RESUMO
Wnt/ß-catenin signaling is upregulated in triple-negative breast cancer (TNBC) compared to other breast cancer subtypes and normal tissues. Current Wnt/ß-catenin inhibitors, such as niclosamide, target the pathway nonspecifically and exhibit poor pharmacokinetics/pharmacodynamics in vivo. Niclosamide targets other pathways, including mTOR, STAT3 and Notch. Novel benzimidazoles have been developed to inhibit Wnt/ß-catenin signaling with greater specificity. The compounds SRI33576 and SRI35889 were discovered to produce more cytotoxicity in TNBC cell lines than in noncancerous cells. The agents also downregulated Wnt/ß-catenin signaling mediators LRP6, cyclin D1, survivin and nuclear active ß-catenin. In addition, SRI33576 did not affect mTOR, STAT3 and Notch signaling in TNBC and noncancerous cells. SRI35889 inhibited mTOR signaling less in noncancerous than in cancerous cells, while not affecting STAT3 and Notch pathways. Compounds SRI32529, SRI35357 and SRI35361 were not selectively cytotoxic against TNBC cell lines compared to MCF10A cells. While SRI32529 inhibited Wnt/ß-catenin signaling, the compound also mitigated mTOR, STAT3 and Notch signaling. SRI33576 and SRI35889 were identified as cytotoxic and selective inhibitors of Wnt/ß-catenin signaling with therapeutic potential to treat TNBC in vivo.
Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Antineoplásicos/síntese química , Benzimidazóis/síntese química , Linhagem Celular Tumoral , Humanos , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Receptores Notch/genética , Receptores Notch/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMO
In search for novel lead compounds as γ-secretase inhibitors, analogs of aminopyrido[2,3-d]pyrimidin-7-ones (I) were synthesized and evaluated for inhibitory effects on amyloid-ß-peptide production and cleavage of the Notch1 receptor mediated by γ-secretase. Selected pyridopyrimidines, such as 1, 8, 9, 10, 11 and 16 are γ-secretase inhibitors that did not have an effect on Notch1 receptor processing.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Piridonas/farmacologia , Pirimidinas/farmacologia , Receptor Notch1/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Humanos , Microssomos Hepáticos/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Inibidores de Proteases/síntese química , Piridonas/síntese química , Pirimidinas/síntese química , Ratos , Relação Estrutura-AtividadeRESUMO
γ-Secretase is one of two proteases directly involved in the production of the amyloid ß-peptide (Aß), which is pathogenic in Alzheimer's disease. Inhibition of γ-secretase to suppress the production of Aß should not block processing of one of its alternative substrates, Notch1 receptors, as interference with Notch1 signaling leads to severe toxic effects. In the course of our studies to identify γ-secretase inhibitors with selectivity for APP over Notch, 1 [3-(benzyl(isopropyl)amino)-1-(naphthalen-2-yl)propan-1-one] was found to inhibit γ-secretase-mediated Aß production without interfering with γ-secretase-mediated Notch processing in purified enzyme assays. As 1 is chemically unstable, efforts to increase the stability of this compound led to the identification of 2 [naphthalene-2-carboxylic acid benzyl-isopropyl-amide] which showed similar biological activity to compound 1. Synthesis and evaluation of a series of amide analogs resulted in benzofuranyl amide analogs that showed promising Notch-sparing γ-secretase inhibitory effects. This class of compounds may serve as a novel lead series for further study in the development of γ-secretase inhibitors.
