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A long series of Michael acceptors are studied computationally as potential alternatives to the maleimides that are used in most antibody-drug conjugates to link Cys of mAbs with cytotoxic drugs. The products of the reaction of methanethiol (CH3SH/MeSH, as a simple model of Cys) with N-methylated ethynesulfonamide, 2-ethynylpyridinium ion, propynamide, and methyl ethynephosphonamidate (that is, with HC≡C-EWG) are predicted by the M06-2X/6-311+G(d,p) method to be thermodynamically more stable, in relation to their precursors, than that of MeSH with N-methylmaleimide and, in general, with H2C═CH-EWG; calculations with AcCysOMe and tBuSH are also included. However, for the addition of the anion (MeS-), which is the reactive species, the order changes and N-methylated 2-vinylpyridinium ion, 2,3-butadienamide, and maleimide may give more easily the anionic adducts than several activated triple bonds; moreover, the calculated ΔG⧧ values increase following the order HC≡C-SO2NHMe, N-methylmaleimide, HC≡C-PO(OMe)NHMe, and HC≡C-CONHMe. In other words, MeS- is predicted to react more rapidly with maleimides than with ethynephosphonamidates and with propynamides, in agreement with the experimental results. New mechanistic details are disclosed regarding the advantageous use of some amides, especially of ethynesulfonamides, which, however, are more prone to double additions and exchange reactions.

Amides from indole-3-glyoxylic acid and 4-benzoyl-2-methylpiperazine, which are related to entry inhibitors developed by Bristol-Myers Squibb (BMS), have been synthesized with aliphatic chains located at the C7 position of the indole ring. These spacers contain an azido group suitable for the well-known Cu(I)-catalyzed (3+2)-cycloaddition or an activated triple bond for the nucleophilic addition of thiols under physiological conditions. Reaction with polyols (β-cyclodextrin and hyperbranched polyglycerol) decorated with complementary click partners has afforded polyol-BMS-like conjugates that are not cytotoxic (TZM.bl cells) and retain the activity against R5-HIV-1

Amides from indole-3-glyoxylic acid and 4 - benzoyl-2-methyl-piperazine, which are related to entry inhibitors developed by Bristol-Myers Squibb (BMS), have been synthesized with aliphatic chains located at the C7 position of the indole ring. These spacers contain an azido group suitable for the well-known Cu(I)-catalyzed (3+2)-cycloaddition or an activated triple bond for the less known nucleophilic addition of thiols under physiological conditions. Reaction with polyols (β-cyclodextrin and hyperbranched polyglycerol) decorated with complementary click partners has afforded polyol-BMS-like conjugates that are not cytotoxic (TZM.bl cells) and retain the activity against R5-HIV-1 NLAD8 isolates. Thus, potential vaginal microbicides based on entry inhibitors, which can be called of 4th generation, are reported here for the first time.

We have developed a conjugation reaction based on the thia-Michael addition to activated triple bonds, which can be an alternative to maleimides, the most commonly used reagents to link thiol groups (of Cys) to drugs and labels. An amino group is converted into its propynamide and, in aqueous media at 37 °C and pH 7.4, Cys derivatives are added. The oxopropene-1,3-diyl linker is formed with excellent Z selectivity without secondary reactions. No exchange with other thiols is observed.

Amphidinolides and iriomoteolides are complex macrolides isolated from cultured marinedinoflagellates of the genus Amphidinium sp. [1−4]. [...]

Background The availability of a species-specific reference material is essential for the harmonization of results obtained in different laboratories by different methods. Objectives We describe the preparation of a canine C-reactive protein (cCRP) serum reference material containing purified cCRP stabilized in a serum matrix. The material can be used by manufacturers to assign values to their calibrator and control materials. Methods The serum matrix was obtained using blood collected from healthy dogs, stabilized and submitted for a delipidation process. The reference material was prepared by diluting purified cCRP in the serum matrix containing 1.0 mol/L HEPES buffer, 3.0 mmol/L calcium chloride, 80,000 kUI/L aprotinin, and 1.0 mmol/L benzamidine hydrochloride monohydrate at a pH of 7.2, and dispensing (0.5 mL) the matrix into vials that were then frozen. Results The pilot batch of 200 vials was shown to be homogeneous and stable after a stability study at various temperatures and over a total time of 110 days. The prepared material was submitted to an assignment value study. Eight laboratories from different European countries participated by using the same reagents for an immunoturbidimetric method adapted for different analyzers. The obtained cCRP concentration in the reference material was 78.5 mg/L with an expanded uncertainty (k = 2) of 4.2 mg/L. Conclusions Canine C-reactive protein serum reference material has been produced that allows harmonization of results obtained by different methods and different laboratories, thus reducing the possibility of errors and misunderstandings.

