Enantiopure dihydro-[5]-helicenequinones via Diels-Alder reactions of vinyl dihydrophenanthrenes and (SS)-2-(p-tolylsulfinyl)-1,4-benzoquinone.
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Journal Article↗
Biomedical subjects
A Urbano
Publications and source records attributed to A Urbano.
Studies of Diastereoselectivity in Diels-Alder Reactions of Enantiopure (SS)-2-(p-Tolylsulfinyl)-1,4-naphthoquinone and Chiral Racemic Acyclic Dienes.
Enantiopure sulfinylnaphthoquinone (+)-5 reacted with racemic acyclic dienes 1a-f bearing a stereogenic allylic center, through a tandem cycloaddition/pyrolytic sulfoxide elimination, to afford optically enriched compounds 8a-f and 9a-f with good like/unlike selectivities (ca. 75:25) and good enantiomeric excesses (68-82%), arising from the partial kinetic resolution of the racemic dienes. The opposite diastereoselection (8g-i: 9g-i, up to 5:95) was observed in reactions with dienes 1g-i, having an additional methyl group at C-3, the enantiomeric purities being moderate (14-25%). Steric effects and torsional interactions in the corresponding approaches account for the observed diastereoselectivities.
Journal Article↗
Enantioselective Diels-Alder approach to C-3-oxygenated angucyclinones from (SS)-2-(p-tolysulfinyl)-1,4-naphthoquinone.
Chiral racemic vinylcyclohexenes 2, bearing oxygenated substituents and/or a methyl group at the C-5 position of the cyclohexene ring, were submitted to Diels-Alder reactions with enantiomerically pure (SS)-(2-p-tolylsulfinyl)-1,4-naphthoquinone [(+)-1]. The domino cycloaddition/pyrolytic sulfoxide elimination process led to the formation of enantiomerically enriched angularly tetracyclic quinones anti-6 and syn-7, which were obtained from the kinetic resolution of the racemic diene. In all cases, (SS)-(2-p-tolylsulfinyl)-1,4-naphthoquinone reacted from the less hindered face of the more reactive s-cis conformation, to form products in good enantiomeric excesses. Steric effects and torsional interactions in the corresponding approaches account for the observed pi-facial diastereoselectivities at both partners. The usefulness of this methodology is illustrated with the four-step totally asymmetric synthesis of the C-3-oxygenated angucyclinone derivative (-)-8-deoxytetrangomycin 10 in 26% overall yield and with 50% enantiomeric purity.
Antibiotics, Antineoplastic↗
Diels-alder reactions with 2-(Arylsulfinyl)-1,4-benzoquinones: effect of aryl substitution on reactivity, chemoselectivity, and pi-facial diastereoselectivity
Diels-Alder reactions of (SS)-2-(2'-methoxynaphthylsulfinyl)-1, 4-benzoquinone (1b), 2-(p-methoxyphenylsulfinyl)-1,4-benzoquinone (1c), and 2-(p-nitrophenylsulfinyl)-1,4-benzoquinone (1d) with cyclopentadiene are reported. These cycloadditions allowed the highly chemo- and stereoselective formation of both diastereoisomeric endo-adducts resulting from reaction on the unsubstituted double bond C(5)-C(6) of quinones working under thermal and Eu(fod)(3)- or BF(3).OEt(2)-catalyzed conditions. The synthesis of endo-adduct [4aS,5S,8R,8aR,SS]-9d resulting from cycloaddition on the substituted C(2)-C(3) double bond was achieved in a chemo- and diastereoselective way from quinone 1d in the presence of ZnBr(2). The reactivity and selectivity of the process proved to be dependent on the electron density of the arylsulfinyl group.
Journal Article↗
Comparison between human and artificial neural network detection of Laplacian-derived electroencephalographic activity related to unilateral voluntary movements.
