z)-but-2-en-1-yl acetic acids. These processes have been studied by DFT computations using (Z)-but-1-en-1-yl allene oxides as model systems. Prior studies on the stepwise cascade process starting from (Z)-but-1-en-1-yl allene oxides established as key steps the ring opening of the oxirane to give oxidopentadienyl biradicals, and their isomerization through formation of alkenylcyclopropanone intermediates prior to the conrotatory electrocyclic ring closure to cis-configured cyclopentenones. Under neutral or under acidic conditions, the corresponding ketols and cyclopropylcarbinols have been computationally characterized as resulting from SN2, SN1 and SN1'-type processes, showing that the rearrangement of vinyl allene oxides is pH-dependent. Moreover, stereoconvergent base-induced Favorskii-type rearrangements to provide bis-(Z)-but-1-en-1-yl substituted acetic acids have also been justified. Since the model system captures the structural features of the vinyl allene oxides of biological relevance, our computations provide the most comprehensive overview of the complex reactivity of these natural species.

Deciphering the Origin of Enantioselectivity on the Cis-Cyclopropanation of Styrene with Enantiopure Di-chloro,Di-gold(I)-SEGPHOS Carbenoids Generated from Propargylic Esters.

The stereoselective synthesis of cis-disubstituted cyclopropanes by the Au(I)/PPh3-catalyzed cycloaddition of propargylic esters and styrene has been studied using density functional theory calculations. The computed mechanistic scheme involves the rate-limiting 1,2-rearrangement of the propargylic ester with the π-coordinated gold complex, followed by the (2 + 1)-cheletropic reaction of styrene with the alkenyl-Au(I) carbene intermediate to afford the cis-disubstituted cyclopropane derivative in a high cis/trans diastereomeric ratio. With a ( R)-di-chloro,di-gold-DTBM-SEGPHOS complex as the catalyst, computations are consistent with a rate-determining (2 + 1)-cheletropic reaction, in which facial discrimination is proposed to result from a combination of subtle steric and electronic effects in the SiRe facial approach transition structure, which favor the formation of the cis-cyclopropane diastereomer of 1 R,2 S absolute configuration, as experimentally observed.

Synthesis of the octahydronaphthalene core of nahuoic acid A via a B(C6F5)3-catalyzed intramolecular Diels-Alder (IMDA) reaction.

Model tetraenal 9b underwent intramolecular Diels-Alder cycloaddition in CH2Cl2 at -10 °C under catalysis by the bulky Lewis acid B(C6F5)3 to deliver as major components the cis-fused angularly-methylated octahydronaphthalene products, which are formed through the alternative exo orientations of the reacting moieties. One of these diastereomers features the relative and absolute configuration present in the core of nahuoic acid A, a natural product that acts as a cofactor-competitive inhibitor of the lysine methyl transferase SETD8. By contrast, catalysis of the reaction by Me2AlCl at -40 °C selectively afforded the trans-fused isomer resulting from the Re-endo orientation.

Rearrangement of vinyl allene oxide geometric isomers to cyclopentenones. Further computational insights with biologically relevant model systems.

Pathways for the rearrangement of the E and Z isomers of allyl- and methyl-substituted vinyl allene oxides to stereodefined cyclopentenones have been studied by DFT computations. Regardless of the reactant geometry, cis-configured cyclopentenones are found to be formed in a stepwise cascade comprising as key steps the ring opening of the oxirane to give an oxidopentadienyl diradical, its isomerization, and electrocyclization. An allyl substituent at the Csp3 atom of the starting vinyl allene oxide induces opposite effects on the activation energies for ring opening: a decrease owing to assistance by homoconjugation for the out motion and an increase due to the stereoelectronic stabilization of the reactant. As a result, allyl- and methyl-substituted vinyl allene oxides exhibit comparable activation energies. Only model systems with crotyl substituents afford lower activation energies than the methyl counterparts due to the additional stabilization of the forming charge deficiency at a secondary carbon by homoconjugation. Moreover, upon homoconjugative interaction reactants of Z geometry are predicted to undergo cyclization more readily than the E isomers. The results with Z-crotyl substituent are congruent with the spontaneous rearrangement of natural vinyl allene oxide derived from α-linolenic acid to a racemic cis-cyclopentenone (12-oxo-PDA).

