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1.
Nature ; 585(7825): E12, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32843756

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

2.
Sci Rep ; 10(1): 14150, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843666

RESUMO

We herein report the synthesis, antioxidant power and neuroprotective properties of nine homo-bis-nitrones HBNs 1-9 as alpha-phenyl-N-tert-butylnitrone (PBN) analogues for stroke therapy. In vitro neuroprotection studies of HBNs 1-9 against Oligomycin A/Rotenone and in an oxygen-glucose-deprivation model of ischemia in human neuroblastoma cell cultures, indicate that (1Z,1'Z)-1,1'-(1,3-phenylene)bis(N-benzylmethanimine oxide) (HBN6) is a potent neuroprotective agent that prevents the decrease in neuronal metabolic activity (EC50 = 1.24 ± 0.39 µM) as well as necrotic and apoptotic cell death. HBN6 shows strong hydroxyl radical scavenger power (81%), and capacity to decrease superoxide production in human neuroblastoma cell cultures (maximal activity = 95.8 ± 3.6%), values significantly superior to the neuroprotective and antioxidant properties of the parent PBN. The higher neuroprotective ability of HBN6 has been rationalized by means of Density Functional Theory calculations. Calculated physicochemical and ADME properties confirmed HBN6 as a hit-agent showing suitable drug-like properties. Finally, the contribution of HBN6 to brain damage prevention was confirmed in a permanent MCAO setting by assessing infarct volume outcome 48 h after stroke in drug administered experimental animals, which provides evidence of a significant reduction of the brain lesion size and strongly suggests that HBN6 is a potential neuroprotective agent against stroke.

3.
Chemistry ; 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32666598

RESUMO

Quantum chemical calculations of the oxides AeO, imides AeNH and dihydrides AeH 2 of the alkaline earth atoms Ae = Be, Mg, Ca, Sr, Ba and the calcium cluster Ca 6 H 9 (N(SiMe 3 ) 2 ) 3 (PMDTA) 3 have been carried out using density functional theory. The analysis of the electronic structures using charge and energy partitioning methods suggests that the valence orbitals of the lighter atoms Be and Mg are the (n)s and (n)p orbitals. In contrast, the valence orbitals of the heavier atoms Ca, Sr and Ba comprise the (n)s and the (n-1)d orbitals. The alkaline earth metals beryllium and magnesium built covalent bonds like typical main-group elements whereas calcium, strontium and barium covalently bind like transition metals. The results not only shed new light on the covalent bonds of the heavier alkaline earth metals, but are also very important for understanding and designing experimental studies.

4.
J Org Chem ; 85(14): 9272-9280, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32589024

RESUMO

The mechanism and selectivity of phosphine-catalyzed [3 + 2] and [3 + 3] annulations of azomethine imines and allenoates have been computationally studied. Exploration of the potential energy surface reveals that the cyclization step is a key step controlling the selectivity of the process. This contrasts with previous studies on related transformations where the initial nucleophilic addition involving the activated allenoate was found to exclusively control the regioselectivity of the transformation. Among the possible reaction pathways, the energetically low-lying reaction channel involves an intramolecular Michael addition leading to the experimentally observed [3 + 2] product. The factors controlling the observed regioselectivity have been quantitatively rationalized by means of state-of-the-art computational methods, namely, the activation strain model of reactivity in combination with the energy decomposition analysis.

5.
Org Lett ; 22(10): 3979-3984, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32338923

RESUMO

α,ß-Unsaturated α'-alkoxy ketones have been prepared under mild conditions from allenes using water as the oxygen source and without the necessity of metals. The organocatalytic oxygenation-rearrangement sequence displays an exquisite chemo-, stereo-, and site-selectivity as well as good functional group compatibility. DFT calculations suggest that stabilizing noncovalent Se···O interactions may be responsible for the observed reactivity.

6.
Elife ; 92020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286223

RESUMO

Taking control of the cellular apparatus for protein production is a requirement for virus progression. To ensure this control, diverse strategies of cellular mimicry and/or ribosome hijacking have evolved. The initiation stage of translation is especially targeted as it involves multiple steps and the engagement of numerous initiation factors. The use of structured RNA sequences, called Internal Ribosomal Entry Sites (IRES), in viral RNAs is a widespread strategy for the exploitation of eukaryotic initiation. Using a combination of electron cryo-microscopy (cryo-EM) and reconstituted translation initiation assays with native components, we characterized how a novel IRES at the 5'-UTR of a viral RNA assembles a functional initiation complex via an uAUG intermediate. The IRES features a novel extended, multi-domain architecture, that circles the 40S head. The structures and accompanying functional data illustrate the importance of 5'-UTR regions in translation regulation and underline the relevance of the untapped diversity of viral IRESs.