Coordinació: Lluís Bosch i Mireia Freixa, [eng] The I coupDefouet International Congress was held in June 2013 to celebrate the tenth anniversary of coupDefouet, the magazine of the Art Nouveau European Route, an association of municipalities and other entities to promote and disseminate Modernista or Art Nouveau heritage. Its success and excellent scientific results led to its continuity with a second congress, held in 2015, whose acts are presented in this volume of Singularities. The congresses are organised by the Urban Landscape Institute (IMPUiQV) of the Barcelona City Council in partnership with GRACMON, a consolidated research group of the University of Barcelona., [cat] El primer Congrés Internacional coupDefouet se celebrà el juny de l’any 2013 per commemorar els deu anys de l’aparició de coupDefouet, la revista de la Ruta Europea del Modernisme, una associació de municipis i altres entitats per a la promoció i la difusió del patrimoni modernista o Art Nouveau. Gràcies a l’èxit i als bons resultats científics es va apostar per la seva continuïtat amb un segon congrés que tingué lloc el 2015, les actes del qual presentem en aquest volum de Singularitats. Aquestes jornades estan organitzades per l’Institut Municipal del Paisatge Urbà i la Qualitat de Vida de l’Ajuntament de Barcelona, amb la col·laboració de GRACMON, grup de recerca consolidat de la Universitat de Barcelona.

A formal total synthesis of the cytotoxic macrolide amphidinolide E is reported. The strategic steps are three Julia-Kocienski reactions (J-K), for the formation of the C5-C6, C9-C10, and C17-C18 double bonds, a Suzuki-Molander C21-C22 bond formation reaction, and a Kita-Trost macrolactonization. The 'instability' of the two dienic systems and of the stereocenter at C2 (allylic methine, alpha to the carboxy group) and the protecting groups at C17-OH and C18-OH have posed difficult challenges. Each Julia-Kocienski olefination has been systematically optimized to provide the highest possible E/Z ratios.

The use of the 2-(4-methylphenylsulfonyl)ethenyl (tosvinyl, Tsv) group for the protection of the NH group of a series of imides, azinones (including AZT), inosines, and cyclic sulfonamides has been examined. The Tsv-protected derivatives are obtained in excellent yields by conjugate addition to tosylacetylene (ethynyl p-tolyl sulfone). The stereochemistry of the double bond can be controlled at will: with only 1 mol % of Et3N or with catalytic amounts of NaH, the Z stereoisomers are generated almost exclusively, while the E isomers are obtained using a stoichiometric amount of DMAP. Analogous phenylsulfonylvinyl-protected groups (with the besvinyl or Bsv group instead of Tsv) are obtained stereospecifically by reaction with (Z)- or (E)-bis(phenylsulfonyl)ethene. For lactams and oxazolidinones, this last method is much better. The Tsv and Bsv groups are stable in the presence of non-nucleophilic bases and to acids. They can be removed highly effectively via a conjugate addition-elimination mechanism using pyrrolidine or sodium dodecanethiolate as nucleophiles.

The use of the 2-(4-methylphenylsulfonyl)ethenyl (tosvinyl, Tsv) group for the protection of the NH group of a series of imides, azinones (including AZT), inosines, and cyclic sulfonamides has been examined. The Tsv-protected derivatives are obtained in excellent yields by conjugate addition to tosylacetylene (ethynyl p-tolyl sulfone). The stereochemistry of the double bond can be controlled at will: with only 1 mol % of Et3N or with catalytic amounts of NaH, the Z stereoisomers are generated almost exclusively, while the E isomers are obtained using a stoichiometric amount of DMAP. Analogous phenylsulfonylvinyl-protected groups (with the besvinyl or Bsv group instead of Tsv) are obtained stereospecifically by reaction with (Z)- or (E)-bis(phenylsulfonyl)ethene. For lactams and oxazolidinones, this last method is much better. The Tsv and Bsv groups are stable in the presence of non-nucleophilic bases and to acids. They can be removed highly effectively via a conjugate addition-elimination mechanism using pyrrolidine or sodium dodecanethiolate as nucleophiles.

Additions of lactams, imides, (S)-4-benzyl-1,3-oxazolidin-2-one, 2-pyridone, pyrimidine-2,4-diones (AZT derivatives), or inosines to the electron-deficient triple bonds of methyl propynoate, tert-butyl propynoate, 3-butyn-2-one, N-propynoylmorpholine, or N-methoxy-N-methylpropynamide in the presence of many potential catalysts were examined. DABCO and, second, DMAP appeared to be the best (highest reaction rates and E/Z ratios), while RuCl3, RuClCp*(PPh3)2, AuCl, AuCl(PPh3), CuI, and Cu2(OTf)2 were incapable of catalyzing such additions. The groups incorporated (for example, the 2-(methoxycarbonyl)ethenyl group that we name MocVinyl) serve as protecting groups for the above-mentioned heterocyclic CONH or CONHCO moieties. Deprotections were accomplished via exchange with good nucleophiles: the 1-dodecanethiolate anion turned out to be the most general and efficient reagent, but in some particular cases other nucleophiles also worked (e.g., MocVinyl-inosines can be cleaved with succinimide anion). Some structural and mechanistic details have been accounted for with the help of DFT and MP2 calculations.

