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5.
Chem Commun (Camb) ; 55(77): 11511-11514, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31490471

RESUMO

A short metallofullere-peapod of Y2@C79N⊂[4]CHBC was constructed. The strong confinement effect from the large π-extended [4]CHBC nanoring induces molecular orientation of the wrapped Y2@C79N, which can be sensed by a Y2@C79N spin probe. The low susceptibility of the spin phase memory time (Tm) for the Y2@C79N spin was also found in a confined space.


Assuntos
Complexos de Coordenação/química , Fulerenos/química , Hidrocarbonetos Cíclicos/química , Marcadores de Spin , Ítrio/química , Compostos Aza/química , Teoria da Densidade Funcional , Conformação Molecular , Transição de Fase , Temperatura , Termodinâmica
7.
Mol Inform ; 38(4): e1800104, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30468317

RESUMO

Here, we report the data visualization, analysis and modeling for a large set of 4830 SN 2 reactions the rate constant of which (logk) was measured at different experimental conditions (solvent, temperature). The reactions were encoded by one single molecular graph - Condensed Graph of Reactions, which allowed us to use conventional chemoinformatics techniques developed for individual molecules. Thus, Matched Reaction Pairs approach was suggested and used for the analyses of substituents effects on the substrates and nucleophiles reactivity. The data were visualized with the help of the Generative Topographic Mapping approach. Consensus Support Vector Regression (SVR) model for the rate constant was prepared. Unbiased estimation of the model's performance was made in cross-validation on reactions measured on unique structural transformations. The model's performance in cross-validation (RMSE=0.61 logk units) and on the external test set (RMSE=0.80) is close to the noise in data. Performances of the local models obtained for selected subsets of reactions proceeding in particular solvents or with particular type of nucleophiles were similar to that of the model built on the entire set. Finally, four different definitions of model's applicability domains for reactions were examined.


Assuntos
Modelos Químicos , Máquina de Vetores de Suporte , Hidrocarbonetos Cíclicos/química , Cinética , Oxirredução
8.
Chemistry ; 25(18): 4590-4647, 2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30387906

RESUMO

Nonconjugated hydrocarbons, like bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, triptycene, and cubane are a unique class of rigid linkers. Due to their similarity in size and shape they are useful mimics of classic benzene moieties in drugs, so-called bioisosteres. Moreover, they also fulfill an important role in material sciences as linear linkers, in order to arrange various functionalities in a defined spatial manner. In this Review article, recent developments and usages of these special, rectilinear systems are discussed. Furthermore, we focus on covalently linked, nonconjugated linear arrangements and discuss the physical and chemical properties and differences of individual linkers, as well as their application in material and medicinal sciences.


Assuntos
Hidrocarbonetos Cíclicos/química , Bioquímica , Catálise , Química Farmacêutica , Hidrocarbonetos Cíclicos/síntese química , Ciência dos Materiais , Termodinâmica
9.
Biofouling ; 34(8): 950-961, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30539667

RESUMO

A range of natural products from marine invertebrates, bacteria and fungi have been assessed as leads for nature-inspired antifouling (AF) biocides, but little attention has been paid to microalgal-derived compounds. This study assessed the AF activity of the spirocyclic imine portimine (1), which is produced by the benthic mat-forming dinoflagellate Vulcanodinium rugosum. Portimine displayed potent AF activity in a panel of four macrofouling bioassays (EC50 0.06-62.5 ng ml-1), and this activity was distinct from that of the related compounds gymnodimine-A (2), 13-desmethyl spirolide C (3), and pinnatoxin-F (4). The proposed mechanism of action for portimine is induction of apoptosis, based on the observation that portimine inhibited macrofouling organisms at developmental stages known to involve apoptotic processes. Semisynthetic modification of select portions of the portimine molecule was subsequently undertaken. Observed changes in bioactivity of the resulting semisynthetic analogues of portimine were consistent with portimine's unprecedented 5-membered imine ring structure playing a central role in its AF activity.


