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1.
Nat Chem Biol ; 17(8): 872-877, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34312563

RESUMO

More than 60% of pharmaceuticals are related to natural products (NPs), chemicals produced by living organisms. Despite this, the rate of NP discovery has slowed over the past few decades. In many cases the rate-limiting step in NP discovery is structural characterization. Here we report the use of microcrystal electron diffraction (MicroED), an emerging cryogenic electron microscopy (CryoEM) method, in combination with genome mining to accelerate NP discovery and structural elucidation. As proof of principle we rapidly determine the structure of a new 2-pyridone NP, Py-469, and revise the structure of fischerin, an NP isolated more than 25 years ago, with potent cytotoxicity but hitherto ambiguous structural assignment. This study serves as a powerful demonstration of the synergy of MicroED and synthetic biology in NP discovery, technologies that when taken together will ultimately accelerate the rate at which new drugs are discovered.


Assuntos
Produtos Biológicos/química , Microscopia Crioeletrônica , Modelos Moleculares , Conformação Molecular
2.
ACS Cent Sci ; 5(9): 1507-1513, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31572777

RESUMO

Here we apply microcrystal electron diffraction (MicroED) to the structural determination of transition-metal complexes. We find that the simultaneous use of 300 keV electrons, very low electron doses, and an ultrasensitive camera allows for the collection of data without cryogenic cooling of the stage. This technique reveals the first crystal structures of the classic zirconocene hydride, colloquially known as "Schwartz's reagent", a novel Pd(II) complex not amenable to solution-state NMR or X-ray crystallography, and five other paramagnetic and diamagnetic transition-metal complexes.

3.
Dalton Trans ; 47(48): 17382-17391, 2018 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-30480701

RESUMO

Saturated N-heterocyclic carbenes have unique ligand properties that differ even from their unsaturated analogs. While the unsaturated version has been extensively used in multidentate ligand scaffolds, the incorporation of the saturated version is less common. Here we report the straightforward synthesis of a new bis-saturated N-heterocyclic carbene ligand wherein the carbene moieties are linked by a flexible meta-xylyl unit. Carbene metal complexes of the proligand can be generated by direct metalation, transmetallation or base assisted metalation all of which lead to monodentate coordination modes of silver or iridium. Attempts at direct metalation using zirconium tetrakis-dimethylamide did not lead to complex formation but to the chloroform adduct or amide addition product. As yet, a method to generate pincer complexes from this ligand has not been found. The flexible nature of the xylyl linker as well as the higher σ-bacisity and π-acidity are postulated to contribute to these results.

4.
Dalton Trans ; 44(40): 17432-47, 2015 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-26396037

RESUMO

Pincer ligands have become ubiquitous in organometallic chemistry and homogeneous catalysis. Recently, new varieties of pincer ligands with non-symmetrical backbones and/or ligating groups have been reported and their application in transition metal complexes has been exploited in a variety of catalytic transformations. This non-symmetric approach vastly increases the structural and electronic diversity of this class of ligand. This approach has proven beneficial in a variety of ways, such as the use of a single weakly coordinating moiety, which can dissociate and thereby create a vacant coordination site to increase the catalyst activity. Additionally, this provides further access to chiral ligands and complexes for asymmetric induction. This perspective highlights recent, important examples of non-symmetric pincer ligands, which feature aryl or pyridine backbones, and the synthesis and use of subsequent complexes in catalytic transformations, and discusses the future potential of this type of ligand system.

5.
Chem Commun (Camb) ; 51(25): 5359-62, 2015 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-25387660

RESUMO

The syntheses of unsymmetrical N-heterocyclic carbenes (NHCs) that contain a single N-bound icosahedral carborane anion substituent are reported. Both anionic C-2 and doubly deprotonated dianionic C-2/C-5 NHC lithium complexes are isolated. The latter species is formed selectively, which reveals a surprising directing effect conveyed by icosahedral carborane anion substituents.

6.
Inorg Chem ; 52(21): 12308-10, 2013 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-24138749

RESUMO

The perchlorinated carba-closo-dodecaborate anion is typically inert toward B-Cl functionalization. We present here the observation of two competing reactions that occur with this anion at ambient temperature. When this molecule is treated with n-BuLi and subsequently reacted with tosyl azide, a cycloaddition occurs and results in chloride substitution at a B-Cl vertex. The competing and dominant pathway is a substitution reaction to form the azide N3CB11Cl11(-). This rare anionic carboranyl azide reacts with PPh3 in FC6H5 to afford a stable anionic phosphazide. When dissolved in tetrahydrofuran, the phosphazide is in equilibrium with free PPh3 and N3CB11Cl11(-). Both the triazole and phosphazide are characterized by single-crystal X-ray diffraction, NMR and IR spectroscopy, and high-resolution mass spectrometry.

7.
Angew Chem Int Ed Engl ; 52(44): 11560-3, 2013 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-24106045

RESUMO

Outside the cage: A change in the redox properties of a triazole fused to a carborane anion through methylation to form a zwitterion enabled facile chemical reduction of the compound to an isolable triazole radical anion (see structure: C gray, H white, N blue, B brown, Cl green). The radical anion is stabilized by kinetic protection by the chlorinated carborane and the delocalization of spin density throughout the exo-cluster π system.