7.
Org Lett ; 22(9): 3637-3641, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32320259

RESUMO

Piperazines are prevalent in pharmaceuticals and natural products, but traditional methods do not typically introduce stereochemical complexity into the ring. To expand access to these scaffolds, we report Rh-catalyzed ring expansions of aziridines and N-sulfonyl-1,2,3-triazoles to furnish dehydropiperazines with excellent diastereocontrol. Productive ring expansion proceeds via a pseudo-1,4-sigmatropic rearrangement of an aziridinium ylide species. However, the structural features of the carbene precursor are important, as pyridotriazoles undergo competing cheletropic extrusion to furnish ketimines.

8.
Antioxidants (Basel) ; 9(4)2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32244303

RESUMO

Nitrones have a well-recognized capacity as spin-traps and are considered powerful free radical scavengers, which are two important issues in hypoxia-induced oxidative stress and cell death in brain ischemia. Consequently, nitrones have been proposed as therapeutic agents in acute ischemic stroke (AIS). In this paper, we update the biological and pharmacological characterization of ISQ-201, a previously identified cholesteronitrone hybrid with antioxidant and neuroprotective activity. This study characterizes ISQ-201 as a neuroprotective agent against the hypoxia-induced ischemic injury. Transitory four-vessel occlusion and middle cerebral artery occlusion (tMCAO) were used to induce cerebral ischemia. Functional outcomes were determined using neurofunctional tests. Infarct area, neuronal death, and apoptosis induction were evaluated. In addition, ISQ-201 reactivity towards free radicals was studied in a theoretical model. ISQ-201 significantly decreased the ischemia-induced neuronal death and apoptosis, in a dose-dependent manner, showing its therapeutic effect when administered up until 6 h after post-ischemic reperfusion onset, effects that remained after 3 months from the ischemic episode. Furthermore, ISQ-201 significantly reduced infarct volume, leading to recovery of the motor function in the tMCAO model. Finally, the theoretical study confirmed the reactivity of ISQ-201 towards hydroxyl radicals. The results reported here prompted us to suggest ISQ-201 as a promising candidate for the treatment of AIS.

9.
Chemistry ; 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32329537

RESUMO

The factors controlling the oxidative addition of C-C and C-H bonds in arenes mediated by AlI have been computationally explored by means of Density Functional Theory calculations. To this end, we compared the processes involving benzene, naphthalene and anthracene which are promoted by a recently prepared anionic AlI -carbenoid. It is found that this species exhibits a strong tendency to oxidatively activate C-H bonds over C-C bonds, with the notable exception of benzene, where the C-C bond activation is feasible but only under kinetic control reaction conditions. State-of-the-art computational methods based on the combination of the Activation Strain Model of reactivity and the Energy Decomposition Analysis have been used to rationalize the competition between both bond activation reactions as well as to quantitatively analyze in detail the ultimate factors controlling these transformations.

10.
Nat Commun ; 11(1): 1273, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152321

RESUMO

The importance of N-heterocycles in drugs has stimulated diverse methods for their efficient syntheses. Methods that introduce significant stereochemical complexity are attractive for identifying new bioactive amine chemical space. Here, we report a [3 + 3] ring expansion of bicyclic aziridines and rhodium-bound vinyl carbenes to form complex dehydropiperidines in a highly stereocontrolled rearrangement. Mechanistic studies and DFT computations indicate that the reaction proceeds through formation of a vinyl aziridinium ylide; this reactive intermediate undergoes a pseudo-[1,4]-sigmatropic rearrangement to directly furnish heterocyclic products with net retention at the new C-C bond. In combination with asymmetric silver-catalyzed aziridination, enantioenriched scaffolds with up to three contiguous stereocenters are rapidly delivered. The mild reaction conditions, functional group tolerance, and high stereospecificity of this method are well-suited for appending piperidine motifs to natural product and complex molecules. Ultimately, our work establishes the value of underutilized aziridinium ylides as key intermediates for converting small, strained rings to larger N-heterocycles.


Assuntos
Aziridinas/química , Piperidinas/química , Catálise , Compostos Heterocíclicos/química , Estereoisomerismo
11.
Chemistry ; 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32182384

RESUMO

The photophysical properties of a series of T-shaped coinage d10 metal complexes, supported by a bis(mesoionic carbene)carbazolide (CNC) pincer ligand, are explored. The series includes a rare new example of a tridentate T-shaped AgI complex. Post-complexation modification of the AuI complex provides access to a linear cationic AuI complex following ligand alkylation, or the first example of a cationic square planar AuIII -F complex from electrophilic attack on the metal centre. Emissions ranging from blue (CuI ) to orange (AgI ) are obtained, with variable contributions of thermally-dependent fluorescence and phosphorescence to the observed photoluminescence. Green emissions are observed for all three gold complexes (neutral T-shaped AuI , cationic linear AuI and square planar cationic AuIII ). The higher quantum yield and longer decay lifetime of the linear gold(I) complex are indicative of increased phosphorescence contribution.

