Potent, selective and reversible hMAO-B inhibition by benzalphthalides: Synthesis, enzymatic and cellular evaluations and virtual docking and predictive studies.

Monoaminooxidases (MAOs) are important targets for drugs used in the treatment of neurological and psychiatric disorders and particularly on Parkinson's Disease (PD). Compounds containing a trans-stilbenoid skeleton have demonstrated good selective and reversible MAO-B inhibition. Here, twenty-two (Z)-3-benzylidenephthalides (benzalphthalides, BPHs) displaying a trans-stilbenoid skeleton have been synthesised and evaluated as inhibitors of the MAO-A and MAO-B isoforms. Some BPHs have selectively inhibited MAO-B, with IC50 values ranging from sub-nM to µM. The most potent compound with IC50 = 0.6 nM was the 3',4'-dichloro-BPH 16, which showed highly selective and reversible MAO-B inhibitory activity. Furthermore, the most selective BPHs displayed a significant protection against the apoptosis, and mitochondrial toxic effects induced by 6-hydroxydopamine (6OHDA) on SH-SY5Y cells, used as a cellular model of PD. The results of virtual binding studies on the most potent compounds docked in MAO-B and MAO-A were in agreement with the potencies and selectivity indexes found experimentally. Additionally, related to toxicity risks, drug-likeness and ADME properties, the predictions found for the most relevant BPHs in this research were within those ranges established for drug candidates.

Computational Structural Revision of Elaeophorbate and Other Triterpenoids with the Help of NAPROC-13. A New Strategy for Structural Revision of Natural Products.

A considerable number of natural products have been published in recent years with misassigned structure, even though they had been correctly elucidated in the past. The availability of databases containing revised structures can prevent the amplification of errors in structural elucidation. NAPROC-13, a dereplication tool based on the 13C chemical shift, has been used to search for substances that, possessing the same chemical shifts, have been described with different structures. The correct structure of these different structural proposals is verified by computational chemistry. This paper reports the structural revision of nine triterpenoids following this methodology.

Synergistic Combination of NAPROC-13 and NMR 13C DFT Calculations: A Powerful Approach for Revising the Structure of Natural Products.

This article describes the structure revision of nine triterpenoids that have been reported corresponding to the same 13C NMR data set. In addition, 13C NMR calculation shows that some chemical shift assignments must be swapped. Our analysis improves the fit between the experimental and calculated data. Correcting misassigned structures and correctly assigning each signal is essential for elucidating new structurally related compounds. Furthermore, the ambiguity of several compounds, the structure of which differs in the literature and the Sci-Finder database, has been eliminated. Misassigned structures were found by chemical shift searches in NAPROC-13, and the results provide two or more different compounds with the same 13C NMR data. The process to determine the correct, most likely structural proposal in agreement with the experimental 13C NMR data was carried out by DFT calculations.

New Cable Delay Measurement System for VGOS Stations.

This paper presents the new cable delay measurement system (CDMS) designed at Yebes Observatory (IGN, Spain), which is required for the VLBI Global Observing System (VGOS) stations. This system measures the phase difference between the 5 MHz reference signal from the hydrogen maser and the 5 MHz signal that reaches the broadband receiver through a coaxial cable, for the generation of calibration tones. As a result, the system detects the changes in the length of that coaxial cable due to temperature variations along the cable run and flexures caused by VGOS radio telescope movements. This CDMS outperforms the previous versions: firstly, it does not require a frequency counter for phase/delay measurements; secondly, it largely reduces the use of digital circuits; hence, reducing digital noise; and thirdly, it has a remotely controlled automatic calibration subsystem. The system was tested in the laboratory and in the radio telescope, and the measurements of both set-ups are shown. These measurements include the total noise, accuracy, hysteresis, and stability. The results in the radio telescope can be correlated with the different factors that affect the cable, such as temperature and flexures. The system allows to achieve an RMS noise of less than 0.5 ps, significantly improving the requirements established in VGOS. The system is currently installed in the Red Atlántica de Estaciones Geodinámicas y Espaciales (RAEGE)Yebes VGOS 13.2 m radio telescope, and will be installed in the Norwegian Mapping Authority (NMA) twin VGOS radio telescopes, in the Finnish Geospatial Research Institute (FGI) VGOS station and in the RAEGE Santa María VGOS radio telescope (Açores, Portugal).

