Structure, bioactivity and synthesis of natural products with hexahydropyrrolo[2,3-b]indole

Research on natural products containing hexahydropyrrolo[2,3-b]indole (HPI) has dramatically increased during the past few years. Newly discovered natural products with complex structures and important biological activities have recently been isolated and synthesized. This review summarizes the structures, biological activities, and synthetic routes for natural compounds containing HPI, emphasizing the different strategies for assembling this motif. It covers a broad gamut of molecules, from small alkaloids to complex peptides

Resource recovery from sulphate-rich sewage through an innovative anaerobic-based water resource recovery facility (WRRF)

[EN] This research work proposes an innovative water resource recovery facility (WRRF) for the recovery of energy, nutrients and reclaimed water from sewage, which represents a promising approach towards enhanced circular economy scenarios. To this aim, anaerobic technology, microalgae cultivation, and membrane technology were combined in a dedicated platform. The proposed platform produces a high-quality solid- and coliform-free effluent that can be directly discharged to receiving water bodies identified as sensitive areas. Specifically, the content of organic matter, nitrogen and phosphorus in the effluent was 45 mg COD.L-1 , 14.9 mg N.L-1 and 0.5 mg P.L-1 , respectively. Harvested solar energy and carbon dioxide biofixation in the form of microalgae biomass allowed remarkable methane yields (399 STP L CH 4.kg(-1) CODinf ) to be achieved, equivalent to theoretical electricity productions of around 0.52 kWh per m 3 of wastewater entering the WRRF. Furthermore, 26.6% of total nitrogen influent load was recovered as ammonium sulphate, while nitrogen and phosphorus were recovered in the biosolids produced (650 +/- 77 mg N.L-1 and 121.0 +/- 7.2 mg P.L-1).This research was supported by the Spanish Ministry of Economy and Competitiveness (MINECO, Projects CTM2014-54980-C2-1-R and CTM2014-54980-C2-2-R) jointly with the European Regional Development Fund (ERDF), which are gratefully acknowledged. This research was also supported by the Spanish Ministry of Education, Culture and Sport via two pre-doctoral FPU fellowships (FPU14/05082 and FPU15/02595) and by the Spanish Ministry of Economy and Competitiveness via two pre-doctoral FPI fellowships (BES-2015-071884, BES-2015-073403) and one Juan de la Cierva contract (FJCI-2014-21616). The authors would also like to acknowledge the support received from Generalitat Valenciana via two VALithornd post-doctoral grants (APOSTD/2014/049 and APOSTD/2016/104) and via the fellowships APOTI/2016/059 and CPI-16-155, as well as the financial aid received from the European Climate KIC association for the 'MAB 2.0' Project (APIN0057_ 2015-3.6-230_ P066-05) and Universitat Politecnica de Valencia via a pre-doctoral FPI fellowship to the seventh author.Seco Torrecillas, A.; Aparicio Antón, SE.; Gonzalez-Camejo, J.; Jiménez Benítez, AL.; Mateo-Llosa, O.; Mora-Sánchez, JF.; Noriega-Hevia, G.... (2018). Resource recovery from sulphate-rich sewage through an innovative anaerobic-based water resource recovery facility (WRRF). Water Science & Technology. 78(9):1925-1936. https://doi.org/10.2166/wst.2018.492S19251936789Bair, R. A., Ozcan, O. O., Calabria, J. L., Dick, G. H., & Yeh, D. H. (2015). Feasibility of anaerobic membrane bioreactors (AnMBR) for onsite sanitation and resource recovery (nutrients, energy and water) in urban slums. Water Science and Technology, 72(9), 1543-1551. doi:10.2166/wst.2015.349Barat, R., Serralta, J., Ruano, M. V., Jiménez, E., Ribes, J., Seco, A., & Ferrer, J. (2013). Biological Nutrient Removal Model No. 2 (BNRM2): a general model for wastewater treatment plants. Water Science and Technology, 67(7), 1481-1489. doi:10.2166/wst.2013.004Batstone, D. J., Hülsen, T., Mehta, C. M., & Keller, J. (2015). Platforms for energy and nutrient recovery from domestic wastewater: A review. Chemosphere, 140, 2-11. doi:10.1016/j.chemosphere.2014.10.021Bilad, M. R., Arafat, H. A., & Vankelecom, I. F. J. (2014). Membrane technology in microalgae cultivation and harvesting: A review. Biotechnology Advances, 32(7), 1283-1300. doi:10.1016/j.biotechadv.2014.07.008Carrington E.