12.
J Am Chem Soc ; 142(12): 5568-5573, 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32142272

RESUMO

Amidoallyl cations are appealing three-carbon synthons for the preparation of complex amine-containing carbocycles; however, methods to generate and utilize these reactive species are limited and underexplored compared to those for oxallyl cations. Here we disclose a bioinspired strain-driven ring opening of bicyclic methyleneaziridines to 2-amidopentadienyl cation intermediates that readily engage in Nazarov cyclizations. Advantages of this strategy include ease of generation and improved reactivity compared to 3-pentadienyl cations, control over the ultimate position of the alkene, the potential for high dr between vicinal stereocenters, and the ability to further elaborate the products to fully substituted aminocyclopentanes. Experimental and computational studies support a dual role for the Rh2Ln complex as both a nitrene transfer catalyst and a Lewis acid promoter, insight that provides a framework for the future development of asymmetric 2-imino-Nazarov cyclizations.

13.
Dalton Trans ; 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32073063

RESUMO

The role of frustrated Lewis pairs (FLPs) as ligands in gold(i) catalyzed-reactions has been computationally investigated by using state-of-the-art density functional theory calculations. To this end, the nature of (P,B)-FLP-transition metal interactions in different gold(i)-complexes has been first explored in detail with the help of the energy decomposition analysis method, which allowed us to accurately quantify the so far poorly understood AuB interactions present in these species. The impact of such interactions on the catalytic activity of gold(i)-complexes has been then evaluated by performing the Au(i)-catalyzed hydroarylation reaction of phenylacetylene with mesitylene. With the help of the activation strain model of reactivity, the factors governing the higher activity of Au(i)-complexes having a FLP as a ligand as compared to that of the parent PPh3 system have also been quantitatively identified.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31944503

RESUMO

The Lewis acid(LA)-catalyzed Diels-Alder reaction between isoprene and methyl acrylate was investigated quantum chemically using a combined density functional theory and coupled-cluster theory approach. Computed activation energies systematically decrease as the strength of the LA increases along the series I2

15.
Chem Commun (Camb) ; 56(8): 1290-1293, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31904044

RESUMO

The controlled synthesis of 1,4-naphthoquinones and tetraphene-7,12-diones, which bear the ABCD-ring of landomycins, has been accomplished directly through oxidative rearrangement of common stable precursors, namely, previously non-isolable cyclobuta[a]naphthalen-4(2H)-ones.

16.
Proc Natl Acad Sci U S A ; 117(3): 1429-1437, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31900355

RESUMO

Translation initiation controls protein synthesis by regulating the delivery of the first aminoacyl-tRNA to messenger RNAs (mRNAs). In eukaryotes, initiation is sophisticated, requiring dozens of protein factors and 2 GTP-regulated steps. The GTPase eIF5B gates progression to elongation during the second GTP-regulated step. Using electron cryomicroscopy (cryo-EM), we imaged an in vitro initiation reaction which is set up with purified yeast components and designed to stall with eIF5B and a nonhydrolyzable GTP analog. A high-resolution reconstruction of a "dead-end" intermediate at 3.6 Šallowed us to visualize eIF5B in its ribosome-bound conformation. We identified a stretch of residues in eIF5B, located close to the γ-phosphate of GTP and centered around the universally conserved tyrosine 837 (Saccharomyces cerevisiae numbering), that contacts the catalytic histidine of eIF5B (H480). Site-directed mutagenesis confirmed the essential role that these residues play in regulating ribosome binding, GTP hydrolysis, and translation initiation both in vitro and in vivo. Our results illustrate how eIF5B transmits the presence of a properly delivered initiator aminoacyl-tRNA at the P site to the distant GTPase center through interdomain communications and underscore the importance of the multidomain architecture in translation factors to sense and communicate ribosomal states.


Assuntos
Fatores de Iniciação em Eucariotos/metabolismo , Guanosina Trifosfato/metabolismo , Iniciação Traducional da Cadeia Peptídica , Sítios de Ligação , Microscopia Crioeletrônica , Fatores de Iniciação em Eucariotos/química , Fatores de Iniciação em Eucariotos/genética , Hidrólise , Mutagênese Sítio-Dirigida , Ligação Proteica , Ribossomos/metabolismo , Saccharomyces cerevisiae
17.
J Am Chem Soc ; 142(9): 4162-4172, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-31859500

RESUMO

Two novel homo and hetero three-dimensional nanographenes, NG1 and NG2, featuring a cyclooctatetraene core are designed, synthesized, and characterized. A concise and efficient bottom-up methodology was employed during which 24 new carbon-carbon bonds were formed. By means of a Scholl reaction nanographenes with 53 fused rings are realized, which exhibited good solubility in common organic solvents. The resulting saddle-like structures of NG1 and NG2 are electron-rich and show good chemical and electrochemical stability. Their molecular structures are fully elucidated by single-crystal X-ray crystallography. From their crystal structure analysis is concluded that both nanographenes are chiral and crystallize as a racemic mixture. Our work was rounded-off by excited state investigations such as electron and energy transfer with electron-acceptors and -donors.