Synthesis of Cannabinoids: "In Water" and "On Water" Approaches: Influence of SDS Micelles.

We have proven that the biomimetic-like synthesis of cannabinoids from citral and the corresponding phenolic counterpart may well be carried out using water as a solvent. The influence of different additives such as surfactants was also analyzed. Rationalization of the reaction mode and regiochemistry of the processes were provided in terms of "on water" and "in water" reactions. The same reactions were conducted in organic media using Ga(III) salts as catalysts. Worthy of being underlined, an unprecedented formal [2+2+2] process was found to occur between two citral molecules and the corresponding phenolic species in both aqueous and organic environments. Computational studies were performed in order to gain a comprehensive mechanistic and energetic understanding of the different steps of this singular process. Finally, the influence of SDS micelles in the chemical behavior of olivetol and citral was also pursued using PGSE diffusion and NOESY NMR studies. These data permitted to tentatively propose the existence of a mixed micelle between olivetol and SDS assemblies.

A Tri-Band Cooled Receiver for Geodetic VLBI.

This paper shows a simultaneous tri-band (S: 2.2-2.7 GHz, X: 7.5-9 GHz and Ka: 28-33 GHz) low-noise cryogenic receiver for geodetic Very Long Baseline Interferometry (geo-VLBI) which has been developed at Yebes Observatory laboratories in Spain. A special feature is that the whole receiver front-end is fully coolable down to cryogenic temperatures to minimize receiver noise. It was installed in the first radio telescope of the Red Atlántica de Estaciones Geodinámicas y Espaciales (RAEGE) project, which is located in Yebes Observatory, in the frame of the VLBI Global Observing System (VGOS). After this, the receiver was borrowed by the Norwegian Mapping Autorithy (NMA) for the commissioning of two VGOS radiotelescopes in Svalbard (Norway). A second identical receiver was built for the Ishioka VGOS station of the Geospatial Information Authority (GSI) of Japan, and a third one for the second RAEGE VGOS station, located in Santa María (Açores Archipelago, Portugal). The average receiver noise temperatures are 21, 23, and 25 Kelvin and the measured antenna efficiencies are 70%, 75%, and 60% in S-band, X-band, and Ka-band, respectively.

Mimicking Halimane Synthases: Monitoring a Cascade of Cyclizations and Rearrangements from Epoxypolyprenes.

We have developed and rationalized a biomimetic transformation mimicking halimane synthases based on a Lewis acid-catalyzed cascade of cyclizations and rearrangements of epoxypolyprenes. Two rings, three stereogenic centers, and a new double bond were generated in a single chemical operation. Based on this cascade transformation, we achieved a unified strategy toward the stereoselective total syntheses of halimene-type terpenoids and analogues as a proof-of-concept study. This method has been applied to the rapid synthesis of diterpene isotuberculosinol, a virulence factor of Mycobacterium tuberculosis as a representative example.

Germacrone Derivatives as new Insecticidal and Acaricidal Compounds: A Structure-Activity Relationship.

Currently, the use of synthetic pesticides is the main method of plant protection applied in agri- and horticulture. However, its excessive use leads to the development of pesticide resistance, a contamination of the environment, toxicity to non-target organisms, and risks for human health. With the ultimate aim of contributing to the develop of a more sustainable pest management, we used the natural product germacrone (compound 1), reported to possess significant insecticidal activity, as starting material for the generation of molecular diversity (2-24). Some of the generated derivatives are natural compounds, such as 1,10-epoxygermacrone (2), 4,5-epoxygermacrone (3), gajutsulactone A (7), germacrol (11), isogermacrone (14), 9-hydroxyeudesma-3,7(11)dien-6-one (19), eudesma-4,7(11),dien-8-one (20), eudesma-3,7(11)-dien-8-one (21) and eudesma-4(15),7(11)-dien-8-one (22). Compounds, 7,11-9,10-diepoxigermacr-4,5-en-8-ol (17), 7,11-epoxieudesma-4,7(11)-dien-8-one (23) and 7,11-epoxieudesma-3,7(11)-dien-8-one (24) are described for the first time. The biocidal activity of most of these compounds was assayed against the tick Hyalomma lusitanicum. The acaricidal effects of compound 24 were four times higher than that of germacrone (1). Compound 2 is an insect antifeedant a thousand times more potent than germacrone against Rhopalosiphum padi, which makes this substance a promising selective antifeedant against this cereal pest.