Assuntos
Amidas/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Benzofuranos/farmacologia , Naftalenos/farmacologia , Inibidores de Proteases/farmacologia , Receptor Notch1/metabolismo , Amidas/síntese química , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Benzofuranos/síntese química , Benzilaminas/síntese química , Benzilaminas/farmacologia , Humanos , Microssomos Hepáticos/metabolismo , Naftalenos/síntese química , Fragmentos de Peptídeos/antagonistas & inibidores , Inibidores de Proteases/síntese química , Ratos , Transdução de Sinais , Relação Estrutura-AtividadeRESUMO
One therapeutic approach for Alzheimer's disease is to inhibit the cleavage of the amyloid precursor protein (APP) by γ-secretase. At the beginning of a series of studies from our laboratories, a series of novel γ-amino alcohols (1) were found to possess γ-secretase inhibitory activity and Notch-sparing effects. A new one-pot synthesis of γ-amino alcohols and the structure-activity relationship (SAR) of these analogs will be discussed.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Propanolaminas/farmacologia , Inibidores de Proteases/farmacologia , Receptor Notch1/metabolismo , Amino Álcoois/síntese química , Amino Álcoois/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Humanos , Microssomos Hepáticos/metabolismo , Naftalenos/síntese química , Naftalenos/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Propanolaminas/síntese química , Inibidores de Proteases/síntese química , Ratos , Relação Estrutura-AtividadeRESUMO
A practical one-pot and regiospecific three-component process for the synthesis of 2,3-disubstituted indoles from 2-bromoanilides was developed via consecutive palladium-catalyzed Sonogashira coupling, amidopalladation, and reductive elimination.
Assuntos
Amidas/química , Anilidas/química , Hidrocarbonetos Bromados/química , Indóis/síntese química , Paládio/química , Catálise , Ciclização , Indóis/química , Estrutura Molecular , Compostos Organometálicos/química , OxirreduçãoRESUMO
[Structure: see text] A practical one-pot, regiospecific three-component process for the synthesis of 2,3-disubstituted indoles was developed via consecutive Pd-catalyzed Sonogashira coupling, amidopalladation, and reductive elimination.
Assuntos
Técnicas de Química Combinatória , Indóis/síntese química , Catálise , Estrutura Molecular , Paládio/químicaRESUMO
[reaction: see text] A new three-component halo aldol reaction has been discovered for the tandem formations of I-C/C-C bonds by activating the alpha',beta-positions of alpha,beta-acetylenic ketones. The key intermediates, 1-iodo-3-siloxy-1,3-butadienes, were generated from allenolates and directly monitored by (1)H NMR spectroscopic analysis. Excellent geometric selectivity (>95%) and good yields (65-82%) have been achieved for 10 examples.
Assuntos
Aldeídos/química , Cetonas/química , EstereoisomerismoRESUMO
Low-temperature crystal structures of three pyrrolediones (3-5) and a furandione (9) were obtained and compared to structurally related compounds that cannot undergo decarbonylation. Systematic trends in bond lengths and angles are consistent with distortions along the reaction coordinate, in accord with the structure correlation principle of Dunitz. Since the pyrroledione and furandione rings in 3-5 and 9 are planar, these ground-state geometries prefigure the calculated planar, pseudopericyclic transition states.
RESUMO
The Baylis-Hillman condensation of three types of alpha,beta-conjugate cycloketones with aldehydes was successfully performed by using diethylaluminum iodide as the Lewis acid promoter alone without the direct use of a Lewis base. The reaction proceeded to completion at 0 degree C in CH2Cl2 within 24 h to give modest to good yields (53-72%).
Assuntos
Aldeídos/química , Técnicas de Química Combinatória , Cetonas/química , Hidrocarbonetos Cíclicos/química , Indicadores e Reagentes , Compostos Organometálicos/químicaRESUMO
The Baylis-Hillman-type reaction of alpha,Beta-ethyl thioacrylate with aldehydes has been achieved using diethylaluminium iodide as the promoter without the direct use of any Lewis bases. The reaction provides an effective access to various alpha-methylene-Beta-hydroxy thioesters.
Assuntos
Aldeídos/química , Ésteres/química , Ácidos/química , Química Orgânica , Estrutura Molecular , Fenômenos de Química OrgânicaRESUMO
A three-component electrophilic reaction transforms olefins into imidazoline and diamine derivatives. Rhodium(II) heptafluorobutyrate dimer (2 mol %) was utilized as the catalyst and N,N-dichloro-p-toluenesulfonamide (TsNCl2 ) and acetonitrile as the nitrogen sources. Modest to good yields (45-82 %) and high regio- and stereoselectivity were achieved.