Pd-catalysed reactions of 2-Cl, 2-Br and 2-I derivatives of a 6-chloropurine nucleoside with benzamide have been compared, using Pd 2 dba 3 , Xantphos and Cs 2 CO 3 in toluene, between 20 and 80!C. The reactivity order was 2-I > 2-Br > 6-Cl!2-Cl. The 2-I substituent could be replaced even at 0!C, under conditions disclosed here for the first time. On the other hand, the replacement of the chlorine atom at position 2 (2Cl) required 110!C.

N3 of thymidine and of 3′-azido-3′-deoxythymidine (AZT) has been linked to a tetrazole ring by condensation of nucleoside-derived 2-oxonitriles with the lithium salt of 5-acetyl-1-(4-fluorobenzyl)tetrazole (obtained by a 'click' reaction). 4-Acetyl-1,2,3-triazole, also prepared by a Cu-catalysed cycloaddition, has been similarly linked. A route for the conjugation of NRTIs with pharmacophoric elements of integrase inhibitors (INIs) has thus been disclosed.

N-Hydroxy-4-oxoquinazoline-2-carboxamide derivatives (cyclic hydroxamic acids) and related pyrido- and thieno-substituted analogues, as well as a N-hydroxyhypoxanthine-2-carboxamide were synthesised for the first time, by means of a four-step sequence that involves a smooth reaction of aminohydroxamates with methyl trimethoxyacetate. Other strategies were unsuccessful.

Recent data suggest that statins block HIV-1 replication, which may have important implications for an alternative treatment for AIDS. We tested different statins in cell culture against HIV and conducted a pilot study in HIV-positive patients receiving simvastatin. No anti-HIV activity was detected at subtoxic concentrations and simvastatin did not induce a significant change in the mean viral load or CD4 cell count in study patients. We caution on the use of statins as antiretroviral agents.

The paper aims to describe the results of the on-going EU founded research titled “PEDRERA Positive energy districts renovation model” which scope is to design a tool able to support smart district renovation programmes. The key goal of the model is to facilitate the multiplestakeholders’engagementinlarge- scale renovation actions according a Positive Energy District (PED) vision, and to predict the sustainability and positive outcomes of distinct renovation scenarios. One of the main barriers to reach this goal is the lack of integration of disaggregated information coming from heterogeneous data sources. The PEDRERA model means to build trust in the business opportunities by allowing better support to decision-making and impact assessment in order to understand and manage both the complexity of financing renewal processes at district scale and the interests of each stakeholder. The paper addresses these challenges and will examine how data sources from different domains could be adopted in PED design once the information is aggregated, systematized and addressed to specific key performance indicators. Furthermore, the customized model will run data through a special wizard able to filter input data which are displayed and shared on a GIS platform. According to this approach, the novel tool will be able to (1) guide and support the entire retrofit process according different issues, (2) meet the most relevant requirements from each stakeholder by prioritizing and designing energy efficient measures based on a reliable business model, and (3) help on willing sustainable energy communities to come.

El Congrés Internacional coupDefouet Barcelona 2013 ha estat una iniciativa de l'Art Nouveau European Route – Ruta Europea del Modernisme, organitzada per l'Institut del Paisatge Urbà de l'Ajuntament de Barcelona i el grup de recerca GRACMON de la Universitat de Barcelona, Coordinació: Lluís Bosch, Mireia Freixa., [eng] In 2013 the magazine coupDefouet reached its first decade of existence. As a way of celebrating this, the Art Nouveau European Route – the association of cities and other local institutions for the promotion and diffusion of Art Nouveau heritage that created the magazine – organised a magnificent international congress as a framework for scientific exchange and raising public awareness. The first coupDefouet International Congress on Art Nouveau was held in Barcelona, the city from which coupDefouet is published and one of the undisputable world capitals of Art Nouveau. This volume of the Singularitats series comprises the proceedings of that event., [cat] L’any 2013 va fer deu anys de l’aparició de coupDefouet, la revista de la Ruta Europea del Modernisme, una associació de municipis i altres entitats locals per a la promoció i la difusió del patrimoni modernista o Art Nouveau. Per commemorar-ho, s’organitzà un congrés internacional amb l’objectiu de contribuir al coneixement científic i la difusió d’aquest moviment artístic. El primer Congrés Internacional coupDefouet se celebrà a Barcelona, la ciutat en què s’edita coupDefouet i una de les capitals indiscutibles de l’Art Nouveau. En aquest volum de Singularitats s’apleguen les actes d’aquell esdeveniment.