Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
J Am Chem Soc ; 144(43): 19953-19972, 2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-36269121

RESUMO

The total syntheses of aflastatin A and its C3-C48 degradation fragment (6a, R = H) have been accomplished. The syntheses feature several complex diastereoselective fragment couplings, including a Felkin-selective trityl-catalyzed Mukaiyama aldol reaction, a chelate-controlled aldol reaction involving soft enolization with magnesium, and an anti-Felkin-selective boron-mediated oxygenated aldol reaction. Careful comparison of the spectroscopic data for the synthetic C3-C48 degradation fragment to that reported by the isolation group revealed a structural misassignment in the lactol region of the naturally derived degradation product. Ultimately, the data reported for the naturally derived aflastatin A C3-C48 degradation lactol (6a, R = H) were attributed to its derivative lactol trideuteriomethyl ether (6c, R = CD3). Additionally, the revised absolute configurations of six stereogenic centers (C8, C9, and C28-C31) were confirmed.


Assuntos
Aldeídos , Pirrolidinonas , Boro , Estereoisomerismo , Estrutura Molecular
2.
Proc Natl Acad Sci U S A ; 106(7): 2200-5, 2009 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-19164757

RESUMO

The ubiquitin-proteasome system has recently emerged as a major target for drug development in cancer therapy. The proteasome inhibitor bortezomib has clinical activity in multiple myeloma and mantle cell lymphoma. Here we report that Eeyarestatin I (EerI), a chemical inhibitor that blocks endoplasmic reticulum (ER)-associated protein degradation, has antitumor and biologic activities similar to bortezomib and can synergize with bortezomib. Like bortezomib, EerI-induced cytotoxicity requires the up-regulation of the Bcl-2 homology3 (BH3)-only pro-apoptotic protein NOXA. We further demonstrate that both EerI and bortezomib activate NOXA via an unanticipated mechanism that requires cooperation between two processes. First, these agents elicit an integrated stress response program at the ER to activate the CREB/ATF transcription factors ATF3 and ATF4. We show that ATF3 and ATF4 form a complex capable of binding to the NOXA promoter, which is required for NOXA activation. Second, EerI and bortezomib also block ubiquitination of histone H2A to relieve its inhibition on NOXA transcription. Our results identify a class of anticancer agents that integrate ER stress response with an epigenetic mechanism to induce cell death.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Retículo Endoplasmático/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Complexo de Endopeptidases do Proteassoma/química , Ubiquitina/química , Proteínas Adaptadoras de Transdução de Sinal , Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Bortezomib , Linhagem Celular , Linhagem Celular Tumoral , Células HeLa , Humanos , Hidrazonas/metabolismo , Hidroxiureia/análogos & derivados , Hidroxiureia/metabolismo , Neoplasias/metabolismo , Pirazinas/farmacologia , Transcrição Gênica
3.
Bioorg Med Chem Lett ; 21(9): 2740-5, 2011 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-21185184

RESUMO

Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine derivatives such as SCH 442416 display high affinity and selectivity as antagonists for the human A(2A) adenosine receptor (AR). We extended ether-linked chain substituents at the p-position of the phenyl group using optimized O-alkylation. The conjugates included an ester, carboxylic acid and amines (for amide condensation), an alkyne (for click chemistry), a fluoropropyl group (for (18)F incorporation), and fluorophore reporter groups (e.g., BODIPY conjugate 14, K(i) 15 nM). The potent and A(2A)AR-selective N-aminoethylacetamide 7 and N-[2-(2-aminoethyl)-aminoethyl]acetamide 8 congeners were coupled to polyamidoamine (PAMAM) G3.5 dendrimers, and the multivalent conjugates displayed high A(2A)AR affinity. Theoretical docking of an AlexaFluor conjugate to the receptor X-ray structure highlighted the key interactions between the heterocyclic core and the binding pocket of the A(2A)AR as well as the distal anchoring of the fluorophore. In conclusion, we have synthesized a family of high affinity functionalized congeners as pharmacological probes for studying the A(2A)AR.


Assuntos
Antagonistas do Receptor A2 de Adenosina , Desenho de Fármacos , Pirazóis/síntese química , Pirimidinas/síntese química , Humanos , Modelos Moleculares , Sondas Moleculares/síntese química , Sondas Moleculares/química , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia
4.
Tetrahedron Lett ; 52(32): 4103-4105, 2011 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-21931465

RESUMO

The HIV-1 nucleocapsid (NCp7), structurally defined by zinc-binding domains, participates in crucial stages of the HIV-1 lifecycle and is mutationally nonpermissive, making it an attractive anti-HIV target. Mode of action studies have shown that the secondary structure and activity of NCp7 can be disrupted by acyl transfer from N-2-mercaptobenzoyl-amino amides. We have developed an improved one-pot reaction that affords N-2-mercaptobenzoyl-amino acids on multi-gram scales. This synthetic route allows for rapid modular construction and has greatly expanded the scope of easily accessible potential NCp7 inhibitors.