A back-propagation artificial neural network (ANN) was tested to verify its capacity to select different classes of single trials (STs) based on the spatial information content of electroencephalographic activity related to voluntary unilateral finger movements. The rationale was that ipsilateral and contralateral primary sensorimotor cortex can be involved in a nonstationary way in the control of unilateral voluntary movements. The movement-related potentials were surface Laplacian-transformed (SL) to reduce head volume conductor effects and to model the response of the primary sensorimotor cortex. The ANN sampled the SL from four or two central channels overlying the primary motor area of both sides in the period of 80 ms preceding the electromyographic response onset in the active muscle. The performance of the ANN was evaluated statistically by calculating the percentage value of agreement between the STs classified by the ANN and those of two investigators (used as a reference). The results showed that both investigator and ANN were capable of selecting STs with the SL maximum in the central area contralateral to the movement (contralateral STs, about 25%), STs with considerable SL values also in the ipsilateral central area (bilateral STs, about 50%), and STs with neither the contralateral nor bilateral pattern ("spatially incoherent" single trials; about 25%). The maximum agreement (64-84%) between the ANN and the investigator was obtained when the ANN used four spatial inputs (P < 0.0000001). Importantly, the common means of all single trials showed a weak or absent ipsilateral response. These results may suggest that a back-propagation ANN could select EEG single trials showing stationary and nonstationary responses of the primary sensorimotor cortex, based on the same spatial criteria as the experimenter.
Electroencephalography↗
"Gating" of human short-latency somatosensory evoked cortical responses during execution of movement. A high resolution electroencephalography study.
The present study aimed at investigating gating of median nerve somatosensory evoked cortical responses (SECRs), estimated during executed continuous complex ipsilateral and contralateral sequential finger movements. SECRs were modeled with an advanced high resolution electroencephalography technology that dramatically improved spatial details of the scalp recorded somatosensory evoked potentials. Integration with magnetic resonance brain images allowed us to localize different SECRs within cortical areas. The working hypothesis was that the gating effects were time varying and could differently influence SECRs. Maximum statistically significant (p<0. 01) time-varying gating (magnitude reduction) of the short-latency SECRs modeled in the contralateral primary motor and somatosensory and supplementary motor areas was computed during the executed ipsilateral movement. The gating effects were stronger on the modeled SECRs peaking 30-45 ms (N30-P30, N32, P45-N45) than 20-26 ms (P20-N20, P22, N26) post-stimulus. Furthermore, the modeled SECRs peaking 30 ms post-stimulus (N30-P30) were significantly increased in magnitude during the executed contralateral movement. These results may delineate a distributed cortical sensorimotor system responsible for the gating effects on SECRs. This system would be able to modulate activity of SECR generators, based on the integration of afferent somatosensory inputs from the stimulated nerve with outputs related to the movement execution.
Adult↗
Isolation and characterization of NUC70, a cytoplasmic, hematopoietic apoptotic endonuclease.
Endonucleolytic DNA fragmentation is the common end point and the prevailing indicator of apoptosis. We have identified a 70-kDa endonuclease (NUC70) that is activated in drug-induced apoptosis of human hematopoietic cells. We purified NUC70 to homogeneity and generated a rabbit polyclonal antibody to distinguish it from previously identified nucleases. Biochemical characterization of isolated NUC70 demonstrates that it is Ca2+/Mg2+-dependent and active over a pH range of 6-8. When incubated with isolated HeLa nuclei, NUC70 was capable of generating internucleosomal DNA fragmentation. This endonucleolytic activity was inhibited by Zn2+, aurintricarboxylic acid, N-ethylmaleimide, spermine, and iodoacetamide. Western immunoblots using the anti-NUC70 antibody and DNA-SDS-polyacrylamide gel electrophoresis assays indicate that NUC70 expression and activity is restricted to human hematopoietic cells. No such activity was detected in human epithelial cell lines or murine hematopoietic cells. We also observed no difference in levels of NUC70 expression between apoptotic and nonapoptotic cells, suggesting that activation of NUC70 may be by posttranslational modification. We demonstrate that NUC70 activity is diminished in cells pretreated with the caspase inhibitors z-DEVD-fmk, z-VAD-fmk, and Z-CH2-Asp-DCB. Time course studies of cytoplasmic and nuclear endonuclease activities during apoptosis show that NUC70 is a cytoplasmic endonuclease that is translocated to the nucleus after the initiation of apoptosis. We confirmed this with immunostaining studies using anti-NUC70 antibody. These results demonstrate that NUC70 is an endogenous cytoplasmic endonuclease that is activated during apoptosis in a caspase-dependent mechanism.