Assuntos
Alcaloides/farmacologia , Incrustação Biológica/prevenção & controle , Compostos Heterocíclicos com 3 Anéis/farmacologia , Hidrocarbonetos Cíclicos/farmacologia , Iminas/farmacologia , Microalgas/química , Compostos de Espiro/farmacologia , Alcaloides/síntese química , Alcaloides/química , Organismos Aquáticos/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Hidrocarbonetos Cíclicos/síntese química , Hidrocarbonetos Cíclicos/química , Iminas/síntese química , Iminas/química , Estrutura Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade
10.
Mar Drugs ; 16(11)2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30441860

RESUMO

Cyclic imine toxins are neurotoxic, macrocyclic compounds produced by marine dinoflagellates. Mass spectrometric screenings of extracts from natural plankton assemblages revealed a high chemical diversity among this toxin class, yet only few toxins are structurally known. Here we report the structural characterization of four novel cyclic-imine toxins (two gymnodimines (GYMs) and two spirolides (SPXs)) from cultures of Alexandrium ostenfeldii. A GYM with m/z 510 (1) was identified as 16-desmethylGYM D. A GYM with m/z 526 was identified as the hydroxylated degradation product of (1) with an exocyclic methylene at C-17 and an allylic hydroxyl group at C-18. This compound was named GYM E (2). We further identified a SPX with m/z 694 as 20-hydroxy-13,19-didesmethylSPX C (10) and a SPX with m/z 696 as 20-hydroxy-13,19-didesmethylSPX D (11). This is the first report of GYMs without a methyl group at ring D and SPXs with hydroxyl groups at position C-20. These compounds can be conceived as derivatives of the same nascent polyketide chain, supporting the hypothesis that GYMs and SPXs are produced through common biosynthetic genes. Both novel GYMs 1 and 2 were detected in significant amounts in extracts from natural plankton assemblages (1: 447 pg; 2: 1250 pg; 11: 40 pg per mL filtered seawater respectively).


Assuntos
Dinoflagelados/química , Compostos Heterocíclicos com 3 Anéis/química , Hidrocarbonetos Cíclicos/química , Iminas/química , Toxinas Marinhas/química , Fitoplâncton/química , Compostos de Espiro/química , Compostos Heterocíclicos com 3 Anéis/isolamento & purificação , Hidrocarbonetos Cíclicos/isolamento & purificação , Iminas/isolamento & purificação , Toxinas Marinhas/isolamento & purificação , Estrutura Molecular , Compostos de Espiro/isolamento & purificação
12.
Mar Drugs ; 16(8)2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30072624

RESUMO

One new bisabolane sesquiterpene, bisabolan-1,10,11-triol (1), one new norbisabolane sesquiterpene, 12-nor-11-acetoxybisabolen-3,6,7-triol (2), two new naturally occurring monoterpenes, (7S)- and (7R)-1-hydroxy-3-p-menthen-9-oic acids (3 and 4), one new naturally occurring trichodenone, dechlorotrichodenone C (5), one new chlorine-containing trichodenone, 3-hydroxytrichodenone C (6), one new diketopiperazine, methylcordysinin A (7), and one new naturally occurring oxazole derivative, 4-oxazolepropanoic acid (8), were isolated from the culture of a marine brown alga-endophytic strain (cf44-2) of Trichoderma asperellum. Their structures and relative configurations were determined by extensive 1D/2D NMR and mass spectrometric data, and the absolute configurations of 3⁻6 were assigned by analysis of the ECD spectra aided by quantum chemical computations. Compounds 1, 2, 5, and 6 showed growth inhibition of some marine phytoplankton species and pathogenic bacteria.