18.
Nature ; 577(7789): 271-274, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31853065

RESUMO

Bacteria use adaptive immune systems encoded by CRISPR and Cas genes to maintain genomic integrity when challenged by pathogens and mobile genetic elements1-3. Type I CRISPR-Cas systems typically target foreign DNA for degradation via joint action of the ribonucleoprotein complex Cascade and the helicase-nuclease Cas34,5, but nuclease-deficient type I systems lacking Cas3 have been repurposed for RNA-guided transposition by bacterial Tn7-like transposons6,7. How CRISPR- and transposon-associated machineries collaborate during DNA targeting and insertion remains unknown. Here we describe structures of a TniQ-Cascade complex encoded by the Vibrio cholerae Tn6677 transposon using cryo-electron microscopy, revealing the mechanistic basis of this functional coupling. The cryo-electron microscopy maps enabled de novo modelling and refinement of the transposition protein TniQ, which binds to the Cascade complex as a dimer in a head-to-tail configuration, at the interface formed by Cas6 and Cas7 near the 3' end of the CRISPR RNA (crRNA). The natural Cas8-Cas5 fusion protein binds the 5' crRNA handle and contacts the TniQ dimer via a flexible insertion domain. A target DNA-bound structure reveals critical interactions necessary for protospacer-adjacent motif recognition and R-loop formation. This work lays the foundation for a structural understanding of how DNA targeting by TniQ-Cascade leads to downstream recruitment of additional transposase proteins, and will guide protein engineering efforts to leverage this system for programmable DNA insertions in genome-engineering applications.


Assuntos
Sistemas CRISPR-Cas , Elementos de DNA Transponíveis , DNA Bacteriano/química , Vibrio cholerae/química , Microscopia Crioeletrônica , DNA Bacteriano/genética , Modelos Moleculares , Conformação de Ácido Nucleico , Multimerização Proteica , Estrutura Quaternária de Proteína , RNA Bacteriano/química , Vibrio cholerae/genética
19.
J Phys Chem A ; 123(46): 10095-10101, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31689361

RESUMO

The influence of the nature of the group 14 elements (E = Si, Ge, Sn) on the reactivity of (F5C2)3E-CH2-P(tBu)2 geminal frustrated Lewis pairs (FLPs) has been computationally explored by means of density functional theory calculations. To this end, the experimentally described activation reactions of CO2 and phenyl isocyanate have been investigated and compared to the analogous processes involving the corresponding B/P geminal FLP. It is found that the reactivity of these species is kinetically enhanced when going down the group 14 (Si < Ge < Sn). This trend of reactivity is quantitatively analyzed in detail by means of the activation strain model of reactivity in combination with the energy decomposition analysis method, which identify the interaction energy between the deformed reactants as the main factor controlling the reactivity of these group 14 containing geminal FLPs.

20.
EMBO J ; 38(21): e102226, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31609474

RESUMO

Colony collapse disorder (CCD) is a multi-faceted syndrome decimating bee populations worldwide, and a group of viruses of the widely distributed Dicistroviridae family have been identified as a causing agent of CCD. This family of viruses employs non-coding RNA sequences, called internal ribosomal entry sites (IRESs), to precisely exploit the host machinery for viral protein production. Using single-particle cryo-electron microscopy (cryo-EM), we have characterized how the IRES of Israeli acute paralysis virus (IAPV) intergenic region captures and redirects translating ribosomes toward viral RNA messages. We reconstituted two in vitro reactions targeting a pre-translocation and a post-translocation state of the IAPV-IRES in the ribosome, allowing us to identify six structures using image processing classification methods. From these, we reconstructed the trajectory of IAPV-IRES from the early small subunit recruitment to the final post-translocated state in the ribosome. An early commitment of IRES/ribosome complexes for global pre-translocation mimicry explains the high efficiency observed for this IRES. Efforts directed toward fighting CCD by targeting the IAPV-IRES using RNA-interference technology are underway, and the structural framework presented here may assist in further refining these approaches.


Assuntos
Biomimética , Dicistroviridae/fisiologia , Sítios Internos de Entrada Ribossomal/genética , Biossíntese de Proteínas , RNA de Transferência/genética , RNA Viral/genética , Ribossomos/metabolismo , Microscopia Crioeletrônica , Dicistroviridae/ultraestrutura , Humanos , Modelos Moleculares , Conformação de Ácido Nucleico , RNA de Transferência/ultraestrutura , Ribossomos/ultraestrutura
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