Animals↗
Improved realistic Laplacian estimate of highly-sampled EEG potentials by regularization techniques.
In this study we investigated the effects of lambda correction, generalized cross-validation (GCV), and Tikhonov regularization techniques on the realistic Laplacian (RL) estimate of highly-sampled (128 channels) simulated and actual EEG potential distributions. The simulated EEG potential distributions were mathematically generated over a 3-shell spherical head model (analytic potential distributions). Noise was added to the analytic potential distributions to mimic EEG noise. The magnitude of the noise was 20, 40 and 80% that of the analytic potential distributions. Performance of the regularization techniques was evaluated by computing the root mean square error (RMSE) between regularized RL estimates and analytic surface Laplacian solutions. The actual EEG data were human movement-related and short-latency somatosensory-evoked potentials. The RL of these potentials was estimated over a realistically-shaped, magnetic resonance-constructed model of the subject's scalp surface. The RL estimate of the simulated potential distributions was improved with all the regularization techniques. However, the lambda correction and Tikhonov regularization techniques provided more precise Laplacian solutions than the GCV computation (P < 0.05); they also improved better than the GCV computation the spatial detail of the movement-related and short-latency somatosensory-evoked potential distributions. For both simulated and actual EEG potential distributions the Tikhonov and lambda correction techniques provided nearly equal Laplacian solutions, but the former offered the advantage that no preliminary simulation was required to regularize the RL estimate of the actual EEG data.
Adult↗
Dynamic functional coupling of high resolution EEG potentials related to unilateral internally triggered one-digit movements.
Between-electrode cross-covariances of delta (0-3 Hz)- and theta (4-7 Hz)-filtered high resolution EEG potentials related to preparation, initiation. and execution of human unilateral internally triggered one-digit movements were computed to investigate statistical dynamic coupling between these potentials. Significant (P < 0.05, Bonferroni-corrected) cross-covariances were calculated between electrodes of lateral and median scalp regions. For both delta- and theta-bandpassed potentials, covariance modeling indicated a shifting functional coupling between contralateral and ipsilateral frontal-central-parietal scalp regions and between these two regions and the median frontal-central scalp region from the preparation to the execution of the movement (P < 0.05). A maximum inward functional coupling of the contralateral with the ipsilateral frontal-central-parietal scalp region was modeled during the preparation and initiation of the movement, and a maximum outward functional coupling during the movement execution. Furthermore, for theta-bandpassed potentials, rapidly oscillating inward and outward relationships were modeled between the contralateral frontal-central-parietal scalp region and the median frontal-central scalp region across the preparation, initiation, and execution of the movement. We speculate that these cross-covariance relationships might reflect an oscillating dynamic functional coupling of primary sensorimotor and supplementary motor areas during the planning, starting, and performance of unilateral movement. The involvement of these cortical areas is supported by the observation that averaged spatially enhanced delta- and theta-bandpassed potentials were computed from the scalp regions where task-related electrical activation of primary sensorimotor areas and supplementary motor area was roughly represented.
Adult↗
Arginine butyrate downregulates p210 bcr-abl expression and induces apoptosis in chronic myelogenous leukemia cells.
Downregulation of bcr-abl expression in the chronic myelogenous leukemia cell line K562 using antisense oligonucleotides has been shown to enhance the sensitivity of the cells to apoptotic stimuli, suggesting that p210 bcr-abl, like bcl-2 functions as an anti-apoptosis factor (McGahon A et al, Blood 1994, 83: 1179). In these experiments, the inhibition of p210 bcr-abl expression alone was not sufficient to induce apoptosis. We demonstrated that exposure to low doses (0.5 mM) of a butyric acid analog, arginine butyrate, was capable of inducing apoptosis in selected leukemia cell lines, including K562 cells, and in fresh leukemia cells from patients with chronic myelogenous leukemia. To further explore the mechanisms of this effect, we examined expression of p210 bcr-abl after butyrate exposure and found a dose-related inhibition of p210 bcr-abl protein without concordant change in other phosphoproteins, including the JAK-1 kinase. Further analysis revealed that the inhibition of bcr-abl expression occurs due to transcriptional regulation of the bcr-abl gene by arginine butyrate. These results suggest that arginine butyrate and other butyrate analogs alone or in combination may be useful in the therapy of patients with chronic myelogenous leukemia or bcr-abl expressing acute leukemias.