Impact of a focused antimicrobial stewardship program in adherence to antibiotic prophylaxis and antimicrobial consumption in appendectomies.

Antibiotic use in appendectomy constitutes a fundamental practice to achieve the clinical outcomes and the prevention of surgical site infection. A prospective interventional study was performed in a community hospital from January 2013 to December 2015 with the aim of determining the effect of a focused antimicrobial stewardship program in the compliance with antibiotic prophylaxis and the antimicrobial consumption in appendectomies. The compliance with the antibiotic prophylaxis was monitored for the timing of administration, the selection and dose and the discontinuation. The monitoring of antimicrobial consumption was performed by a pharmacist using ATC/DDD methodology. The stewardship program includes the education of the staff and the monitoring of the quality of antibiotic prophylaxis and consumption, and feedback. Comparison of the variables over the years was performed using student's t-test or chi-square test as required. In 603 appendectomies performed the compliance with timely administration was achieved in 72.9%, 99.6% and 100% during 2013, 2014 and 2015 respectively and the compliance with the discontinuation had an increase from 86.4% (2013) to 96.7% in 2015. Consumption of antimicrobial was 355.1 DDD/100 procedures (DDD) in flemonous, 447.3 DDD in suppurative, 892.8 DDD in gangrenous and 1162.7 DDD in perforated appendectomies. Reduction in consumption for cefuroxime (26.2%), metronidazole (12.6%) and ceftriaxone (18.1%) was observed. The consumption of antimicrobials in flemonous and suppurated appendectomies achieved the lowest figure in 2015. The focused antimicrobial stewardship program was effective to improve the timely administration and the proper discontinuation of prophylactic antibiotic, with an important reduction of antimicrobial consumption.

Exploiting the Multidentate Nature of Chiral Disulfonimides in a Multicomponent Reaction for the Asymmetric Synthesis of Pyrrolo[1,2-a]indoles: A Remarkable Case of Enantioinversion.

A new multicomponent coupling reaction for the enantioselective synthesis of pyrrolo[1,2-a]indoles under the catalysis of a chiral disulfonimide is described. The high specificity of the reaction is a consequence of the multidentate character of the Brønsted acid catalyst. Insights from DFT calculations helped explain the unexpected high enantioselectivity observed with the simplest 3,3'-unsubstituted binaphthyl catalyst as a result of transition-state stabilization by a network of cooperative noncovalent interactions. The remarkable enantioinversion resulting from the simple introduction of substituents at 3- and 3'-positions, the first reported example of this phenomenon in the context of binaphthalene-derived Brønsted acid catalysis, was instead attributed to destabilizing steric interactions.

Stereoselective [3+2] Carbocyclization of Indole-Derived Imines and Electron-Rich Alkenes: A Divergent Synthesis of Cyclopenta[b]indole or Tetrahydroquinoline Derivatives.

An unprecedented stereoselective [3+2] carbocyclization reaction of indole-2-carboxaldehydes, anilines, and electron-rich alkenes to obtain cyclopenta[b]indoles is disclosed. This pathway is different from the well-established Povarov reaction: the formal [4+2] cycloaddition involving the same components, which affords tetrahydroquinolines. Moreover, by simply changing the Brønsted acid catalyst, this multicomponent coupling process could be divergently directed towards the conventional Povarov pathway to produce tetrahydroquinolines or to the new pathway (anti-Povarov) to generate cyclopenta[b]indoles. Supported by computational studies, a stepwise Mannich/Friedel-Crafts cascade is proposed for the new anti-Povarov reaction, whereas a concerted [4+2] cycloaddition mechanism is proposed for the Povarov reaction.

A unifying mechanism for the rearrangement of vinyl allene oxide geometric isomers to cyclopentenones.