Assuntos
Ânions/química , Boro/química , Triazóis/química , Modelos Moleculares , Estrutura Molecular
8.
J Am Chem Soc ; 134(2): 886-9, 2012 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-22191559

RESUMO

Reaction of the disilyne-NHC complex 1 [RLSi═SiR: (R = Si(i)Pr[CH(SiMe(3))(2)](2), L = NHC)] with MeOTf gave the cation 2 [RLSi═SiRMe](+), which is the first example of a base-stabilized heavy group 14 element analogue with vinyl cation character. Cation 2 has been fully characterized by multinuclear NMR spectroscopy and X-ray diffraction analysis. The molecular structure indicates that there are significant contributions from the NHC-stabilized cationic resonance structure 2A, the disilene-like structure 2B, and even some contribution from the silylene-like structure 2C.

9.
Angew Chem Int Ed Engl ; 50(41): 9589-92, 2011 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-21882326
10.
J Am Chem Soc ; 133(9): 2868-71, 2011 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-21322569

RESUMO

The first N-donor-stabilized phosphasilene LSi(SiMe(3))═PSiMe(3) (L = PhC(NtBu)(2)) has been synthesized in 87% yield through 1,2-silyl migration of the (Me(3)Si)(2)P-substituted, N-heterocyclic silylene [LSi-P(SiMe(3))(2)]. Remarkably, the latter reacts with dichlorotriphenylphosphorane Ph(3)PCl(2) to give the unprecedented 4π-electron Si(2)P(2)-cycloheterobutadiene [(LSi)(2)P(2)] with two-coordinate phosphorus atoms. The striking molecular structures as well as the (29)Si and (31)P NMR spectroscopic features of both products indicate the presence of zwitterionic Si═P bonds which is also in accordance with results by DFT calculations.

11.
Neurosci Lett ; 487(1): 3-7, 2011 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-20430067

RESUMO

The astrocytic glutamate transporter GLAST (also known as EAAT1) is a key regulator of extracellular glutamate levels in many regions of vertebrate brains. To identify novel interacting partners that might regulate the localization and function of GLAST in astrocytes, we screened the transporter's C-terminus (GLAST-CT) against a proteomic array of 96 different PDZ domains. The GLAST-CT robustly and specifically interacted with PDZ domains from two related scaffolding proteins, the Na(+)/H(+) exchanger regulatory factors 1 and 2 (NHERF-1 and NHERF-2). Studies on cultured rat cortical astrocytes revealed that these cells are highly enriched in NHERF-2 relative to NHERF-1. Endogenous GLAST and NHERF-2 from cultured astrocytes were found to robustly co-immunoprecipitate, and further co-immunoprecipitation studies on mutant versions of GLAST expressed in transfected cells revealed the GLAST/NHERF-2 interaction to be dependent on the last amino acid of the GLAST-CT. Knockdown of endogenous NHERF-2 in astrocytes via siRNA treatment resulted in a significant reduction in GLAST activity, which corresponded to significantly reduced total expression of GLAST protein and reduced half-life of GLAST, as assessed in pulse-chase metabolic labeling studies. These findings reveal that NHERF-2 can interact with GLAST in astrocytes to enhance GLAST stability and activity.


Assuntos
Transportador 1 de Aminoácido Excitatório/metabolismo , Domínios PDZ/fisiologia , Fosfoproteínas/metabolismo , Trocadores de Sódio-Hidrogênio/metabolismo , Animais , Ácido Aspártico/farmacocinética , Astrócitos , Células Cultivadas , Embrião de Mamíferos , Transportador 1 de Aminoácido Excitatório/genética , Regulação da Expressão Gênica/genética , Humanos , Imunoprecipitação/métodos , Mutação de Sentido Incorreto/genética , Neocórtex/citologia , Domínios PDZ/efeitos dos fármacos , Fosfoproteínas/genética , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Estrutura Terciária de Proteína , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Sprague-Dawley , Trocadores de Sódio-Hidrogênio/genética , Transfecção/métodos , Trítio/farmacocinética
13.
Org Lett ; 10(19): 4299-302, 2008 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-18763790

RESUMO

The biphenyl and binaphthyl diisopropylaminocarbenes were found to be only transient species that spontaneously and quantitatively rearrange into the corresponding aminofluorenes. DFT calculations confirm that these insertion reactions of aminocarbenes into proximal aromatic C-H bonds require only a moderate energy barrier and support a concerted, strongly asynchronous, mechanism dominated by C arom-->C carbene proton transfer.


Assuntos
Alcinos/química , Carbono/química , Dioxolanos/química , Hidrogênio/química , Teoria Quântica
15.
Inorg Chem ; 47(10): 3949-51, 2008 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-18422308

RESUMO

The 3-(triphenylphosphonio)-N-(2,6-diisopropylphenyl)pyrrole reacts with 2 equiv of methyllithium to afford a lithium adduct in which a cyclic (amino)[bis(ylide)]carbene, a novel type of NHC, acts as a 1,4-bidentate ligand via the carbene center and the exocyclic ylidic carbon. This species readily undergoes transmetalation reactions, which allows for the synthesis of a variety of transition-metal complexes.