-G. 2001 Evaluation of Sludge Treatments for Pathogen Reduction. http://europa.eu.int/comm/environment/pubs/home.htm.Cookney, J., Mcleod, A., Mathioudakis, V., Ncube, P., Soares, A., Jefferson, B., & McAdam, E. J. (2016). Dissolved methane recovery from anaerobic effluents using hollow fibre membrane contactors. Journal of Membrane Science, 502, 141-150. doi:10.1016/j.memsci.2015.12.037De Morais, M. G., & Costa, J. A. V. (2007). Biofixation of carbon dioxide by Spirulina sp. and Scenedesmus obliquus cultivated in a three-stage serial tubular photobioreactor. Journal of Biotechnology, 129(3), 439-445. doi:10.1016/j.jbiotec.2007.01.009Giménez, J. B., Robles, A., Carretero, L., Durán, F., Ruano, M. V., Gatti, M. N., … Seco, A. (2011). Experimental study of the anaerobic urban wastewater treatment in a submerged hollow-fibre membrane bioreactor at pilot scale. Bioresource Technology, 102(19), 8799-8806. doi:10.1016/j.biortech.2011.07.014Giménez, J. B., Martí, N., Ferrer, J., & Seco, A. (2012). Methane recovery efficiency in a submerged anaerobic membrane bioreactor (SAnMBR) treating sulphate-rich urban wastewater: Evaluation of methane losses with the effluent. Bioresource Technology, 118, 67-72. doi:10.1016/j.biortech.2012.05.019Giménez, J. B., Bouzas, A., Carrere, H., Steyer, J.-P., Ferrer, J., & Seco, A. (2018). Assessment of cross-flow filtration as microalgae harvesting technique prior to anaerobic digestion: Evaluation of biomass integrity and energy demand. Bioresource Technology, 269, 188-194. doi:10.1016/j.biortech.2018.08.052González-Camejo, J., Serna-García, R., Viruela, A., Pachés, M., Durán, F., Robles, A., … Seco, A. (2017). Short and long-term experiments on the effect of sulphide on microalgae cultivation in tertiary sewage treatment. Bioresource Technology, 244, 15-22. doi:10.1016/j.biortech.2017.07.126Martí, N., Barat, R., Seco, A., Pastor, L., & Bouzas, A. (2017). Sludge management modeling to enhance P-recovery as struvite in wastewater treatment plants. Journal of Environmental Management, 196, 340-346. doi:10.1016/j.jenvman.2016.12.074Moosbrugger R. , WentzelM. & EkamaG.1992Simple Titration Procedures to Determine H2CO3 Alkalinity and Short-chain Fatty Acids in Aqueous Solutions Containing Known Concentrations of Ammonium, Phosphate and Sulphide Weak Acid/Bases. Water. Res. Commission, Report, No. TT 57/92.Morales, N., Boehler, M., Buettner, S., Liebi, C., & Siegrist, H. (2013). Recovery of N and P from Urine by Struvite Precipitation Followed by Combined Stripping with Digester Sludge Liquid at Full Scale. Water, 5(3), 1262-1278. doi:10.3390/w5031262Pretel, R., Durán, F., Robles, A., Ruano, M. V., Ribes, J., Serralta, J., & Ferrer, J. (2015). Designing an AnMBR-based WWTP for energy recovery from urban wastewater: The role of primary settling and anaerobic digestion. Separation and Purification Technology, 156, 132-139. doi:10.1016/j.seppur.2015.09.047Pretel, R., Robles, A., Ruano, M. V., Seco, A., & Ferrer, J. (2016). Economic and environmental sustainability of submerged anaerobic MBR-based (AnMBR-based) technology as compared to aerobic-based technologies for moderate-/high-loaded urban wastewater treatment. Journal of Environmental Management, 166, 45-54. doi:10.1016/j.jenvman.2015.10.004Sharma, B., Sarkar, A., Singh, P., & Singh, R. P. (2017). Agricultural utilization of biosolids: A review on potential effects on soil and plant grown. Waste Management, 64, 117-132. doi:10.1016/j.wasman.2017.03.002Sialve, B., Bernet, N., & Bernard, O. (2009). Anaerobic digestion of microalgae as a necessary step to make microalgal biodiesel sustainable. Biotechnology Advances, 27(4), 409-416. doi:10.1016/j.biotechadv.2009.03.001Sid, S., Volant, A., Lesage, G., & Heran, M. (2017). Cost minimization in a full-scale conventional wastewater treatment plant: associated costs of biological energy consumption versus sludge production. Water Science and Technology, 76(9), 2473-2481. doi:10.2166/wst.2017.423Viruela, A., Murgui, M., Gómez-Gil, T., Durán, F., Robles, Á., Ruano, M. V., … Seco, A. (2016). Water resource recovery by means of microalgae cultivation in outdoor photobioreactors using the effluent from an anaerobic membrane bioreactor fed with pre-treated sewage. Bioresource Technology, 218, 447-454. doi:10.1016/j.biortech.2016.06.11