5.
PLoS One ; 16(6): e0253269, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34138962

RESUMO

AMP-activated protein kinase (AMPK) is an evolutionarily conserved energy sensor. Activation of AMPK leads to a number of metabolic benefits, including improved mitochondrial function in skeletal muscle and lowering of serum glucose levels in type-2 diabetes models. However, direct activation of AMPK leads to cardiac enlargement, and an alternative strategy that activates AMPK without affecting the heart is needed. Inhibition of phosphodiesterase 4 (PDE4), which is poorly expressed in the human heart, activates AMPK in other tissues. In a screen to identify novel PDE4 inhibitors, we discovered compound CBU91, which is 5-10 fold more potent than rolipram, the best characterized PDE4 inhibitor. CBU91, like rolipram, is able to activate AMPK and Sirt1 and increase mitochondrial function in myotubes. These findings suggest that activation of AMPK in myotubes is a general property of PDE4 inhibition and that PDE4 inhibition may activate AMPK in metabolically relevant tissues without affecting the heart.


Assuntos
Adenilato Quinase/metabolismo , Mitocôndrias Musculares/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Animais , AMP Cíclico/metabolismo , Camundongos , Mitocôndrias Musculares/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Biogênese de Organelas , Rolipram/farmacologia
6.
Bioorg Med Chem Lett ; 20(19): 5690-4, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20801028

RESUMO

Movement disorders such as Parkinson's disease and Huntington's disease are serious life-limiting and debilitating movement disorders. Their onset typically occurs from mid-life to late in life, and effective diagnostic techniques for detecting and following the disease course are lacking. Our goal is to develop receptor imaging agents for positron emission tomography (PET) that selectively target the most relevant subtype of adenosine receptors (AR) that are highly expressed in the striatum, that is, the A(2A) AR. To further this goal, we have synthesized and characterized pharmacologically a family of high affinity A(2A) AR ligands, based on the known antagonist, SCH 442416 (R=-Me), which have structural variability on the terminus (R=-Et, -i-Pr, -allyl, and others). A O-fluoroethyl analogue suitable for use as a PET tracer had a K(i) value of 12.4 nM and was highly selective for the A(2A) AR in comparison to the A(1) and A(3) ARs.


Assuntos
Antagonistas do Receptor A2 de Adenosina/síntese química , Meios de Contraste/síntese química , Pirimidinas/química , Receptor A2A de Adenosina/química , Triazóis/química , Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Sítios de Ligação , Linhagem Celular , Simulação por Computador , Meios de Contraste/química , Radioisótopos de Flúor/química , Humanos , Tomografia por Emissão de Pósitrons , Estrutura Terciária de Proteína , Pirazóis/química , Pirimidinas/síntese química , Receptor A2A de Adenosina/metabolismo
7.
Org Lett ; 8(6): 1161-3, 2006 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-16524293

RESUMO

[reaction: see text] beta-Ketonitriles are important precursors for a wide variety of biologically active heterocycles. A facile procedure for the high-yielding acylation of nitrile anions with unactivated esters to provide beta-ketonitriles is reported. The procedure is successful with enolizable and nonenolizable esters as well as hindered nitrile anions.

8.
Org Lett ; 7(15): 3335-8, 2005 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-16018654

RESUMO

[reaction: see text]. The C(8)-C(18) ethyl ketone and C(19)-C(28) aldehyde aflastatin A fragments were synthesized and coupled using a diastereoselective anti aldol reaction. This adduct was successfully converted into the C(9)-C(27) polyol degradation product of (-)-aflastatin A to confirm the relative and absolute stereochemistry of this region of the natural product.


Assuntos
Polímeros/química , Estrutura Molecular , Pirrolidinonas/síntese química , Pirrolidinonas/química , Estereoisomerismo , Streptomyces/química
9.
Org Lett ; 5(18): 3333-5, 2003 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-12943420

RESUMO

[reaction: see text] A Thorpe condensation is the key bond construction in a rapid and efficient synthesis of substituted cytosine derivatives from readily available starting materials.


Assuntos
Acetonitrilas/química , Citosina/análogos & derivados , Acilação , Ciclização , Éteres/química , Isocianatos/química , Estrutura Molecular , Pirimidinas/química
10.
Nucl Med Biol ; 38(6): 897-906, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21843786

