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1.
Chem Res Toxicol ; 32(3): 400-404, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30523678

RESUMO

The dithiolopyrrolone (DTP) natural products contain a unique ene-disulfide that is essential for their antimicrobial and anticancer activities. The ene-disulfide in some DTPs is oxidized to a cyclic thiosulfonate, but it is unknown how the DTP thiosulfonates react with biomolecules. We studied the reactivity of the thiosulfonate derivative of the DTP holomycin, oxo-holomycin, and discovered a unique redox reaction: Oxo-holomycin is reduced to its parent disulfide, while oxidizing small molecule and protein thiols to disulfides. Our work reveals that the DTP core is a privileged scaffold that undergoes unusual redox chemistry. The redox chemistry of the DTP natural products may contribute to their mechanism of action.


Assuntos
Dissulfetos/química , Lactamas/química , Pirrolidinonas/química , Compostos de Sulfidrila/química , Ácidos Sulfônicos/química , Estrutura Molecular , Oxirredução
2.
J Org Chem ; 83(23): 14362-14384, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30376626

RESUMO

The evolution of a more reactive chiral vanadium catalyst for enantioselective oxidative coupling of phenols is reported, ultimately resulting in a simple monomeric vanadium species combined with a Brønsted or Lewis acid additive. The resultant vanadium complex is found to effect the asymmetric oxidative ortho-ortho coupling of simple phenols and 2-hydroxycarbazoles with good to excellent levels of enantioselectivity. Experimental and quantum mechanical studies of the mechanism indicate that the additives aggregate the vanadium monomers. In addition, a singlet to triplet crossover is implicated prior to carbon-carbon bond formation. The two lowest energy diastereomeric transition states leading to the enantiomeric products differ substantially with the path to the minor enantiomer involving greater torsional strain between the two phenol moieties.


Assuntos
Acoplamento Oxidativo , Produtos Biológicos/química , Catálise , Modelos Moleculares , Estrutura Molecular , Naftóis/química , Fenóis/química , Vanádio/química
3.
J Am Chem Soc ; 136(33): 11783-91, 2014 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-25050843

RESUMO

The N-heterocyclic carbene and hydroxamic acid cocatalyzed kinetic resolution of cyclic amines generates enantioenriched amines and amides with selectivity factors up to 127. In this report, a quantum mechanical study of the reaction mechanism indicates that the selectivity-determining aminolysis step occurs via a novel concerted pathway in which the hydroxamic acid plays a key role in directing proton transfer from the incoming amine. This modality was found to be general in amide bond formation from a number of activated esters including those generated from HOBt and HOAt, reagents that are broadly used in peptide coupling. For the kinetic resolution, the proposed model accurately predicts the faster reacting enantiomer. A breakdown of the steric and electronic control elements shows that a gearing effect in the transition state is responsible for the observed selectivity.


Assuntos
Amidas/síntese química , Aminas/química , Ésteres/química , Compostos Heterocíclicos/química , Ácidos Hidroxâmicos/química , Metano/análogos & derivados , Amidas/química , Aminas/síntese química , Catálise , Cinética , Metano/química , Estrutura Molecular , Teoria Quântica , Estereoisomerismo
4.
J Am Chem Soc ; 134(29): 12098-103, 2012 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-22765294

RESUMO

The N-heterocyclic carbene catalyzed [4 + 2] cycloaddition has been shown to give γ,δ-unsaturated δ-lactones in excellent enantio- and diastereoselectivity. However, preliminary computational studies of the geometry of the intermediate enolate rendered ambiguous both the origins of selectivity and the reaction pathway. Here, we show that a concerted, but highly asynchronous, Diels-Alder reaction occurs rather than the stepwise Michael-type or Claisen-type pathways. In addition, two crucial interactions are identified that enable high selectivity: an oxyanion-steering mechanism and a CH-π interaction. The calculations accurately predict the enantioselectivity of a number of N-heterocyclic carbene catalysts in the hetero-Diels-Alder reaction.


