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1.
Chem Sci ; 8(2): 1186-1194, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-28451259

RESUMO

We apply a combination of state-of-the-art experimental and quantum-chemical methods to elucidate the electronic and chemical energetics of hydrogen adduction to a model open-shell graphene fragment. The lowest-energy adduct, 1H-phenalene, is determined to have a bond dissociation energy of 258.1 kJ mol-1, while other isomers exhibit reduced or in some cases negative bond dissociation energies, the metastable species being bound by the emergence of a conical intersection along the high-symmetry dissociation coordinate. The gas-phase excitation spectrum of 1H-phenalene and its radical cation are recorded using laser spectroscopy coupled to mass-spectrometry. Several electronically excited states of both species are observed, allowing the determination of the excited-state bond dissociation energy. The ionization energy of 1H-phenalene is determined to be 7.449(17) eV, consistent with high-level W1X-2 calculations.

2.
J Med Chem ; 58(19): 7707-18, 2015 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-26359549

RESUMO

The Grb7 adaptor protein is a therapeutic target for both TNBC and HER2+ breast cancer. A nonphosphorylated cyclic peptide 1 (known as G7-18NATE) inhibits Grb7 via targeting the Grb7-SH2 domain, but requires the presence of phosphate ions for both affinity and specificity. Here we report the discovery of malonate bound in the phosphotyrosine binding pocket of the apo-Grb7-SH2 structure. Based on this, we carried out the rational design and synthesis of two analogues of peptide 1 that incorporate carboxymethylphenylalanine (cmF) and carboxyphenylalanine (cF) as mimics of phosphotyrosine (pY). Binding studies using SPR confirmed that affinity for Grb7-SH2 domain is improved up to 9-fold over peptide 1 under physiological phosphate conditions (KD = 2.1-5.7 µM) and that binding is specific for Grb7-SH2 over closely related domains (low or no detectable binding to Grb2-SH2 and Grb10-SH2). X-ray crystallographic structural analysis of the analogue bearing a cmF moiety in complex with Grb7-SH2 has identified the precise contacts conferred by the pY mimic that underpin this improved molecular interaction. Together this study identifies and characterizes the tightest specific inhibitor of Grb7 to date, representing a significant development toward a new Grb7-targeted therapeutic.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proteína Adaptadora GRB7/antagonistas & inibidores , Peptídeos Cíclicos/química , Fosfotirosina/química , Antineoplásicos/síntese química , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Cristalografia por Raios X , Feminino , Proteína Adaptadora GRB7/metabolismo , Humanos , Malonatos/química , Terapia de Alvo Molecular , Peptídeos Cíclicos/síntese química , Peptidomiméticos , Fosfatos/química , Fosfatos/metabolismo , Conformação Proteica , Domínios de Homologia de src
3.
J Med Chem ; 57(24): 10557-63, 2014 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-25412465

RESUMO

Analogues of the natural product gallinamide A were prepared to elucidate novel inhibitors of the falcipain cysteine proteases. Analogues exhibited potent inhibition of falcipain-2 (FP-2) and falcipain-3 (FP-3) and of the development of Plasmodium falciparum in vitro. Several compounds were equipotent to chloroquine as inhibitors of the 3D7 strain of P. falciparum and maintained potent activity against the chloroquine-resistant Dd2 parasite. These compounds serve as promising leads for the development of novel antimalarial agents.


Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Cisteína Endopeptidases/química , Peptídeos/química , Peptídeos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Peptídeos Catiônicos Antimicrobianos , Cisteína Endopeptidases/metabolismo , Células HEK293 , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
4.
J Biol Chem ; 289(9): 5580-95, 2014 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-24436331

RESUMO

Oxidants derived from myeloperoxidase (MPO) contribute to inflammatory diseases. In vivo MPO activity is commonly assessed by the accumulation of 3-chlorotyrosine (3-Cl-Tyr), although 3-Cl-Tyr is formed at low yield and is subject to metabolism. Here we show that MPO activity can be assessed using hydroethidine (HE), a probe commonly employed for the detection of superoxide. Using LC/MS/MS, (1)H NMR, and two-dimensional NOESY, we identified 2-chloroethidium (2-Cl-E(+)) as a specific product when HE was exposed to hypochlorous acid (HOCl), chloramines, MPO/H2O2/chloride, and activated human neutrophils. The rate constant for HOCl-mediated conversion of HE to 2-Cl-E(+) was estimated to be 1.5 × 10(5) M(-1)s(-1). To investigate the utility of 2-Cl-E(+) to assess MPO activity in vivo, HE was injected into wild-type and MPO-deficient (Mpo(-/-)) mice with established peritonitis or localized arterial inflammation, and tissue levels of 2-Cl-E(+) and 3-Cl-Tyr were then determined by LC/MS/MS. In wild-type mice, 2-Cl-E(+) and 3-Cl-Tyr were detected readily in the peritonitis model, whereas in the arterial inflammation model 2-Cl-E(+) was present at comparatively lower concentrations (17 versus 0.3 pmol/mg of protein), and 3-Cl-Tyr could not be detected. Similar to the situation with 3-Cl-Tyr, tissue levels of 2-Cl-E(+) were decreased substantially in Mpo(-/-) mice, indicative of the specificity of the assay. In the arterial inflammation model, 2-Cl-E(+) was absent from non-inflamed arteries and blood, suggesting that HE oxidation occurred locally in the inflamed artery. Our data suggest that the conversion of exogenous HE to 2-Cl-E(+) may be a useful selective and sensitive marker for MPO activity in addition to 3-Cl-Tyr.