Maximizing resource recovery from urban wastewater through an innovative facility layout

[EN] This research work proposes an innovative layout for urban wastewater treatment based on anaerobic technology, microalgal cultivation and membrane technology. The proposed Water Resource Recovery Facility (WRRF) system can treat urban wastewater efficiently, complying with legal discharge limits and allowing for resource recovery, i.e. energy, nutrients and reclaimed water. In addition, the proposed layout produces less solid wastes than a conventional wastewater treatment plant (WWTP) and it is possible to recover energy as biogas, not only from the original wastewater sources but also from the biomass generated in the WRRF system

Síntesi total de productes marins amb l’estructura triptòfan-pirroloindole

[cat] L’estudi d’espècies marines (micro- i macroorganismes) és interessant perquè ha conduit a l’aïllament de substàncies amb una estructura química totalment diferent de les trobades en productes naturals aïllats d’organismes terrestres i a més amb una amplia gama de activitat biològica força interessant. La mayotlida és un producte natural d’origen marí aïllat per la empresa Pharmamar d’una mostra de Spongia sp. La mayotlida presenta activitat inhibidora del creixement (GI50) del ordre nanomolar. Des del punt de vista estructural, la mayotlida és un sistema octapeptídic i té la peculiaritat de la unió entre dos triptòfans (Trps), mitjançant l’enllaç entre el N indòlic d’un i el C3a de l’altre, que es troba ciclat constituint una unitat hexahidropirroloindole (HPI). Aquesta estructura triptòfan-pirroloindole ha sigut detectada, fins el moment en pocs productes naturals, i la mayotlida és el primer exemple d’un compost bis-macrocíclic amb aquest enllaç. En el capítol 1 de la memòria s’estudia la formació del sistema triptòfan-pirroloindole, per a lo qual s’ha assajat la reacció entre un Trp i un anàleg halogenat de l’HPI en diferents condicions experimentals a fi de trobar les més adients. Estàn descrites dues rutes sintètiques que condueixen a la formació de l’HPI halogenat en la posicióo 3a, conduint cadascuna a un diastereòmer distint. A més, en la formació de l’enllaç entre el C3a de l’HPI i el N indòlic del Trp, s’han escollit els grups protectors més adients i amb ortogonalitat entre ells per al creixement ordenat i selectiu del sistema Trp-HPI. En el capítol 2 s’inicia la síntesis de la mayotlida. En primer lloc, s’ha estudiat la formació de l’anell A, que és l’anell petit de la mayotlida. L’anell A és un macrocicle de tretze puntes format per tres aminoàcids: un Trp, l’HPI i l’Ile. S’han assajat tres posicions de macrociclació per a comprovar el punt idoni per tancar l’anell. S’ha determinat l’estereoquímica relativa dels estereocentres d’aquest anell mitjançant experiments de RMN mono i bidimensionals. La segona part d’aquest capítol es dedica a la formació del segon macrocicle, que anomenem anell B. S’ha sintetitzat, en fase sòlida, la cadena lineal pentapeptídica que unida als grups àcid i amina de l’anell A conduirà a l’anell B de la mayotlida. S’ha acoblat aquesta cadena amb l’anell A i s’ha realitzat la macrociclació de l’anell B per fornir la mayotlida. S’ha comparat la mayotlida sintètica amb la natural, coeluint ambdues al mateix temps. En el capítol 3 s’ha plantejat la síntesi de dos anàlegs de la mayotlida, els quals tenen la mateixa seqüència peptídica que l’anell B de la mayotlida i es diferèncien en que no tenen l’enllaç Trp-HPI, és a dir, no contenen l’anell A en la seva estructura; a més, un d’ells té un Trp enlloc de l’HPI. Endemés, s’ha assajat l’activitat de l’anell A de la mayotlida i d’un dels anàlegs sintetitzats.