Assuntos
Compostos Heterocíclicos/química , Lactonas/química , Metano/análogos & derivados , Oxigênio/química , Ânions/química , Catálise , Ciclização , Lactonas/síntese química , Metano/química , Modelos Moleculares , Estereoisomerismo
6.
Circ Res ; 99(8): 870-7, 2006 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-16973909

RESUMO

Caveolin-1, the caveolae scaffolding protein, binds to and negatively regulates eNOS activity. As caveolin-1 also regulates caveolae-mediated endocytosis after activation of the 60-kDa albumin-binding glycoprotein gp60 in endothelial cells, we addressed the possibility that endothelial NO synthase (eNOS)-dependent NO production was functionally coupled to caveolae internalization. We observed that gp60-induced activation of endocytosis increased NO production within 2 minutes and up to 20 minutes. NOS inhibitor N(G)-nitro-L-arginine (L-NNA) prevented the NO production. To determine the role of caveolae internalization in the mechanism of NO production, we expressed dominant-negative dynamin-2 mutant (K44A) or treated cells with methyl-beta-cyclodextrin. Both interventions inhibited caveolae-mediated endocytosis and NO generation induced by gp60. We determined the role of signaling via Src kinase in the observed coupling of endocytosis to eNOS activation. Src activation induced the phosphorylation of caveolin-1, Akt and eNOS, and promoted dissociation of eNOS from caveolin-1. Inhibitors of Src kinase and Akt also prevented NO production. In isolated perfused mouse lungs, gp60 activation induced NO-dependent vasodilation, whereas the response was attenuated in eNOS(-/-) or caveolin-1(-/-) lungs. Together, these results demonstrate a critical role of caveolae-mediated endocytosis in regulating eNOS activation in endothelial cells and thereby the NO-dependent vasomotor tone.


Assuntos
Cavéolas/fisiologia , Endocitose/fisiologia , Células Endoteliais/enzimologia , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Cálcio/fisiologia , Caveolina 1/deficiência , Caveolina 1/metabolismo , Células Cultivadas , Células Endoteliais/metabolismo , Ativação Enzimática/fisiologia , Subunidades beta da Proteína de Ligação ao GTP/fisiologia , Subunidades gama da Proteína de Ligação ao GTP/fisiologia , Pulmão/irrigação sanguínea , Camundongos , Camundongos Knockout , Óxido Nítrico/biossíntese , Proteínas Proto-Oncogênicas c-akt/fisiologia , Ratos , Sialoglicoproteínas/fisiologia , Fatores de Tempo , Distribuição Tecidual , Vasodilatação , Quinases da Família src/fisiologia
7.
mSystems ; 2(6)2017.
Artigo em Inglês | MEDLINE | ID: mdl-29152584

RESUMO

Bacteria possess an amazing capacity to synthesize a diverse range of structurally complex, bioactive natural products known as specialized (or secondary) metabolites. Many of these specialized metabolites are used as clinical therapeutics, while others have important ecological roles in microbial communities. The biosynthetic gene clusters (BGCs) that generate these metabolites can be identified in bacterial genome sequences using their highly conserved genetic features. We analyzed an unprecedented 1,566 bacterial genomes from Bacillus species and identified nearly 20,000 BGCs. By comparing these BGCs to one another as well as a curated set of known specialized metabolite BGCs, we discovered that the majority of Bacillus natural products are comprised of a small set of highly conserved, well-distributed, known natural product compounds. Most of these metabolites have important roles influencing the physiology and development of Bacillus species. We identified, in addition to these characterized compounds, many unique, weakly conserved BGCs scattered across the genus that are predicted to encode unknown natural products. Many of these "singleton" BGCs appear to have been acquired via horizontal gene transfer. Based on this large-scale characterization of metabolite production in the Bacilli, we go on to connect the alkylpyrones, natural products that are highly conserved but previously biologically uncharacterized, to a role in Bacillus physiology: inhibiting spore development. IMPORTANCEBacilli are capable of producing a diverse array of specialized metabolites, many of which have gained attention for their roles as signals that affect bacterial physiology and development. Up to this point, however, the Bacillus genus's metabolic capacity has been underexplored. We undertook a deep genomic analysis of 1,566 Bacillus genomes to understand the full spectrum of metabolites that this bacterial group can make. We discovered that the majority of the specialized metabolites produced by Bacillus species are highly conserved, known compounds with important signaling roles in the physiology and development of this bacterium. Additionally, there is significant unique biosynthetic machinery distributed across the genus that might lead to new, unknown metabolites with diverse biological functions. Inspired by the findings of our genomic analysis, we speculate that the highly conserved alkylpyrones might have an important biological activity within this genus. We go on to validate this prediction by demonstrating that these natural products are developmental signals in Bacillus and act by inhibiting sporulation.