Assuntos
Hidrocarbonetos Cíclicos/química , Hidrocarbonetos Halogenados/química , Trichoderma/química , Trichoderma/metabolismo , Hidrocarbonetos Cíclicos/metabolismo , Hidrocarbonetos Halogenados/metabolismo , Estrutura Molecular
13.
J Am Chem Soc ; 140(32): 10233-10241, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30063341

RESUMO

A diastereodivergent hydroarylation of terminal alkynes is accomplished using tandem catalysis. The hydroarylation allows highly selective synthesis of both E and Z diastereoisomers of aryl alkenes, from the same set of starting materials, using the same combination of palladium and copper catalysts. The selectivity is controlled by simple changes in the stoichiometry of the alcohol additive. The hydroarylation has excellent substrate scope and can be accomplished in the presence of various classes of compounds, including esters, nitriles, alkyl halides, epoxides, carbamates, acetals, ethers, silyl ethers, and thioethers. The Z-selective hydroarylation is accomplished using a new approach based on tandem Sonogashira coupling and catalytic semireduction. The E-selective hydroarylation involves an additional catalytic isomerization of the Z-alkene. Our explorations of the reaction mechanism explain the role of individual reaction components and how the subtle changes in the reaction conditions influence the rates of specific steps of the hydroarylation. Our studies also show that, although the Z- and E-selective hydroarylation reactions are mechanistically closely related, the roles of the palladium and copper catalysts in the two reactions are different.


Assuntos
Alquinos/síntese química , Alquinos/química , Catálise , Cobre/química , Hidrocarbonetos Cíclicos/síntese química , Hidrocarbonetos Cíclicos/química , Estrutura Molecular , Paládio/química
14.
J Comput Aided Mol Des ; 32(10): 1151-1163, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30073500

RESUMO

The "embedded cluster reference interaction site model" (EC-RISM) integral equation theory is applied to the problem of predicting aqueous pKa values for drug-like molecules based on an ensemble of tautomers. EC-RISM is based on self-consistent calculations of a solute's electronic structure and the distribution function of surrounding water. Following-up on the workflow developed after the SAMPL5 challenge on cyclohexane-water distribution coefficients we extended and improved the methodology by taking into account exact electrostatic solute-solvent interactions taken from the wave function in solution. As before, the model is calibrated against Gibbs energies of hydration from the "Minnesota Solvation Database" and a public dataset of acidity constants of organic acids and bases by adjusting in total 4 parameters, among which only 3 are relevant for predicting pKa values. While the best-performing training model yields a root-mean-square error (RMSE) of 1 pK unit, the corresponding test set prediction on the full SAMPL6 dataset of macroscopic pKa values using the same level of theory exhibits slightly larger error (1.7 pK units) than the best test set model submitted (1.7 pK units for corresponding training set vs. test set performance of 1.6). Post-submission analysis revealed a number of physical optimization options regarding the numerical treatment of electrostatic interactions and conformational sampling. While the experimental test set data revealed after submission was not used for reparametrizing the methodology, the best physically optimized models consequentially result in RMSEs of 1.5 if only improved electrostatic interactions are considered and of 1.1 if, in addition, conformational sampling accounts for quantum-chemically derived rankings. We conclude that these numbers are probably near the ultimate accuracy achievable with the simple 3-parameter model using a single or the two best-ranking conformations per tautomer or microstate. Finally, relations of the present macrostate approach to microstate pKa results are discussed and some illustrative results for microstate populations are presented.


Assuntos
Hidrocarbonetos Cíclicos/química , Modelos Químicos , Simulação por Computador , Bases de Dados de Compostos Químicos , Modelos Teóricos , Conformação Molecular , Soluções/química , Solventes/química , Eletricidade Estática , Termodinâmica , Água/química
15.
J Oleo Sci ; 67(4): 433-443, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29526873

RESUMO

We have studied the phase behavior of distearoylphosphatidylcholine (DSPC) in the presence of sodium ß-sitosteryl sulfate (PSO4). PSO4 was found to induce sterol-rich and sterol-poor domains in the DSPC membrane. These two domains constitute a fluid, liquid ordered (Lo) phase and a gel (Lß) phase. PSO4 was less miscible in DSPC than in a dipalmitoylphosphatidylcholine (DPPC) membrane, as evidenced by its tendency to separate from the bilayer at a concentration of 50 mol%. This lack of miscibility was attributed to the greater van der Waals forces between the PC hydrocarbon chains. In addition to affecting the phase behavior, PSO4 also enhanced the hydration of the membrane. Despite its weaker interaction with DSPC compared to DPPC, its tendency to fluidize this phospholipid and enhance its hydration can be useful in formulating cosmetics and pharmaceutical products.