Assessment of the antinociceptive and anti-inflammatory activities of the stem methanol extract of Diplotropis purpurea.

Context: Since there is still a great need to search for plant species with antinociceptive and anti-inflammatory activities, Diploptropis purpurea (Rich.) Amshoff (Fabaceae) is studied for the first time. Objective: This evaluates the analgesic and anti-inflammatory activities of the stem methanol extract of Diplotropis purpurea (MEDP). Material and methods: The anti-inflammatory and analgesic effects of MEDP of D. purpurea were evaluated in vivo. The antinociceptive activity was assessed in CD1 male mice were treated by oral gavage with 500 mg/kg of MEDP 30 min before submitting to acetic acid-induced abdominal writhing, hot-plate, and formalin tests. Paws oedema induced by carrageenan, histamine or serotonin were performed in male Sprague-Dawley rats to determinate the anti-inflammatory activity. Results: Oral administration of MEDP produced significant antinociceptive effects on the inflammatory phase in the formalin test [12.0 s versus 72.5 s in carboxymethyl cellulose (CMC) control group]. MEDP produced an analgesic effect in the hot-plate model, although the effect was modest compared to tramadol (40 and 60%, respectively). The oral administration of MEDP in a dose of 500 mg/kg showed maximum inhibition (75.1%) after 0.5 h in carrageenan-induced oedema, but it did not modify histamine or serotonin-induced oedemas. Discussion and conclusion: In the peripheral nociception model, acetic acid-induced abdominal writhing, the MEDP did not show a protective effect, but its analgesic effects were evident in the inflammatory phase of the formalin test and in the hot-plate model. These results show that the anti-inflammatory effect was accompanied by a reduction in the perception of painful stimuli.

JADOPPT: java based AutoDock preparing and processing tool.

Motivation: AutoDock is a very popular software package for docking and virtual screening. However, currently it is hard work to visualize more than one result from the virtual screening at a time. To overcome this limitation we have designed JADOPPT, a tool for automatically preparing and processing multiple ligand-protein docked poses obtained from AutoDock. It allows the simultaneous visual assessment and comparison of multiple poses through clustering methods. Moreover, it permits the representation of reference ligands with known binding modes, binding site residues, highly scoring regions for the ligand, and the calculated binding energy of the best ranked results. Availability and Implementation: JADOPPT, supplementary material (Case Studies 1 and 2) and video tutorials are available at http://visualanalytics.land/cgarcia/JADOPPT.html. Contacts: carlosgarcia@usal.es or pelaez@usal.es. Supplementary information: Supplementary data are available at Bioinformatics online.

15-Hydroxygermacranolides as Sources of Structural Diversity: Synthesis of Sesquiterpene Lactones by Cyclization and Rearrangement Reactions. Experimental and DFT Study.

A study on the electrophile-induced rearrangement of two 15-hydroxygermacranolides, salonitenolide and artemisiifolin, was carried out. These compounds underwent electrophilic intramolecular cyclizations or acid-mediated rearrangements to give sesquiterpene lactones with different skeletons such as eudesmanolides, guaianolides, amorphanolides, or other germacranolides. The cyclization that gives guaianolides can be considered a biomimetic route to this type of sesquiterpene lactones. The use of acetone as a solvent changes the reactivity of the two starting germacranolides to the acid catalysts, with a 4,15-diol acetonide being the main product obtained. The δ-amorphenolide obtained by intramolecular cyclization of this acetonide is a valuable intermediate for accessing the antimalarials artemisinin and its derivatives. Mechanistic proposals for the transformations are raised, and to provide support them, quantum chemical calculations [DFT B3LYP/6-31+G(d,p) level] were undertaken.

A DFT-Based Computational-Experimental Methodology for Synthetic Chemistry: Example of Application to the Catalytic Opening of Epoxides by Titanocene.