8.
Org Lett ; 19(20): 5505-5508, 2017 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-29022352

RESUMO

The first examples of asymmetric oxidative coupling of simple phenols and 2-hydroxycarbazoles are outlined. Generation of a more vanadium catalyst by ligand design and by addition of an exogenous Brønsted or Lewis acid was found to be key to coupling the more oxidatively resistant phenols. The resultant vanadium complex is both more Lewis acidic and more strongly oxidizing. Good to excellent levels of enantioselectivity could be obtained, and simple trituration readily provided the products with ≥95% ee.


Assuntos
Fenóis/química , Carbazóis , Catálise , Estrutura Molecular , Acoplamento Oxidativo , Estereoisomerismo
9.
ACS Chem Biol ; 11(1): 10-24, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26575401

RESUMO

Many natural products consist of large and flexible macrocycles that engage their targets via multiple contact points. This combination of contained flexibility and large contact area often allows natural products to bind at target surfaces rather than deep pockets, making them attractive scaffolds for inhibiting protein-protein interactions and other challenging therapeutic targets. The increasing ability to manipulate such compounds either biosynthetically or via semisynthetic modification means that these compounds can now be considered as starting points for medchem campaigns rather than solely as ends. Modern medchem benefits substantially from rational improvements made on the basis of molecular docking. As such, docking methods have been enhanced in recent years to deal with the complicated binding modalities and flexible scaffolds of macrocyclic natural products and natural product-like structures. Here, we comprehensively review methods for treating and docking these large macrocyclic scaffolds and discuss some of the resulting advances in medicinal chemistry.


Assuntos
Compostos Macrocíclicos/química , Simulação de Acoplamento Molecular , Sítios de Ligação , Integrinas/química , Conformação Molecular
10.
ACS Chem Biol ; 11(6): 1737-44, 2016 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-27019323

RESUMO

Sactipeptides are peptide-derived natural products that are processed by remarkable, radical-mediated cysteine sulfur to α-carbon coupling reactions. The resulting sactionine thioether linkages give rise to the unique defined structures and concomitant biological activities of sactipeptides. An E. coli heterologous expression system, based on the biosynthesis of one such sactipeptide, subtilosin A, is described and this expression system is exploited to probe the promiscuity of the subtilosin A sactionine bond-forming enzyme, AlbA. These efforts allowed the facile expression and isolation of a small library of mutant sactipeptides based on the subtilosin A precursor peptide, demonstrating broad substrate promiscuity where none was previously known. Importantly, we show that the positions of the sactionine linkages can be moved, giving rise to new, unnatural sactipeptide structures. E. coli heterologous expression also allowed incorporation of unnatural amino acids into sactipeptides by means of amber-suppression technology, potentially opening up new chemistry and new applications for unnatural sactipeptides.


Assuntos
Bacteriocinas/biossíntese , Peptídeos Cíclicos/biossíntese , Bacteriocinas/genética , Cisteína/química , Escherichia coli , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Expressão Gênica , Estrutura Molecular , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo , Peptídeos Cíclicos/genética , Engenharia de Proteínas , Precursores de Proteínas/biossíntese , Precursores de Proteínas/genética , Especificidade por Substrato
11.
Chemistry ; 13(27): 7780-4, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17591728

RESUMO

Two beta-receptor agonists (-)-denopamine and (-)-arbutamine were prepared in good yields and enantioselectivities by asymmetric hydrogenation of unprotected amino ketones for the first time by using Rh catalysts bearing electron-donating phosphine ligands. A series of alpha-primary and secondary amino ketones were synthesized and hydrogenated to produce various 1,2-amino alcohols in good yields and with good enantioselectivies. This Rh electron-donating phosphine-catalyzed asymmetric hyderogenation represents one of the most promising and convenient approaches towards the asymmetric synthesis of chiral amino alcohols.


Assuntos
Agonistas Adrenérgicos beta/síntese química , Catecolaminas/síntese química , Etanolaminas/síntese química , Hidrogênio/química , Cetonas/química , Estereoisomerismo
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