Assuntos
Peróxido de Hidrogênio/química , Oxidantes/química , Peroxidase/química , Fenantridinas/química , Animais , Arterite/enzimologia , Arterite/genética , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Knockout , Peritonite/enzimologia , Peritonite/genética , Peroxidase/genética , Peroxidase/metabolismo
5.
Org Lett ; 16(1): 290-3, 2014 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-24294973

RESUMO

An efficient methodology for ligation at glutamate (Glu) is described. A γ-thiol-Glu building block was accessed in only three steps from protected glutamic acid and could be incorporated at the N-terminus of peptides. The application of these peptides in one-pot ligation-desulfurization chemistry is demonstrated with a range of peptide thioesters, and the utility of this methodology is highlighted through the synthesis of the osteoporosis peptide drug teriparatide (Forteo).


Assuntos
Ácido Glutâmico/química , Peptídeos/química , Peptídeos/síntese química , Teriparatida/síntese química , Estrutura Molecular , Teriparatida/química
6.
Mar Drugs ; 11(7): 2382-97, 2013 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-23880930

RESUMO

The total syntheses of the marine-derived lipopeptide natural product fellutamide B and deoxy-fellutamides B, C, and D are reported. These compounds were accessed through a novel solid-phase synthetic strategy using Weinreb amide-derived resin. As part of the synthesis, a new enantioselective route to (3R)-hydroxy lauric acid was developed utilizing a Brown allylation reaction followed by an oxidative cleavage-oxidation sequence as the key steps. The activity of these natural products, and natural product analogues was also assessed against Mycobacterium tuberculosis in vitro.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/síntese química , Lipopeptídeos/química , Lipopeptídeos/síntese química , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Produtos Biológicos/farmacologia , Ácidos Láuricos/síntese química , Ácidos Láuricos/química , Ácidos Láuricos/farmacologia , Lipopeptídeos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Estereoisomerismo
7.
Chembiochem ; 14(5): 559-63, 2013 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-23426906

RESUMO

The utility of a new ß-thiol arginine building block in ligation-desulfurization chemistry has been demonstrated through reactions and kinetic studies with a range of peptide thioesters. Application of the method is highlighted by a one-pot, kinetically controlled, rapid ligation to generate a 7 kDa MUC1 glycopeptide.


Assuntos
Arginina/química , Glicopeptídeos/química , Compostos de Sulfidrila/química , Arginina/síntese química , Ésteres , Glicopeptídeos/síntese química , Cinética , Mucina-1/química
8.
Org Biomol Chem ; 10(46): 9223-36, 2012 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-23108268

RESUMO

Mycobacterium tuberculosis salicylate synthase (MbtI) catalyses the first committed step in the biosynthesis of mycobactin T, an iron-chelating siderophore essential for the virulence and survival of M. tuberculosis. Co-crystal structures of MbtI with members of a first generation inhibitor library revealed large inhibitor-induced rearrangements within the active site of the enzyme. This plasticity of the MbtI active site was probed via the preparation of a library of inhibitors based on a 2,3-dihydroxybenzoate scaffold with a range of substituted phenylacrylate side chains appended to the C3 position. Most compounds exhibited moderate inhibitory activity against the enzyme, with inhibition constants in the micromolar range, while several dimethyl ester variants possessed promising anti-tubercular activity in vitro.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Hidroxibenzoatos/química , Liases/antagonistas & inibidores , Mycobacterium tuberculosis/enzimologia , Bibliotecas de Moléculas Pequenas/síntese química , Acrilatos/química , Proteínas de Bactérias/metabolismo , Domínio Catalítico , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Ésteres , Cinética , Liases/metabolismo , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Modelos Moleculares , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/efeitos dos fármacos , Ligação Proteica , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade
10.
12.
Nat Protoc ; 2(10): 2568-73, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17947999

RESUMO

The protocol for the preparation of boron enolates and their subsequent reaction with aldehydes is described, providing convenient access to beta-hydroxy ketones in good yields and with high stereoselectivities. The reaction consists of three steps: first, the ketone is rapidly converted to the corresponding boron enolate, by exposure to a chlorodialkylborane and tertiary amine base, which is then reacted in situ with the aldehyde. Finally, oxidative workup of the resultant boron aldolate provides aldol adduct. The reaction procedure requires approximately 28 h to complete over a 2-d period, consisting of 5 h to set up the reaction, whereupon the reaction mixture is left at -20 degrees C overnight (16 h), followed by 7 h for workup and purification.


Assuntos
Aldeídos/química , Compostos de Boro/química , Compostos de Boro/síntese química , Cetonas/química , Oxirredução
13.
Chem Commun (Camb) ; (13): 1363-5, 2007 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-17377683

RESUMO

The boron-mediated ketone-ketone aldol reaction is demonstrated, through 1H NMR studies, to be reversible, in contrast to the strictly irreversible aldol reactions of boron enolates with aldehydes.


Assuntos
Boro/química , Cetonas/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular
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