A novel DFT-based Reaction Kinetics (DFT-RK) simulation approach, employed in combination with real-time data from reaction monitoring instrumentation (like UV-vis, FTIR, Raman, and 2D NMR benchtop spectrometers), is shown to provide a detailed methodology for the analysis and design of complex synthetic chemistry schemes. As an example, it is applied to the opening of epoxides by titanocene in THF, a catalytic system with abundant experimental data available. Through a DFT-RK analysis of real-time IR data, we have developed a comprehensive mechanistic model that opens new perspectives to understand previous experiments. Although derived specifically from the opening of epoxides, the prediction capabilities of the model, built on elementary reactions, together with its practical side (reaction kinetics simulations of real experimental conditions) make it a useful simulation tool for the design of new experiments, as well as for the conception and development of improved versions of the reagents. From the perspective of the methodology employed, because both the computational (DFT-RK) and the experimental (spectroscopic data) components can follow the time evolution of several species simultaneously, it is expected to provide a helpful tool for the study of complex systems in synthetic chemistry.

Neoflavonoids as Inhibitors of HIV-1 Replication by Targeting the Tat and NF-κB Pathways.

Twenty-eight neoflavonoids have been prepared and evaluated in vitro against HIV-1. Antiviral activity was assessed on MT-2 cells infected with viral clones carrying the luciferase reporter gene. Inhibition of HIV transcription and Tat function were tested on cells stably transfected with the HIV-LTR and Tat protein. Seven 4-phenylchromen-2-one derivatives showed HIV transcriptional inhibitory activity but only the phenylchrome-2-one 10 inhibited NF-κB and displayed anti-Tat activity simultaneously. Compounds 10, 14, and 25, inhibited HIV replication in both targets at concentrations <25 µM. The assays of these synthetic 4-phenylchromen-2-ones may aid in the investigation of some aspects of the anti-HIV activity of such compounds and could serve as a scaffold for designing better anti-HIV compounds, which may lead to a potential anti-HIV therapeutic drug.

Uprolides N, O and P from the Panamanian Octocoral Eunicea succinea.

Three new diterpenes, uprolide N (1), uprolide O (2), uprolide P (3) and a known one, dolabellane (4), were isolated from the CH2Cl2-MeOH extract of the gorgonian octocoral Eunicea succinea, collected from Bocas del Toro, on the Caribbean coast of Panama. Their structures were determined using spectroscopic analyses, including 1D and 2D NMR and high-resolution mass spectrometry (HRMS) together with molecular modeling studies. Compounds 1-3 displayed anti-inflammatory properties by inhibiting production of Tumor Necrosis Factor (TNF) and Interleukin (IL)-6 induced by lipopolysaccharide (LPS) in murine macrophages.

Hirschsprung disease with debut in adult age as acute intestinal obstruction: case report.

Hirschsprung's disease is characterized by absence of ganglion cells in submucosal and myenteric plexus of distal bowel. Most cases become manifest during the neonatal period, but in rare instances, this disease is initially diagnosed in adult age. It usually presents as severe constipation with colonic dilatation proximal to the aganglionic segment. The treatment is surgical, removing the aganglionic segment and restoring continuity of digestive tract. The disease rarely presents as an acute intestinal obstruction. We report a case not previously diagnosed, which presented as a massive colonic dilatation with a maximum diameter of 44 cm, with imminent risk of drilling that forced to perform an emergency surgery. We include a review of existing literature.

Homocoupling versus reduction of radicals: an experimental and theoretical study of Ti(III)-mediated deoxygenation of activated alcohols.

A detailed experimental and theoretical study corroborates that the reductive deoxygenation of activated (allylic or benzylic) alcohols with excess Ti(III) proceeds via an allyl(benzyl)-radical and allyl(benzyl)-Ti, which is protonated, regioselectively in the case of allylic derivatives. The H atom of the newly formed C-H bond in the product originates from the -OH group of the starting material. The deoxygenation of lithium alkoxides or alcohols by using 1.0 mol of Ti(III) leads to the corresponding dimerization products in good yields. An excellent agreement with the experimental data was obtained by using a reaction kinetics simulator to discriminate between competing reactions.

Molecular Diversity from Longipinenes of Santolina viscosa Lag. through Acid Catalysis: Biocidal Activity.