Assuntos
1,2-Dipalmitoilfosfatidilcolina/química , Transição de Fase , Fosfatidilcolinas/química , Sitosteroides/química , Varredura Diferencial de Calorimetria , Hidrocarbonetos Cíclicos/química , Bicamadas Lipídicas , Microscopia de Polarização , Estrutura Molecular , Espalhamento a Baixo Ângulo , Temperatura de Transição
16.
Org Biomol Chem ; 16(11): 1791-1806, 2018 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-29464265

RESUMO

Chemical C-glycosylation has been well developed to improve stereoselectivity in recent years. Due to its high efficiency to build C-glycosides or O-cyclic compounds, C-glycosylation has found widespread use in the synthesis of biologically active molecules. This review highlights the C-glycosylation methods that have been practised in the total synthesis of natural products and pharmaceuticals in the past decade.


Assuntos
Produtos Biológicos/síntese química , Técnicas de Química Sintética/métodos , Preparações Farmacêuticas/síntese química , Produtos Biológicos/química , Glicosídeos/síntese química , Glicosídeos/química , Glicosilação , Hidrocarbonetos Acíclicos/síntese química , Hidrocarbonetos Acíclicos/química , Hidrocarbonetos Cíclicos/síntese química , Hidrocarbonetos Cíclicos/química , Preparações Farmacêuticas/química , Estereoisomerismo
17.
Toxicol Sci ; 157(1): 246-259, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28186253

RESUMO

Nitrated polycyclic aromatic hydrocarbons (NPAHs) and heterocyclic PAHs (HPAHs) are recognized environmental pollutants. However, the health risks of NPAHs and HPAHs to humans and environmental systems are not well-studied. The developmental zebrafish (Danio rerio) model was used to evaluate the toxicity of a structurally diverse set of 27 NPAHs and 10 HPAHs. The individual activity of each compound towards the aryl hydrocarbon receptor (AHR), including the role of the AHR in observed toxicity, and genetic markers of oxidative stress and cardiac toxicity were evaluated. Zebrafish embryos were exposed from 6 to 120 hours post fertilization (hpf), to a broad concentration range of individual compounds, and evaluated for 22 developmental endpoints. The potential role of AHR was determined using the transgenic Tg(cyp1a:nls-egfp) reporter zebrafish line. All compounds were screened computationally through molecular docking using a previously developed AHR models of zebrafish isoforms 1A, 1B, and 2. Some compounds did not induce observable developmental toxic responses, whereas others produced statistically significant concentration-dependent toxicity. The tested compounds also exhibited a range of predicted AHR binding and cyp1a/GFP induction patterns, including cyp1a expression in the liver, vasculature, skin, and yolk, which we determined to be due to distinct isoforms of the AHR, using morpholino oligonucleotide knockdown. Furthermore, we investigated mRNA expression of oxidative and cardiac stress genes at 48 and 120 hpf, which indicated several potential mechanisms-of-action for NPAHs. Overall, we observed a range of developmental toxicities, cyp1a/GFP expression patterns, and gene expression profiles, suggestive of several potential mechanisms of action.


Assuntos
Compostos Heterocíclicos/toxicidade , Hidrocarbonetos Cíclicos/toxicidade , Nitratos/química , Teratogênios/toxicidade , Animais , Animais Geneticamente Modificados , Citocromo P-450 CYP1A1/genética , Técnicas de Silenciamento de Genes , Hidrocarbonetos Cíclicos/química , Estresse Oxidativo/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/genética , Estresse Fisiológico/efeitos dos fármacos , Peixe-Zebra
18.
Nat Prod Commun ; 12(5): 713-732, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-30496682