A new mechanism for the rearrangement of vinyl allene oxide geometric isomers to stereodefined cyclopentenones is proposed based on DFT computations. This mechanism comprises two steps, first the ring opening of the oxirane to give a vinylcyclopropanone, and then a [1,3]-C sigmatropic rearrangement. Depending primarily on the allene oxide double bond geometry the stepwise pathway is either competitive (for E allene oxides) or favored (for Z allene oxides) relative to the already described SN2-like concerted pathway. All bond-forming reactions take place through helically chiral transition states, which allows the stereochemical information of the substrates to be transferred to that of the products, in particular in the case of (enantiopure) Z allene oxides. In addition to revealing one more of the fascinating mechanisms with memory of chirality, the results deepen our understanding of the important jasmonate and clavulone biosynthetic pathways that occur in plants and corals.

Low-lying excited-states of 5-benzyluracil.

A numerical study is reported concerning the first and second singlet excited-states of 5-benzyluracil using the multireference self-consistent field (state-averaged CASSCF) method. The vertical excitation energies of low-lying excited-states were characterized using the SA-CASSCF method, as well as using higher-level methods, such as CASPT2, MRCI and EOM-CCSD. The local minima and conical intersections found on the potential energy surfaces (PESs) were characterized in terms of molecular geometry and natural population analysis. Different relaxation pathways on the PESs are identified and discussed by comparing with the similar pathways found for the individual monomers of uracil and benzene. The molecule can be thought of as a model system for the study of crosslink reaction between DNA and proteins induced by UV light.

Mechanistic and sterochemical insights on the Pt-catalyzed rearrangement of oxiranylpropargylic esters to cyclopentenones.

A mechanism for the rearrangement of oxiranylpropargylic esters to cyclopentenones catalyzed by PtCl(2) is proposed based on DFT calculations (M06/6-31++G(d,p)). Although the basic steps are coincidental with those proposed by Sarpong et al., who characterized a 2H-pyran as intermediate, calculations have revealed other intricate details of this complex rearrangement. The 2H-pyran is proposed to result from the ring-opening of a bicyclic oxonium ion that follows the nucleophilic capture by the epoxide of a platinum carbene generated by an initial Pt-mediated 1,2-propargylic rearrangement. The key steps in the evolution of this system are the electrocyclic ring-opening of the 2H-pyran to a α-methoxycarbonyl dienone and an iso-Nazarov ring closure. Prior to those, changes in hapticity and in the conformation of the dienone are required in order to produce the helical conformation needed to generate a single diastereomer of the cyclopentenone product obtained experimentally. The metal is needed well beyond the first step of the mechanism, and both electrocyclic reactions are favored by coordination to the metal when compared to their uncomplexed counterparts. Moreover, we have experimentally demonstrated that the rearrangement is stereoconvergent, a feature that is traced back to the initial configuration of the epoxide, which determines the somewhat counterthermodynamic placement of the metal syn to the methyl group of the stereogenic center in the 2H-pyran intermediate. Finally, starting from enantiopure oxiranylpropargylic ester 13, a racemate of cyclopentenone (R*,S*)-16 was obtained. Thus, the sequence does not proceed with memory of chirality, and the absolute stereochemical information is already lost at the stage of the 2H-pyran 14.

The role of the excited electronic states in the C+ + H2O reaction.

The electronic excited states of the [COH2]+ system have been studied in order to establish their role in the dynamics of the C+ + H2O-->[COH]+ +H reaction, which is a prototypical ion-molecule reaction. The most relevant minima and saddle points of the lowest excited state have been determined and energy profiles for the lowest excited doublet and quartet electronic states have been computed along the fragmentation and isomerization coordinates. Also, nonadiabatic coupling strengths between the ground and the first excited state have been computed where they can be large. Our analysis suggests that the first excited state could play an important role in the generation of the formyl isomer, which has been detected in crossed beam experiments [D. M. Sonnenfroh et al., J. Chem. Phys. 83, 3985 (1985)], but could not be explained in quasiclassical trajectory computations [Y. Ishikawa et al., Chem. Phys. Lett. 370, 490 (2003); J. R. Flores, J. Chem. Phys. 125, 164309 (2006)].