The search for new compounds with biocidal potential was carried out, focusing on the longipinenes 1-7 from the plant species Santolina viscosa Lag. Compounds 1, 2, and 5 showed remarkable molecular diversity when treated in acidic reaction conditions. Protonic, Lewis, and heterogeneous compounds were used in the treatment. Three main models of reaction have been observed: isomerization of the double bond (8-10); rearrangements to longibornane-based skeleton (11-15) and ring-opening to himachalane-based skeleton (16-18). Secolongibornane aldehydes 23 and 24 were obtained after epoxide opening under the same reaction conditions. The elucidation of the structures of the new compounds was carried out using spectroscopic data and was supported by computational theoretical calculations of 13C NMR spectra. Additionally, high-resolution mass spectrometry and single-crystal X-ray diffraction analysis were employed for certain compounds. Natural longipinenes 4-7, methyl esters 1-3 of corresponding natural carboxylic acids and the isomerized and derivatives compounds 8-19 exhibit moderate to high insecticidal activity against R. padi and M. persicae insects. Longipinene 5 shows potent inhibition against the root growth of the plants L. perenne and L. sativa, as well as compound 2 on the leaves of L. perenne. Furthermore, significant ixocidal and nematicidal activity was found for this latter compound.

Structural diversity from the transannular cyclizations of natural germacrone and epoxy derivatives: a theoretical-experimental study.

Treatment of germacrone (1) with different electrophiles, and of its epoxy derivatives germacrone-4,5-epoxide (2), germacrone-1,10-epoxide (3) and isogermacrone-4,5-epoxide (4) with Brönsted/Lewis acids and Ti(III), gives rise to a great structural diversity. Thus, by using a maximum of two steps, the production of more than 40 compounds corresponding to 14 skeletons is described. Computational calculations rationalizing the structural divergence produced are also described. Finally, since some of the compounds generated are bioactive natural sesquiterpenes, the mechanisms of formation of these substances will provide new insights in their biosynthesis.

Synthesis, bioevaluation and structural study of substituted phthalazin-1(2H)-ones acting as antifungal agents.

Twenty-five polysubstituted phthalazinone derivatives were synthesized and tested for their antifungal activity against a panel of pathogenic and clinically important yeasts and filamentous fungi. Among them, the compound 4-(4-chlorobenzyl)-2-methylphthalazin-1(2H)-one (5) exhibited a remarkable antifungal activity against standardised strains of dermatophytes and Cryptococcus neoformans, as well as against some clinical isolates. A physicochemical study performed on compound 5 revealed its conformational and electronic characteristics, providing us with useful data for the future design of novel related antifungal analogues.

Analgesic and anti-inflammatory activity of podophyllotoxin derivatives.

CONTEXT: Podophyllotoxin is a natural product that inhibits the polymerization of tubulin and has served as a prototype for the development of diverse antitumor agents in clinical use, such as etoposide, teniposide and etopophos. Reumacon, another semisynthetic derivative, reached its clinical phase for the treatment of rheumatoid arthritis. OBJECTIVE: This study investigated the analgesic and anti-inflammatory properties of three compound derivatives from podophyllotoxin. MATERIALS AND METHODS: During a phytochemical study performed on Juniperus thurifera Linne (Cupressaceae) leaves, among other products, several cyclolignans, such as podophyllotoxin, deoxypodophyllotoxin, deoxypicropodophyllotoxin and thuriferic acid were isolated. These compounds, obtained afterwards through semisynthesis, were assayed as analgesic and anti-inflammatory agents. Additionally, the cytotoxic activity of thuriferic acid was evaluated in three cancer cell lines, P-388, A-549 and HT-29, and these data were compared with previous cytotoxicity results obtained for the other three compounds. RESULTS: Analgesic activity results showed that deoxypicropodophyllin is as effective as deoxypodophyllotoxin to inhibit nociceptive perception induced by acetic acid in mice (77.8% ± 4.1% and 71.3% ± 6.5%, respectively), while its cytotoxicity [1.01 × 10(-7) (GI50 M)] is 100-fold less. Other set of experiments showed that thuriferic acid, a derivative of podophyllotoxin a thousand times less citotoxic [1.21 × 10(-5) (GI50 M)] than deoxypodophyllotoxin, caused significant inhibition of paw edema development in the carrageenan-induced inflammation test (63.4% ± 3.3%), effect comparable to those of deoxypodophyllotoxin (66.3% ± 4.4%), and the standard drug indomethacin (61.5% ± 2.5%). CONCLUSION: We conclude that deoxypicropodophyllotoxin and thuriferic acid are effective in reducing edema formation. However, deoxypicropodophyllin is more related with analgesic activity than anti-inflammatory effect.