Assuntos
Pirróis/química , Elementos de Transição/química , Ânions/química , Cristalografia por Raios X , Ligantes , Lítio/química , Modelos Moleculares , Estrutura Molecular , Compostos Organofosforados/química
17.
J Biol Chem ; 281(40): 29949-61, 2006 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-16891310

RESUMO

The two members of the group I metabotropic glutamate receptor family, mGluR1 and mGluR5, both couple to G(q) to mediate rises in intracellular calcium. The alternatively spliced C termini (CT) of mGluRs1 and 5are known to be critical for regulating receptor activity and to terminate in motifs suggestive of potential interactions with PDZ domains. We therefore screened the CTs of both mGluR1a and mGluR5 against a PDZ domain proteomic array. Out of 96 PDZ domains examined, the domain that bound most strongly to mGluR5-CT was the second PDZ domain of the Na(+)/H(+) exchanger regulatory factor 2 (NHERF-2). This interaction was confirmed by reverse overlay, and a single point mutation to the mGluR5-CT was found to completely disrupt the interaction. Full-length mGluR5 robustly associated with full-length NHERF-2 in cells, as assessed by co-immunoprecipitation and confocal microscopy experiments. In contrast, mGluR1a was found to bind NHERF-2 in vitro with a weaker affinity than mGluR5, and furthermore mGluR1a did not detectably associate with NHERF-2 in a cellular context. Immunohistochemical experiments revealed that NHERF-2 and mGluR5 exhibit overlapping patterns of expression in mouse brain, being found most abundantly in astrocytic processes and postsynaptic neuronal elements. In functional experiments, the interaction of NHERF-2 with mGluR5 in cells was found to prolong mGluR5-mediated calcium mobilization and to also potentiate mGluR5-mediated cell death, whereas coexpression of mGluR1a with NHERF-2 had no evident effects on mGluR1a functional activity. These observations reveal that NHERF-2 can selectively modulate mGluR5 signaling, which may contribute to cell-specific regulation of mGluR5 activity.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Fosfoproteínas/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Transdução de Sinais/fisiologia , Trocadores de Sódio-Hidrogênio/metabolismo , Animais , Encéfalo/metabolismo , Células COS , Linhagem Celular , Linhagem Celular Tumoral , Chlorocebus aethiops , Proteína 4 Homóloga a Disks-Large , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Fosfoproteínas/fisiologia , Proteoma , Ratos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/fisiologia , Trocadores de Sódio-Hidrogênio/fisiologia
18.
Brain Res ; 1094(1): 76-85, 2006 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-16725130

RESUMO

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the vertebrate brain. GABA activates both ionotropic (GABA(A)) and metabotropic (GABA(B)) receptors in mammals. Whether non-mammalian vertebrates possess receptors with similar characteristics is not well understood. We used a mammalian GABA(B)-specific antagonist to determine the pharmacology of putative receptors in the brain of an anuran amphibian, the male bullfrog (Rana catesbeiana). Receptor binding assays with the antagonist [(3)H]CGP54626 revealed a single class of high affinity binding sites (with a K(D) of 2.97 nM and a B(max) of 2619 fmol/mg protein). Binding was time- and temperature-dependent, saturable and specific. Specific binding of [(3)H]CGP54626 was inhibited by several mammalian GABA(B) receptor agonists and antagonists. The rank order potency of agonists was: GABA = SKF97541 > (R)-Baclofen > 3-APPA. The rank order for antagonists was: CGP54626 = CGP55845 > CGP52432 > CGP35348. The GABA(A) receptor ligands muscimol and SR95531 had very low affinity for [(3)H]CGP54626 binding sites, while bicuculline compounds had no affinity. Binding of GABA was positively modulated by CGP7930. Taurine did not allosterically modulate GABA binding but did inhibit [(3)H]CGP54626 binding in a linear fashion. Bullfrog brain thus possesses binding sites with significant similarity to mammalian GABA(B) receptors. These receptors differ from mammalian receptors, however, in dissociation kinetics, ligand specificity and allosteric modulation.


Assuntos
Ligação Competitiva/fisiologia , Encéfalo/metabolismo , Membrana Celular/metabolismo , Compostos Organofosforados/metabolismo , Rana catesbeiana/metabolismo , Receptores de GABA-B/metabolismo , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/fisiologia , Ligação Competitiva/efeitos dos fármacos , Interações Medicamentosas/fisiologia , Agonistas GABAérgicos/metabolismo , Antagonistas GABAérgicos/metabolismo , Masculino , Inibição Neural/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ensaio Radioligante , Receptores de GABA-B/química , Receptores de GABA-B/efeitos dos fármacos , Frações Subcelulares , Taurina/metabolismo , Temperatura , Fatores de Tempo , Trítio , Ácido gama-Aminobutírico/metabolismo
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