RESUMO

INTRODUCTION: A(2A) receptors are expressed in the basal ganglia, specifically in striatopallidal GABAergic neurons in the striatum (caudate-putamen). This brain region undergoes degeneration of presynaptic dopamine projections and depletion of dopamine in Parkinson's disease. We developed an (18)F-labeled A(2A) analog radiotracer ([(18)F]-MRS5425) for A(2A) receptor imaging using positron emission tomography (PET). We hypothesized that this tracer could image A(2A) receptor changes in the rat model for Parkinson's disease, which is created following unilateral injection of the monoaminergic toxin 6-hydroxydopamine (6-OHDA) into the substantia nigra. METHODS: [(18)F]-MRS5425 was injected intravenously in anesthetized rats, and PET imaging data were collected. Image-derived percentage injected doses per gram (%ID/g) in regions of interest was measured in the striatum of normal rats and in rats unilaterally lesioned with 6-OHDA after intravenous administration of saline (baseline), D(2) agonist quinpirole (1.0 mg/kg) or D(2) antagonist raclopride (6.0 mg/kg). RESULTS: Baseline %ID/g reached a maximum at 90 s and maintained plateau for 3.5 min, and then declined slowly thereafter. In 6-OHDA-lesioned rats, %ID/g was significantly higher in the lesioned side compared to the intact side, and the baseline total %ID/g (data from both hemispheres were combined) was significantly higher compared to quinpirole stimulation starting from 4.5 min until the end of acquisition at 30 min. Raclopride did not produce any change in uptake compared to baseline or between the hemispheres. CONCLUSION: Thus, increase of A(2A) receptor-mediated uptake of radioactive MRS5425 could be a superior molecular target for Parkinson's imaging.


Assuntos
Neostriado/diagnóstico por imagem , Neostriado/metabolismo , Oxidopamina/toxicidade , Tomografia por Emissão de Pósitrons/métodos , Pirazóis , Pirimidinas , Receptor A2A de Adenosina/metabolismo , Triazóis , Animais , Autorradiografia , Transporte Biológico , Injeções , Masculino , Neostriado/efeitos dos fármacos , Neostriado/patologia , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacocinética , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Quimpirol/farmacologia , Racloprida/farmacologia , Radioquímica , Ratos , Triazóis/química , Triazóis/metabolismo , Triazóis/farmacocinética
11.
PLoS One ; 5(11): e15479, 2010 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-21124757

RESUMO

BACKGROUND: Protein homeostasis in the endoplasmic reticulum (ER) has recently emerged as a therapeutic target for cancer treatment. Disruption of ER homeostasis results in ER stress, which is a major cause of cell death in cells exposed to the proteasome inhibitor Bortezomib, an anti-cancer drug approved for treatment of multiple myeloma and Mantle cell lymphoma. We recently reported that the ERAD inhibitor Eeyarestatin I (EerI) also disturbs ER homeostasis and has anti-cancer activities resembling that of Bortezomib. METHODOLOGY AND PRINCIPAL FINDINGS: Here we developed in vitro binding and cell-based functional assays to demonstrate that a nitrofuran-containing (NFC) group in EerI is the functional domain responsible for the cytotoxicity. Using both SPR and pull down assays, we show that EerI directly binds the p97 ATPase, an essential component of the ERAD machinery, via the NFC domain. An aromatic domain in EerI, although not required for p97 interaction, can localize EerI to the ER membrane, which improves its target specificity. Substitution of the aromatic module with another benzene-containing domain that maintains membrane localization generates a structurally distinct compound that nonetheless has similar biologic activities as EerI. CONCLUSIONS AND SIGNIFICANCE: Our findings reveal a class of bifunctional chemical agents that can preferentially inhibit membrane-bound p97 to disrupt ER homeostasis and to induce tumor cell death. These results also suggest that the AAA ATPase p97 may be a potential drug target for cancer therapeutics.


Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Hidrazonas/farmacologia , Hidroxiureia/análogos & derivados , Proteínas Nucleares/antagonistas & inibidores , Adenosina Trifosfatases/metabolismo , Análise por Conglomerados , Retículo Endoplasmático/metabolismo , Perfilação da Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Hidrazonas/química , Hidrazonas/metabolismo , Hidroxiureia/química , Hidroxiureia/metabolismo , Hidroxiureia/farmacologia , Membranas Intracelulares/metabolismo , Estrutura Molecular , Proteínas Nucleares/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Ligação Proteica , Transporte Proteico/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ressonância de Plasmônio de Superfície
12.
J Org Chem ; 67(22): 7880-3, 2002 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-12398520

RESUMO

The construction of triazacyclopenta[cd]pentalene diesters 6 by the reaction of dihydropyrrole alpha-ketoesters 3 with acylated hydrazines was evaluated further as a potential central strategic step in the total syntheses of complex guanidine alkaloids such as palau'amine and styloguanidine. Successful cyclocondensations were realized with acid-stable 2,2,2-trichloroethyl carbazate and thiosemicarbazide, but not tert-butyl carbazate. The substituent on the pyrrolidine nitrogen can be alkoxycarbonyl, sulfonyl, or an N-alkyl-2-acylpyrrole group. Siloxy substitution at C1 of the alpha-ketoester side chain is also tolerated.


Assuntos
Ciclopentanos/química , Ciclopentanos/síntese química , Iminas/química , Estrutura Molecular , Estereoisomerismo
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa