1 a 20 de 49
Csonka A, Kincses A, Nové M, Vadas Z, Sanmartín C., Domínguez-Álvarez E, Spengler G
Anticancer Research, vol. 39, nº 7, pags. 3777 - 3783 (2019)
Article preview
Background/Aim: Selenium-containing compounds are becoming new alternatives in experimental chemotherapy in order to overcome multidrug resistance in cancer. The main goal of this study was to determine whether combined treatment with new Se-compounds would increase the effect of conventional doxorubicin chemotherapy in breast cancer cell lines. Materials and Methods: Se-compounds were evaluated regarding their cytotoxic and apoptosis-inducing effect on MCF-7 and ATP-binding cassette subfamily B member 1 (ABCB1)-overexpressing KCR breast cancer cell lines. Moreover, the interaction of Se-compounds with doxorubicin was assessed using the MTT assay. Results: Selenoanhydride exerted a selective activity towards the doxorubicin-resistant KCR cell line overexpressing ABCB1. Among the selenoesters, only ketone-containing selenoesters exerted significant cytotoxic activity against MCF-7 and KCR cell lines and the Se-compounds acted synergistically with doxorubicin on the KCR cell line. Conclusion: The importance of the COSeCH2COCH3 and COSeCH2CO(CH3)3 moieties for the cytotoxic and adjuvant role of Se-compounds was highlighted. © 2019 International Institute of Anticancer Research. All rights reserved.
de los Ríos C, Marco-Contelles J.
European Journal of Medicinal Chemistry, pags. 381 - 389 (2019)
Article preview
Tacrine was the first drug approved for the treatment of Alzheimer's disease (AD) in 1993, which was withdrawn in 2013 due to its hepatotoxicity. However, new, non-hepatotoxic tacrine derivatives have been constantly searched for. In this context, since 1997, we have prepared a number of diversely functionalized tacrines by changing the benzene ring present in tacrine to five- or six-membered aromatic ring cores that could present anticholinesterasic activity and additional pharmacological properties. The new compounds were designed as juxtaposed structures between tacrine and the well-known Ca 2+ antagonists 1,4-dihydropyridines, with the goal of obtaining multi-target directed ligands for AD. In this account, we present our results on the PyridoTacrine (PyrTac) family of tacrine analogues, resulting from the substitution of the benzene ring by a pyridine. We highlight their pharmacological profile and review similar analogues in the literature. A first set of PyrTac showed inhibitory activity of cholinesterases (ChE) and a blocking profile of voltage-gated Ca 2+ channels (VGCC). A second family with improved ChE inhibition lost VGCC blocking activity. However, the lead compound of this family (5f) presented an activating profile of the phosphatase 2A (PP2A) and showed interesting outcomes in experimental in vivo models of AD and stroke. We have identified the PyrTac ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b] [1,8]naphthyridine-3-carboxylate (5f), which presents additional pharmacological properties beyond the mere cholinergic improvement. These new properties warrant attention to 5f and its further development as a new potential therapeutic agent for AD therapy. © 2019 Elsevier Masson SAS
González-Gaya B, Martínez-Varela A, Vila-Costa M, Casal P, Cerro-Gálvez E, Berrojalbiz N, Lundin D, Vidal M, Mompeán C, Bode A, Jiménez B., Dachs J.
Nature Geoscience, vol. 12, nº 2, pags. 119 - 125 (2019)
Article preview
Atmospheric deposition of semivolatile aromatic hydrocarbons accounts for an important input of organic matter to the surface ocean. Nevertheless, the biogeochemical cycling and sinks of semivolatile aromatic hydrocarbons in the ocean remain largely uncharacterized. Here we present measurements of 64 polycyclic aromatic hydrocarbons in plankton and seawater from the Atlantic, Pacific, Indian and Southern Oceans, as well an assessment of their microbial degradation genes. Concentrations of the more hydrophobic compounds decreased when the plankton biomass was higher, consistent with the relevance of the biological pump. The mass balance for the global oceans showed that the settling fluxes of aromatic hydrocarbons in the water column were two orders of magnitude lower than the atmospheric deposition fluxes. This imbalance was high for low molecular weight hydrocarbons, such as phenanthrene and methylphenanthrenes, highly abundant in the dissolved phase. Parent polycyclic aromatic hydrocarbons were depleted to a higher degree than alkylated polycyclic aromatic hydrocarbons, and the degradation genes for polycyclic aromatic hydrocarbons were found to be ubiquitous in oceanic metagenomes. These observations point to a key role of biodegradation in depleting the bioavailable dissolved hydrocarbons and to the microbial degradation of atmospheric inputs of organic matter as a relevant process for the marine carbon cycle. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.
Bartalini A, Muñoz-Arnanz J, Marsili L, Mazzariol S, Fossi M.C, Jiménez B.
Science of the Total Environment, vol. 653, pags. 1417 - 1425 (2019)
Article preview
Numerous studies to date have reported concentrations of Persistent Organic Pollutants (POPs) in different marine mammal species worldwide. Yet data on sperm whales are scarce from rich and unique biodiverse areas such as the Mediterranean Sea. This work aimed to assess levels of dioxin-like polychlorinated biphenyls (dl-PCBs), polybrominated diphenyl ethers (PBDEs), and polychlorodibenzo-p-dioxins and furans (PCDD/Fs) in blubber of sperm whales stranded along the Italian coast between 2008 and 2016. POP mean concentrations (dl-PCBs: 6410 ng/g l.w.; PBDEs: 612 ng/g l.w.; PCDD/Fs: 57.8 pg/g l.w.) were mostly in line with what has been previously reported on the same species in the Mediterranean environment and tended to be higher than those reported from other geographical regions. The relative abundance followed the order dl-PCBs > PBDEs ≫ PCDD/Fs. Interestingly, the non-ortho dl-PCB pattern (126 > 169 > 77) was similar to that described in other studies worldwide and different from what is described in its main prey. This could be linked to particular metabolic activities in sperm whales against these highly toxic contaminants. Total TEQs ranged from 275 to 987 pg/g l.w. and showed the pattern Σnon-ortho-dl-PCBs > Σortho-dl-PCBs > PCDDs > PCDFs, with PCBs’ contribution about 96\%. These findings highlight the high abundance of PCBs still found in the Mediterranean environment despite having been banned for decades. All sperm whales analyzed in this study surpassed the threshold of 210 pg WHO-TEQ/g l.w. proposed as starting point of immunosuppression in harbour seals; a level of contamination that may have contributed to an impairment of their immune system. © 2018
Dgachi Y, Martin H, Malek R, Jun D, Janockova J, Sepsova V, Soukup O, Iriepa I, Moraleda I, Maalej E, Carreiras M.C, Refouvelet B, Chabchoub F, Marco-Contelles J., Ismaili L.
Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 34, nº 1, pags. 163 - 170 (2019)
Article preview
In view of the multifactorial nature of Alzheimer’s disease (AD), multitarget small molecules (MTSM) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer’s disease therapy. The new MTSM KojoTacrines (KTs) were designed and synthesized by juxtaposition of selected pharmacophoric motifs from kojic acid and tacrine. Among them, 11-amino-2-(hydroxymethyl)-12-(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano [2',3':5,6] pyrano[2,3-b]quinolin-4(8H)-one (KT2d) was identified as less-hepatotoxic than tacrine, at higher concentration, a moderate, but selective human acetylcholinesterase inhibitor (IC 50 = 4.52 ± 0.24 µM), as well as an antioxidant agent (TE = 4.79) showing significant neuroprotection against Aβ 1–40 at 3 µM and 10 µM concentrations. Consequently, KT2d is a potential new hit-ligand for AD therapy for further biological exploration. © 2019, © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Megías-Pérez R, Ruiz-Matute A.I, Corno M, Kuhnert N.
Journal of Chromatography A, vol. 1584, pags. 135 - 143 (2019)
Article preview
The low molecular weight carbohydrate (LMWC) profile of cocoa beans has recently been studied using hydrophilic interaction liquid chromatography coupled to electrospray ionization-time of flight mass spectrometry (HILIC-ESI-TOF MS) and HILIC-ESI-tandem mass spectrometry (HILIC-ESI-MSn). However, different LMWC could not be unambiguously identified. Thus, as a first approach in this paper, gas chromatography coupled to mass spectrometry (GC–MS) was used as a complementary analytical technique to characterize LMWC of cocoa beans. Different mono-, di-, tri- and tetrasaccharides, as well as myo-inositol, galactinol and a diglycosil glycerol were detected. scyllo-Inositol, 1-kestose and 6-kestose were identified in unfermented cocoa beans for the first time. Moreover, other minor LMWC were tentatively assigned as fructosyl-fructose, fructosyl-glucose and glucosyl-sucrose. As a second step, in order to evaluate new possible indicators of cocoa bean origin or fermentation status, scyllo-inositol, 1-kestose and galactinol were selected as target compounds and a HILIC-ESI-TOF MS method was optimized for their analysis. The optimized conditions, using an acetonitrile:water gradient with 0.05\% ammonium hydroxide at 40 °C showed narrow peaks (wh: 0.3-0.5 min) with good resolution values (Rs: 0.83–2.83). The validated HILIC-ESI-TOF MS method was applied to the analysis of 35 cocoa bean samples from different origins and fermentation status. The content of scyllo-inositol, 1-kestose and galactinol in unfermented beans (n = 21) was in the range of traces-504.9, 36.1–133.5 and traces-1970.4 μg g−1 cocoa DM respectively. In fermented beans (n = 14), the content of scyllo-inositol and 1-kestose was in the range of 15.5–491.9 and traces-115.5 μg g−1 cocoa DM respectively. Galactinol was absent in fermented beans, indicating that it could be a potential indicator of fermentation status. The methodology proposed could be used for quality control of natural products and other food ingredients containing inositols and oligosaccharides. © 2018
Carrero-Carralero C, Escobar-Arnanz J, Ros M, Jiménez-Falcao S, Sanz M.L, Ramos L.
Talanta, vol. 195, pags. 800 - 806 (2019)
Article preview
This study reports on the potential of comprehensive two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GC×GC−ToF MS) for the exhaustive untargeted characterization of the volatile and semi-volatile analytes migrating from four commercial polypropylene food containers into four simulants (water, 3\% acetic acid, 10\% ethanol, and isooctane) according to European Regulation 10/2011. Collected extracts were concentrated and directly subjected to GC×GC−ToF MS analysis without any further treatment to preserve migrants integrity. As expected, the nature and total number of compounds detected in the migrates depended on both the brand (i.e., manufacture and/or sterilization procedure) and the simulant applied. In total, 107 analytes, including some less volatile compounds, were either positively or tentatively identified in the investigated simulants, a number of these compounds being reported for the first time as migrants from this type of material. A database containing chromatographic, mass spectral and partition information concerning these compounds, plus 23 remaining unidentified, is provided. © 2018 Elsevier B.V.
Martínez C, Roscales J.L, Sanz-Aguilar A, González-Solís J.
Ardeola, vol. 66, nº 1, pags. 13 - 32 (2019)
Article preview
Bird migration studies have been given added impetus recently thanks to the miniaturisation of tracking devices. However, tracking methodologies have remained impractical for the smallest pelagic species and so important gaps in knowledge still exist. In the case of the European Storm-petrel Hydrobates pelagicus, while Atlantic populations are thought to overwinter along the south-western African coast, the winter quarters of Mediterranean birds remain more enigmatic. We performed stable isotope analysis (SIA) of C and N on P1, S8 and P10 feathers from 33 adult birds captured in three Atlantic colonies and 156 adult birds in seven western Mediterranean colonies to infer their wintering areas. In addition, we collated all observational field data, both from peer-reviewed publications and the wider literature, to complement our inferences from SIA. Within the Atlantic, isotopic profiles of feathers moulted at the breeding grounds (P1) differed between birds captured at northern Atlantic and Canary Islands colonies, but were similar for feathers moulted in winter quarters (S8 and P10), indicating low migratory connectivity. Isotopic values of feathers from western Mediterranean birds differed from those of Atlantic birds and showed Mediterranean values for all feathers, indicating that the former overwinter in Mediterranean waters. Variance in the isotopic values was greater in winter than in breeding season feathers, suggesting that birds disperse over larger areas in winter. Isotopic values of feathers moulted during the non-breeding period could match a post-breeding movement towards the southern and eastern Mediterranean. This inference matches the distribution of the few winter reports, which are mainly concentrated in the south-central Mediterranean, mostly in the Tunisian Platform. Our results suggest that this region is the principal wintering area of Mediterranean Storm-petrels.-Martínez, C., Roscales, J.L., Sanz-Aguilar, A. & González-Solís, J. (2019). Inferring the wintering distribution of the Mediterranean populations of European Storm-petrels Hydrobates pelagicus melitensis from stable isotope analysis and observational field data. © 2019 SEO/ Birdlife. All rights reserved.
Benchekroun M, Pachón-Angona I, Luzet V, Martin H, Oset-Gasque M.J, Marco-Contelles J., Ismaili L.
Bioorganic Chemistry, vol. 85, pags. 221 - 228 (2019)
Article preview
We report herein the synthesis antioxidant and Aβ anti-aggregation capacity of (E)-N-benzyl-N-[2-(benzylamino)-2-oxoethyl]-3-(aryl)acrylamides and related (R)-N-benzyl-N-(2-(benzylamino)-2-oxoethyl)-5-(1,2-dithiolan-3-yl)pentanamides 1–12. These compounds have been obtained, via Ugi four-component reaction, from modest to good yields. Their antioxidant analysis, using the DPPH and ORAC assays, allowed us to identify compounds 8 and 9, as potent antioxidant agents, showing also strong Aβ 1–40 self-aggregation inhibition, two biological properties of interest in pathologies linked to the oxidative stress, such as Alzheimer's disease. © 2018 Elsevier Inc.
Martín-Ortiz A, Ruiz-Matute A.I, Sanz M.L, Moreno F.J, Herrero M.
Analytica Chimica Acta, vol. 1060, pags. 125 - 132 (2019)
Article preview
Carbohydrates are one of the most important ingredients in foods. They are normally present as complex mixtures with different glycosidic linkages, monomeric units and degrees of polymerization. This structural heterogeneity impairs their comprehensive characterization and requires the use of analytical techniques with high resolving power and sensitivity. The use of chromatographic techniques, especially liquid chromatography (LC), has been extremely helpful for the analysis of carbohydrates. However, in many cases, the use of monodimensional LC is not enough to resolve these complex mixtures; then, the use of techniques with a higher resolving power, as multidimensional LC, could be a good alternative. To the best of our knowledge, our findings are pioneer in applying online LC × LC for the analysis of carbohydrate mixtures. For this purpose, different conditions such as stationary phases (BEH amide, C 18 and PGC columns) and chromatographic conditions for the separation of di- and trisaccharide mixtures were optimized. The BEH amide × C 18 combination was selected for the LC × LC analysis of carbohydrate standards with different degrees of polymerization, linkages and monomeric units. In order to allow their proper UV detection, carbohydrates were previously derivatized using p-aminobenzoic ethyl ester. This method also resulted to be successful for the separation of commercial prebiotic mixtures of galacto-oligosaccharides and gentio-oligosaccharides. This is the first time that LC × LC has been applied for the separation of bioactive carbohydrate mixtures and it could be considered as a powerful analytical technique for the characterization of other oligosaccharide complex mixtures. © 2019 Elsevier B.V.
Jiménez-Almarza A, Diez-Iriepa D, Chioua M, Chamorro B, Iriepa I, Martínez-Murillo R, Hadjipavlou-Litina D, Oset-Gasque M.J, Marco-Contelles J.
Bioorganic Chemistry, vol. 86, pags. 445 - 451 (2019)
Article preview
In this work six PBN-related indanonitrones 1–6 have been designed, synthesized, and their neuroprotection capacity tested in vitro, under OGD conditions, in SH-SY5Y human neuroblastoma cell cultures. As a result, we have identified indanonitrones 1, 3 and 4 (EC 50 = 6.64 ± 0.28 μM) as the most neuroprotective agents, and in particular, among them, indanonitrone 4 was also the most potent and balanced nitrone, showing antioxidant activity in three experiments [LOX (100 μM), APPH (51\%), DPPH (36.5\%)], being clearly more potent antioxidant agent than nitrone PBN. Consequently, we have identified (Z)-5-hydroxy-N-methyl-2,3-dihydro-1H-inden-1-imine oxide (4) as a hit-molecule for further investigation. © 2019 Elsevier Inc.
Marco-Contelles J.
ACS Chemical Neuroscience, vol. 10, nº 3, pags. 1127 - 1128 (2019)
Article preview
Credit should be granted to medicinal chemists with a solid background in organic chemistry and computational chemistry, able to read, understand, and discuss the biological data, in order to design new and more efficient therapeutic approaches for Alzheimer's disease. © 2019 American Chemical Society.
Companión I, Guerreiro A, Mangini V, Castro-López J, Escudero-Casao M, Avenoza A, Busto J.H, Castillón S, Jiménez-Barbero J, Asensio J.L, Jiménez-Osés G, Boutureira O, Peregrina J.M, Hurtado-Guerrero R, Fiammengo R, Bernardes G.J.L, Corzana F.
Journal of the American Chemical Society, vol. 141, nº 9, pags. 4063 - 4072 (2019)
Article preview
GalNAc-glycopeptides derived from mucin MUC1 are an important class of tumor-associated antigens. α-O-glycosylation forces the peptide to adopt an extended conformation in solution, which is far from the structure observed in complexes with a model anti-MUC1 antibody. Herein, we propose a new strategy for designing potent antigen mimics based on modulating peptide/carbohydrate interactions by means of O â†' S/Se replacement at the glycosidic linkage. These minimal chemical modifications bring about two key structural changes to the glycopeptide. They increase the carbohydrate-peptide distance and change the orientation and dynamics of the glycosidic linkage. As a result, the peptide acquires a preorganized and optimal structure suited for antibody binding. Accordingly, these new glycopeptides display improved binding toward a representative anti-MUC1 antibody relative to the native antigens. To prove the potential of these glycopeptides as tumor-associated MUC1 antigen mimics, the derivative bearing the S-glycosidic linkage was conjugated to gold nanoparticles and tested as an immunogenic formulation in mice without any adjuvant, which resulted in a significant humoral immune response. Importantly, the mice antisera recognize cancer cells in biopsies of breast cancer patients with high selectivity. This finding demonstrates that the antibodies elicited against the mimetic antigen indeed recognize the naturally occurring antigen in its physiological context. Clinically, the exploitation of tumor-associated antigen mimics may contribute to the development of cancer vaccines and to the improvement of cancer diagnosis based on anti-MUC1 antibodies. The methodology presented here is of general interest for applications because it may be extended to modulate the affinity of biologically relevant glycopeptides toward their receptors. Copyright © 2019 American Chemical Society.
Hernáiz-Izquierdo M, Galindo-Iranzo P, García-Armada M.P, Saiz-López A, Gómara B, Quintanilla-López J.E, Lebrón-Aguilar R.
Journal of Chromatography A, vol. 1588, pags. 99 - 107 (2019)
Article preview
Atmospheric iodine plays a relevant role in climate change. Bearing in mind that most of this iodine comes from the oceans, analytical methods capable of determining iodine in a challenging matrix as seawater are necessary. In this work, the first method capable of direct determination of total inorganic iodine in seawater at subnanomolar level based on mixed-mode liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) without any sample treatment is presented. Analytical characteristics of the developed method were studied in terms of linear range, limits of detection and quantification, precision, trueness, matrix effect, and robustness. The detection limit for iodide was as low as 0.16 nM, injecting 5 μL of seawater without any sample treatment and the working linear range of four orders of magnitude was wide enough to cover the broad concentration range observed in seawater samples. Average values for repeatability and intermediate precision were 4.1\% and 8.1\%, respectively. The suitability of the method was demonstrated through its application to the analysis of several types of samples, including seawater samples taken at different locations along the Spanish Mediterranean coast and some domestic iodized salts. According to the results obtained, the method developed is rapid, easy to apply and to be automated, avoids sample treatment and requires only few microliters of sample. Furthermore, it has a low detection limit and allows the quantification of inorganic iodine over a wide concentration range. © 2018 Elsevier B.V.
Alcaide B, Almendros P, Fernández I, del Campo T.M, Palop G, Toledano-Pinedo M, Delgado-Martínez P.
Advanced Synthesis and Catalysis, vol. 361, nº 5, pags. 1160 - 1165 (2019)
Article preview
Tunable chemoselectivity (O- versus C-attack) in the rhodium-catalyzed reactions of allenols with 4-substituted-1-sulfonyl-1,2,3-triazoles has been achieved through the replacement of the 4-aryl substituent by a 4-acetyl moiety. (Figure presented.). © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chioua M, Martínez-Alonso E, Gonzalo-Gobernado R, Ayuso M.I, Escobar-Peso A, Infantes L, Hadjipavlou-Litina D, Montoya J.J, Montaner J, Alcázar A, Marco-Contelles J.
Journal of Medicinal Chemistry, vol. 62, nº 4, pags. 2184 - 2201 (2019)
Article preview
We describe herein the synthesis and neuroprotective capacity of an array of 31 compounds comprising quinolyloximes, quinolylhydrazones, quinolylimines, QNs, and related heterocyclic azolylnitrones. Neuronal cultures subjected to oxygen-glucose deprivation (OGD), as experimental model for ischemic conditions, were treated with our molecules at the onset of recovery period after OGD and showed that most of these QNs, but not the azo molecules, improved neuronal viability 24 h after recovery. Especially, QN (Z)-N-tert-butyl-1-(2-chloro-6-methoxyquinolin-3-yl)methanimine oxide (23) was shown as a very potent neuroprotective agent. Antioxidant analysis based on the ability of QN 23 to trap different types of toxic radical oxygenated species supported and confirmed its strong neuroprotective capacity. Finally, QN 23 showed also neuroprotection induction in two in vivo models of cerebral ischemia, decreasing neuronal death and reducing infarct size, allowing us to conclude that QN 23 can be considered as new lead-compound for ischemic stroke treatment. © 2019 American Chemical Society.
Pachón-Angona I, Refouvelet B, Andrýs R, Martin H, Luzet V, Iriepa I, Moraleda I, Diez-Iriepa D, Oset-Gasque M.J, Marco-Contelles J., Musilek K, Ismaili L.
Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 34, nº 1, pags. 479 - 489 (2019)
Article preview
We describe herein the design, multicomponent synthesis and biological studies of new donepezil + chromone + melatonin hybrids as potential agents for Alzheimer’s disease (AD) therapy. We have identified compound 14n as promising multitarget small molecule showing strong BuChE inhibition (IC50 = 11.90 ± 0.05 nM), moderate hAChE (IC50 = 1.73 ± 0.34 μM), hMAO A (IC50 = 2.78 ± 0.12 μM), and MAO B (IC50 = 21.29 ± 3.85 μM) inhibition, while keeping a strong antioxidant power (3.04 TE, ORAC test). Consequently, the results reported here support the development of new multitarget Donepezil + Chromone + Melatonin hybrids, such as compound 14n, as a potential drug for AD patients cure. © 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Mascareñas J.L., Varela I, López F
Accounts of Chemical Research (2019)
Article preview
ConspectusCycloaddition reactions, by involving the formation of at least two bonds and one cycle in a single operation, represent one of the more practical ways to assemble carbo- and heterocyclic structures from simple acyclic precursors. Especially appealing are formal cycloadditions promoted by transition metals, owing to the ability of these reagents to open mechanisms that are not accessible using classical chemistry. Therefore, along the years, a great variety of annulations based on first-, and particularly second-row transition metals have been discovered. Most of these reactions involve inner sphere mechanisms, with the metal participating via standard oxidative addition or reductive elimination processes. Curiously, metals of the third row like platinum and, especially, gold remained largely unexplored, likely because of the belief that they were inert and expensive. However, from the beginning of this century, many groups realized that these metals can open very interesting mechanistic scenarios and promote novel types of transformations. In particular, the π-acidic, carbophilic behavior of gold(I) complexes, together with the possibility of tuning their reactivity using designed ligands, has triggered important activity in the field. Many gold-catalyzed transformations involved addition or cycloisomerization processes, but during recent years, there have been also important advances in the development of formal cycloaddition reactions. While many of these reactions rely on the activation of alkynes, there has been an increasing number of reports that exploit the peculiar reactivities of allenes and derivatives.In this Account, we present recent efforts on the development of platinum- and gold-catalyzed formal cycloadditions of allenes. For the sake of simplicity, we only include annulations initiated by a direct metal-promoted activation of the allene moiety. Thus, alternative Pt- or Au-catalyzed reactions wherein the allene does not interact with the metal catalyst are not covered. Upon activation by the metals, allenes generate allyl-cation alkenylmetal species that can behave as 1,2- or 1,3-carbon dipoles in cycloaddition processes. Especially relevant is the reactivity of allenamides. The presence of the amide substituent provides for the generation of gold intermediates with a good balance of reactivity and stability, which can therefore react with the corresponding partners in a controlled manner. Moreover, despite the difficulties associated with the transfer of stereochemical information from chiral linear gold(I) complexes, a variety of enantioselective gold-catalyzed annulations have been discovered.This Account is organized considering the number of atoms engaged in the annulation process, and when possible, we present the results in a chronological order. © 2019 American Chemical Society.
Destito P, Sousa-Castillo A, Couceiro J.R, López F, Correa-Duarte M.A, Mascareñas J.L.
Chemical Science, vol. 10, nº 9, pags. 2598 - 2603 (2019)
Article preview
We describe the fabrication of hollow microspheres consisting of mesoporous silica nanoshells decorated with an inner layer of palladium nanoparticles and their use as Pd-nanoreactors in aqueous media. These palladium-equipped capsules can be used to promote the uncaging of propargyl-protected phenols, as well as Suzuki-Miyaura cross-coupling, in water and at physiologically compatible temperatures. Importantly, the depropargylation reaction can be accomplished in a bioorthogonal manner in the presence of relatively high concentrations of biomolecular components and even in the presence of mammalian cells. © The Royal Society of Chemistry.
Martí S, Bastida A, Świderek K.
Frontiers in Chemistry, vol. 7, nº JAN (2019)
Article preview
This work is focused on mechanistic studies of the transfer of an adenylyl group (Adenoside-5'-monophosfate) from adenosine 5'-triphosphate (ATP) to a OH-4' hydroxyl group of an antibiotic. Using hybrid quantum mechanics/molecular mechanics (QM/MM) techniques, we study the substrate and base-assisted mechanisms of the inactivation process of kanamycin A (KAN) catalyzed by 4'-O-Nucleotidyltransferase [ANT(4')], an active enzyme against almost all aminoglycoside antibiotics. Free energy surfaces, obtained with Free Energy Perturbation methods at the M06-2X/MM level of theory, show that the most favorable reaction path presents a barrier of 12.2 kcal·mol-1 that corresponds to the concerted activation of O4' from KAN by Glu145. In addition, the primary and secondary 18O kinetic isotope effects (KIEs) have been computed for bridge O3α, and non-bridge O1α, O2α, and O5' atoms of ATP. The observed normal 1°-KIE of 1.2\% and 2°-KIE of 0.07\% for the Glu145-assisted mechanism are in very good agreement with experimentally measured data. Additionally, based on the obtained results, the role of electrostatic and compression effects in enzymatic catalysis is discussed. © 2019 Martí, Bastida and Świderek.