Antineoplastic Agents↗
Responses of human primary sensorimotor and supplementary motor areas to internally triggered unilateral and simultaneous bilateral one-digit movements. A high-resolution EEG study.
We modelled the responses of human primary sensorimotor areas and supplementary motor area to simple, self-initiated unilateral and simultaneous bilateral middle finger movements using a novel high-resolution electroencephalography technology. The results support the view that these cortical motor areas are involved in parallel and present similar activity in the preparation, initiation, and execution of the contralateral and bilateral movements. Furthermore, the left primary sensorimotor area (dominant hemisphere) appears to be activated more than the right primary sensorimotor area during the preparation and performance of the ipsilateral movements.
Adult↗
Human short latency cortical responses to somatosensory stimulation. A high resolution EEG study.
Human short-latency cortical responses to median nerve stimulation were investigated with a new high resolution electroencephalography technology that markedly enhanced spatial details of somatosensory-evoked potentials (SEPs). Maximum amplitude potentials were estimated over contralateral and/or frontal-mesial scalp regions about 20, 22, 24, 26, 30, 32 and 45 ms following the stimulation. Frontal-lateral P20-N24-N30-P45 and parietal-lateral N20-P24-P30-N45 showed dipolar patterns, whereas frontal-mesial N24-N30-P45 and central-lateral P22-N26-N32-P45 presented no clearcut dipole counterpart. Plausibly, the spatially enhanced frontal-parietal SEP components were generated (tangential dipoles) within the lateral central sulcus cortex, and anticipated the central-lateral and frontal-mesial components generated (radial dipoles) from the crown of the pre- and/or post-central gyri and the supplementary motor area, respectively.
Cerebral Cortex↗
Topography of spatially enhanced human short-latency somatosensory evoked potentials.
In the present study modern high resolution electroencephalography (EEG) was used to spatially enhance human median nerve short-latency somatosensory evoked potentials (SEPs). It was shown that the spatially enhanced N30 consisted of two frontal subcomponents, one located in the frontal-lateral area of the scalp, the other located in the frontal-mesial area. Both of these subcomponents were most reduced in amplitude (or disappeared) during concomitant hand movement ipsilateral to the stimulus, but were differentially influenced by executed contralateral movement and imagined ipsilateral movement. These results support the hypothesis of an involvement of the frontal-mesial cortex (including the supplementary motor area) in the generation of the frontal N30.
Brain↗
A high resolution EEG method based on the correction of the surface Laplacian estimate for the subject's variable scalp thickness.
To improve the spatial resolution of human event-related potentials, we developed a new high resolution EEG method based on the improved estimate of the realistic surface Laplacian (SL). The novelty of this method consisted in the computation of the local scalp resistance that was assumed to be inversely proportional to the local scalp thickness measured from magnetic resonance images of the subject's head. The local scalp thickness was then multiplied by the SL estimate of the potential over a realistic magnetic resonance-constructed model of the subject's scalp surface. The new method was applied on human movement-related and somatosensory-evoked potentials, the SL estimate at a constant scalp thickness being used as a reference. The locally-predicted scalp thickness was significantly (P < 0.05) higher in the temporal areas (9.5 +/- 2.6 mm) than in the parieto-occipital (6.6 +/- 1.3 mm) and frontal (4.8 +/- 1.1 mm) areas. Compared to the SL estimate at constant scalp thickness, the improved SL estimate enhanced the spatial detail of both movement-related and somatosensory-evoked potentials.
Brain Mapping↗
High resolution EEG: a new model-dependent spatial deblurring method using a realistically-shaped MR-constructed subject's head model.