[eng] Marine natural products research is interesting because marine species (micro- and macroorganisms) biosynthesize compounds with different chemical structures and bioactivities from terrestrial natural products. Mayotlide is a marine natural product; it was isolated by Pharmarmar from a sample of Spongia sp. Mayotlide shows a nanomolar GI50 activity. Structurally, mayotlide is an octapeptidic system and it has the characteristic trait: the bond between Trp’s – the N-indole of a Trp and the C3a of a cycled Trp: a hexahydropyrroloindole unit (HPI). Few natural products contain this Trp-HPI system in their structures until the moment, and mayotlide is the first example of a bis-macrocyclic compound with this bond. The chapter 1 of the manuscript studies the synthesis of tryptophan-pyrroloindole system, which requires the reaction between a Trp and a halogenated HPI. Two synthetic routes have been reported to afford the halogenated HPI at C3a, each of which afford one mainly different diastereomer. In addition, the most suitable orthogonal protecting groups have been selected to allow the selective growing from the Trp-HPI system. The chapter 2 is about the beginning of the synthesis of mayotlide. First, the synthesis of the A ring has been studied, which is the small ring of mayotlide. The A ring is composed of three amino acids: Trp, Ile, and HPI. Three closing points of macrocycle have been tested. Several mono and bidimensional NMR experiments have made relative stereochemistry of stereocenters possible. The second half of this chapter is about the second macrocycle formation. The elongation of peptide chain of mayotlide has been synthesized on solid phase. Then, the couplings between the peptide chain and the A ring have been performed, affording the synthetic mayotlide. The natural and synthetic mayotlide have coeluted at the same time in a HPLC. The syntheses of two analogues of mayotlide have been studied in chapter 3. The structures of these analogues are one cycle which contain the same peptide sequence of the B ring of mayotlide; one of them has change the HPI for a Trp. In addition, the activities of the A ring and one analogue have been tested

Structure, bioactivity and synthesis of natural products with hexahydropyrrolo[2,3-b]indole

Research on natural products containing hexahydropyrrolo[2,3-b]indole (HPI) has dramatically increased during the past few years. Newly discovered natural products with complex structures and important biological activities have recently been isolated and synthesized. This review summarizes the structures, biological activities, and synthetic routes for natural compounds containing HPI, emphasizing the different strategies for assembling this motif. It covers a broad gamut of molecules, from small alkaloids to complex peptides

Orthogonal protecting groups in the synthesis of tryptophanyl-hexahydropyrroloindoles