[The evaluation of cell proliferation in gliomas]. / Estimación de la proliferación celular en gliomas.

INTRODUCTION: The homeostasis of tissues depends on a strict control of cell growth, differentiation and death. Several proteins, which are involved on the regulation of the cell cycle, can suffer diverse alterations and produce an uncontrolled cell proliferation and the genesis of a neoplastic process. The assessment of cell proliferation is an useful method applied to Neuro-oncology in order to know the behavior of gliomas. DEVELOPMENT: This work is focussed on the analysis of different methods, all of them employed to study the cell proliferation: immunostaining of proliferating cell nuclear antigen (PCNA) and Ki-67, DNA content and ploidy by flow cytometry, in vitro incorporation of bromodeoxyuridine (BrdU) and the identification of apoptotic cells. The study of the DNA by flow cytometry establishes a relationship between ploidy and the prognostic of gliomas. The assessment of PCNA provides us with objective data about the proliferative activity of gliomas. Both Ki-67 expression and BrdU incorporation are also useful methods in the study of gliomas. CONCLUSIONS: In short, the most malignant gliomas are characterized by a high frequency of aneuploidies and high PCNA, Ki-67 and BrdU labelling indexes. All of these described methods can be used as prognostic markers complementary to the classic criteria employed nowadays.

Effects of chronic deep hypoxia on the expression of nitric oxide synthase in the rat brain.

Experimental studies in extreme hypoxic conditions affecting the brain have been performed mainly in acute but not chronic models. Twenty rats were housed and exposed to decreasing concentrations of oxygen (from 21% to 7% over 130 days) and ten normal rats were used as control. Paraffin slices from representative sections containing cerebral cortex, cerebellum, striatum, hippocampus, thalamus and hypothalamus were incubated with antisera against nitric oxide synthase. Cortex and striatum showed small randomly distributed positive neurons with bipolar features, in greater numbers in the hypoxic group (p < 0.02). The granular layer of the cerebellum showed a strongly positive rim around some cell nuclei. Purkinje cells were immunopositive in hypoxic rats. Hipoccampal, thalamic and hypothalamic nuclei showed no quantitative differences in the number of positive neurons. The increased number of blood vessels and their dilation observed in some brain regions in hypoxic rats, mainly in ventral striatum, lead us to hypothesise that NOS may be overexpressed and act at these sites as vasomodulator and/or mediator of secondary cell injury affecting selective neuronal populations. We conclude that prolonged periods of adaptation to deep hypoxia reduces the effect of hypoxia on the upregulation of NOS in the brain tissue.

Expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor-beta (PDGFR-beta) in human gliomas.

The growth of solid tumors is highly dependent on vascular proliferation. Vascular endothelial growth factor (VEGF), the main mediator of angiogenesis, and platelet-derived growth factor receptor-beta (PDGFR-beta), receptor for the potent mitogen PDGF, are two indicators of the angiogenic potential of human gliomas. We studied a series of 57 surgical biopsies of astrocytic neoplasms by immunohistochemistry to elucidate the relationship between tumor proliferation, quantified as Ki67-LI, and the expression of these two proteins. Ki67-LI increases throughout histological malignancy, although staining in endothelial cells has rarely been recorded. Elevated amounts of VEGF-positive tumor cells (VEGF-LI) were found in anaplastic astrocytomas and glioblastomas, mainly around areas of necrosis, cysts, or edema. Endothelium of blood vessels was consistently stained. PDGFR-beta positivity was found in glomeruloid formations and in tumor cells, excluding pilocytic astrocytomas. Multinucleated giant cells and perivascular tumor cells were positive in glioblastomas. In addition, peritumoral microglia-like cells were also stained in some cases. Statistical correlation was only found between PDGFR-beta and Ki67 LIs. In conclusion, VEGF as permeability factor is involved in the development of secondary neoplastic changes, whereas PDGFR-beta is directly correlated to proliferation indexes. Strong expression of VEGF and PDGFR-beta found in endothelium and tumor cells would seem to support a combined role in tumoral neoangiogenesis.