This paper presents a new model-dependent method for the spatial deblurring of scalp-recorded EEG potentials based on boundary-element and cortical imaging techniques. This model-dependent spatial deblurring (MDSD) method used MR images for the reconstruction of the subject's head model, and a layer of 364 radially-oriented equivalent current dipoles as a source model. The validation of the MDSD method was performed on simulated potential distributions generated from equivalent dipoles oriented radially, obliquely, and tangentially to the head surface. Furthermore, this method was used to localize neocortical sources of human movement-related and somatosensory-evoked potentials. It was shown that the new MDSD method improved markedly the spatial resolution of the simulated surface potentials and scalp-recorded event-related potentials. The spatial information content of the scalp-recorded EEG potentials increased progressively by increasing the spatial sampling from 28 to 128 channels. These results indicate that the new method could be satisfactorily used for high resolution EEG studies.
Brain↗
Human cortical activity related to unilateral movements. A high resolution EEG study.
In the present study a modern high resolution electroencephalography (EEG) technique was used to investigate the dynamic functional topography of human cortical activity related to simple unilateral internally triggered finger movements. The sensorimotor area (M1-S1) contralateral to the movement as well as the supplementary motor area (SMA) and to a lesser extent the ipsilateral M1-S1 were active during the preparation and execution of these movements. These findings suggest that both hemispheres may cooperate in both planning and production of simple unilateral volitional acts.
Adult↗
Spline Laplacian estimate of EEG potentials over a realistic magnetic resonance-constructed scalp surface model.
This paper presents a realistic Laplacian (RL) estimator based on a tensorial formulation of the surface Laplacian (SL) that uses the 2-D thin plate spline function to obtain a mathematical description of a realistic scalp surface. Because of this tensorial formulation, the RL does not need an orthogonal reference frame placed on the realistic scalp surface. In simulation experiments the RL was estimated with an increasing number of "electrodes" (up to 256) on a mathematical scalp model, the analytic Laplacian being used as a reference. Second and third order spherical spline Laplacian estimates were examined for comparison. Noise of increasing magnitude and spatial frequency was added to the simulated potential distributions. Movement-related potentials and somatosensory evoked potentials sampled with 128 electrodes were used to estimate the RL on a realistically shaped, MR-constructed model of the subject's scalp surface. The RL was also estimated on a mathematical spherical scalp model computed from the real scalp surface. Simulation experiments showed that the performances of the RL estimator were similar to those of the second and third order spherical spline Laplacians. Furthermore, the information content of scalp-recorded potentials was clearly better when the RL estimator computed the SL of the potential on an MR-constructed scalp surface model.
Brain Mapping↗
Performances of surface Laplacian estimators: a study of simulated and real scalp potential distributions.
This paper presents a study of the performance of various local and spherical spline methods currently in use for the surface Laplacian (SL) estimate of scalp potential distributions. The SL was estimated from simulated instantaneous event-related scalp potentials generated over a three-shell spherical head model. Laplacian estimators used planar and spherical scalp models. Noise of increasing magnitude and spatial frequency was added to the potential distributions in order to simulate noise presumed to contaminate scalp-recorded event-related potentials. A comparison of noise effects on various Laplacian estimates was made for increasing number of "electrode" positions in variants of the 10-20 system. Furthermore, to evaluate the error due to the use of unrealistic scalp models, the matching between SL estimates of human scalp-recorded movement-related potentials computed on spherical and realistically-shaped MRI-constructed models of the scalp was examined. With all methods the error of the SL estimate increased proportionally with the magnitude and spatial frequency of noise. Increased number of "electrodes" up to 256 significantly reduced the error (p < 0.05). In general, the best SL estimates were computed by second and third order splines including lambda correction, the performances of the second order spline being better with more than 64 "electrodes". Compared with spline Laplacians, the best local methods provided nearly equal estimates with low spatial sampling (19 and 28 "electrodes"), as well as high spatial frequency noise. The error of the SL estimate due to unrealistic scalp model was significant, and it augmented with increased spatial sampling from 64 to 128 electrodes.
Brain↗