The synthesis of various polycyclic systems containing a C3a-Ni bond between a hexahydropyrrolo[2,3-b]indole and an indole tryptophan is described here. A series of experiments were performed to determine the best combination of five orthogonal protecting groups and the best reaction conditions for formation of said bond, which is a common feature among many recently discovered marine natural products

A locked mode indicator for disruption prediction on JET and ASDEX upgrade

The aim of this paper is to present a signal processing algorithm that, applied to the raw Locked Mode signal, allows us to obtain a disruption indicator in principle exploitable on different tokamaks. A common definition of such an indicator for different machines would facilitate the development of portable systems for disruption prediction, which is becoming of increasingly importance for the next tokamak generations. Moreover, the indicator allows us to overcome some intrinsic problems in the diagnostic system such as drift and offset. The behavior of the proposed indicator as disruption predictor, based on crossing optimized thresholds of the signal amplitude, has been analyzed using data of both JET and ASDEX Upgrade experiments. A thorough analysis of the disruption prediction performance shows how the indicator is able to recover some missed and tardy detections of the raw signal. Moreover, it intervenes and corrects premature or even wrong alarms due to, e.g., drifts and/or offsets

Comparison of runaway electron generation parameters in small, medium-sized and large tokamaks - A survey of experiments in COMPASS, TCV, ASDEX-Upgrade and JET

This paper presents a survey of the experiments on runaway electrons (RE) carried out recently in frames of EUROFusion Consortium in different tokamaks: COMPASS, ASDEX-Upgrade, TCV and JET. Massive gas injection (MGI) has been used in different scenarios for RE generation in small and medium-sized tokamaks to elaborate the most efficient and reliable ones for future RE experiments. New data on RE generated at disruptions in COMPASS and ASDEX-Upgrade was collected and added to the JET database. Different accessible parameters of disruptions, such as current quench rate, conversion rate of plasma current into runaways, etc have been analysed for each tokamak and compared to JET data. It was shown, that tokamaks with larger geometrical sizes provide the wider limits for spatial and temporal variation of plasma parameters during disruptions, thus extending the parameter space for RE generation. The second part of experiments was dedicated to study of RE generation in stationary discharges in COMPASS, TCV and JET. Injection of Ne/Ar have been used to mock-up the JET MGI runaway suppression experiments. Secondary RE avalanching was identified and quantified for the first time in the TCV tokamak in RE generating discharges after massive Ne injection. Simulations of the primary RE generation and secondary avalanching dynamics in stationary discharges has demonstrated that RE current fraction created via avalanching could achieve up to 70-75% of the total plasma current in TCV. Relaxations which are reminiscent the phenomena associated to the kinetic instability driven by RE have been detected in RE discharges in TCV. Macroscopic parameters of RE dominating discharges in TCV before and after onset of the instability fit well to the empirical instability criterion, which was established in the early tokamaks and examined by results of recent numerical simulations

Real-time-capable prediction of temperature and density profiles in a tokamak using RAPTOR and a first-principle-based transport model

The RAPTOR code is a control-oriented core plasma profile simulator with various applications in control design and verification, discharge optimization and real-time plasma simulation. To date, RAPTOR was capable of simulating the evolution of poloidal flux and electron temperature using empirical transport models, and required the user to input assumptions on the other profiles and plasma parameters. We present an extension of the code to simulate the temperature evolution of both ions and electrons, as well as the particle density transport. A proof-of-principle neural-network emulation of the quasilinear gyrokinetic QuaLiKiz transport model is coupled to RAPTOR for the calculation of first-principle-based heat and particle turbulent transport. These extended capabilities are demonstrated in a simulation of a JET discharge. The multi-channel simulation requires ∼0.2 s to simulate 1 second of a JET plasma, corresponding to ∼20 energy confinement times, while predicting experimental profiles within the limits of the transport model. The transport model requires no external inputs except for the boundary condition at the top of the H-mode pedestal. This marks the first time that simultaneous, accurate predictions of Te, Tiand nehave been obtained using a first-principle-based transport code that can run in faster-than-real-time for present-day tokamaks