RESUMO

Metathesis reactions is firmly established as a valuable synthetic tool in organic chemistry, clearly comparable with the venerable Diels-Alder and Wittig reactions and, more recently, with the metal-catalyzed cross-coupling reactions. Metathesis reactions can be considered as a fascinating synthetic methodology, allowing different variants regarding substrate (alkene and alkyne metathesis) and type of metathetical reactions. On the other hand, tandem metathesis reactions such.Ring Rearrangement Metathesis (RRM) and the coupling of metathesis reaction with other reactions of alkenes such as Diels-Alder or Heck reactions,.makes metathesis one of the most powerful and reliable synthetic procedure. In particular, Ring-Rearrangement Metathesis (RRM) refers to the combination of several metathesis transformations into a domino process such as ring- opening metathesis (ROM)/ring-closing metathesis (RCM) and ROM-cross metathesis (CM) in a one-pot operation. RRM delivers complex frameworks that are difficult to assemble by conventional methods constitutingan atom economic process. RRM is applicable to mono- and polycyclie systems of varying ring sizes such as cyclopropene, cyclobutene, cyclopentene, cyclohexene, pyran systems, bicyclo[2.2.1]heptene derivatives, bicyclo[2.2.2]octene derivatives, bicyclo[3.2.l]octene derivatives and bicyclo[3.2.1]octene derivatives. In this review our attention has focused on the RRM reactions in 7-oxabicyclo[2.2.I]heptene derivatives and on their application in the synthesis of natural products or significant subunits of them.


Assuntos
Produtos Biológicos/química , Hidrocarbonetos Cíclicos/química , Estrutura Molecular
19.
Chem Commun (Camb) ; 52(23): 4329-32, 2016 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-26923422

RESUMO

A palladium-catalyzed regioselective C-2 arylation of 7-azaindoles, indoles, and pyrroles with arenes has been developed. This study unveils that a critical substrate dependent acid concentration is essential for achieving exclusive C-2 selectivity as well as mono-arylation in pyrroles. Incongruent to the literature, the protocol uses a reduced volume (at least 5 times) of arenes for workable access to C-2 arylated heterocycles.


Assuntos
Hidrocarbonetos Cíclicos/química , Indóis/química , Paládio/química , Pirróis/química , Catálise
20.
Toxicon ; 112: 68-76, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26829651

RESUMO

Gymnodimines are lipophilic toxins produced by the marine dinoflagellates Karenia selliformis and Alexandrium ostenfeldii. Currently four gymnodimine analogues are known and characterized. Here we describe a novel gymnodimine and a range of gymnodimine related compounds found in an A. ostenfeldii isolate from the northern Baltic Sea. Gymnodimine D (1) was extracted and purified from clonal cultures, and characterized by liquid chromatography-tandem mass spectrometry (LC-MS/MS), nuclear magnetic resonance (NMR) spectroscopy, and liquid chromatography-high resolution mass spectrometry (LC-HRMS) experiments. The structure of 1 is related to known gymnodimines (2-5) with a six-membered cyclic imine ring and several other fragments typical of gymnodimines. However, the carbon chain in the gymnodimine macrocyclic ring differs from the known gymnodimines in having two tetrahydrofuran rings in the macrocyclic ring.


Assuntos
Dinoflagelados/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Hidrocarbonetos Cíclicos/metabolismo , Toxinas Marinhas/metabolismo , Oceano Atlântico , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Células Clonais , Dinoflagelados/química , Dinoflagelados/citologia , Dinoflagelados/crescimento & desenvolvimento , Proliferação Nociva de Algas , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/isolamento & purificação , Compostos Heterocíclicos com 3 Anéis/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/isolamento & purificação , Hidrocarbonetos Cíclicos/química , Hidrocarbonetos Cíclicos/isolamento & purificação , Iminas/química , Iminas/isolamento & purificação , Iminas/metabolismo , Toxinas Marinhas/química , Toxinas Marinhas/isolamento & purificação , Metilação , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Espectrometria de Massas por Ionização por Electrospray , Estereoisomerismo , Suécia , Espectrometria de Massas em Tandem
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