RESUMO
A highly concise and convergent synthesis of HCV polymerase inhibitor Deleobuvir (BI 207127, 1) was achieved, featuring efficient Pd-catalyzed one-pot borylation-Suzuki coupling where TFP was identified as the unique ligand effective for these transformations.
Assuntos
Acrilatos/síntese química , Acrilatos/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Acrilatos/química , Antivirais/química , Benzimidazóis/química , Catálise , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Ligantes , Estrutura Molecular , Paládio/químicaRESUMO
Volicitin (17-hydroxylinolenoyl-l-Gln) present in the regurgitant of Spodoptera exigua (beet armyworm caterpillars) activates the emission of volatile organic compounds (VOCs) when in contact with damaged Zea mays cv Delprim (maize) leaves. VOC emissions in turn serve as a signaling defense for the plant by attracting female parasitic wasps that prey on herbivore larvae. A tritiated form of volicitin was synthesized and shown to induce volatiles in the same fashion as the biological form. [(3)H]-l-volicitin rapidly, reversibly, and saturably bound to enriched plasma membrane fractions isolated from Z. mays leaves with an apparent K(d) of 1.3 nM and a Hill coefficient of 1.07. Analog studies showed that the l-Gln and hydroxy moieties of volicitin play an important role in binding. Treatment of plants with methyl jasmonate (MeJA) increased the total binding of [(3)H]-l-volicitin to the enriched plasma membrane more than threefold, suggesting that MeJA activates transcription of the gene encoding the binding protein. S. exigua feeding also increased total binding fourfold. Cycloheximide pretreatment of plants significantly decreased binding of radiolabeled volicitin to the enriched plasma membrane. These data provide the first experimental evidence that initiation of plant defenses in response to herbivore damage can be mediated by a binding protein-ligand interaction.
Assuntos
Glutamina/análogos & derivados , Glutamina/metabolismo , Proteínas de Membrana/metabolismo , Zea mays/metabolismo , Ácido alfa-Linolênico/análogos & derivados , Ácido alfa-Linolênico/metabolismo , Acetatos/farmacologia , Animais , Sítios de Ligação/genética , Ciclopentanos/farmacologia , Glutamina/química , Glutamina/farmacologia , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/genética , Imunidade Inata/fisiologia , Controle de Insetos/métodos , Proteínas de Membrana/genética , Estrutura Molecular , Oxilipinas , Doenças das Plantas/parasitologia , Reguladores de Crescimento de Plantas/farmacologia , Folhas de Planta/genética , Folhas de Planta/metabolismo , Folhas de Planta/parasitologia , Ligação Proteica , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Spodoptera/crescimento & desenvolvimento , Spodoptera/parasitologia , Transcrição Gênica/efeitos dos fármacos , Trítio , Volatilização , Vespas/crescimento & desenvolvimento , Zea mays/genética , Zea mays/parasitologia , Ácido alfa-Linolênico/química , Ácido alfa-Linolênico/farmacologiaRESUMO
A new direct electrophilic diamination reaction of alpha,beta-unsaturated ketones and esters has been established without the use of any metal catalysts. Three types of nitriles (CH(3)CN, CH(3)CH(2)CN, and CH(3)CH(2)CH(2)CN) were employed as nucleophilic nitrogen sources. A new mechanism has also been proposed to explain the resulting regio- and stereoselectivity.
Assuntos
Alcenos/química , Diaminas/química , Química Farmacêutica/métodos , Ésteres/química , Cetonas , Nitrilas/químicaRESUMO
The FeCl(3)-PPh(3) complex was found to effectively catalyze the electrophilic diamination reaction of electron-deficient alkenes. Improvements on yields and stereoselectivity have been achieved for both alpha,beta-unsaturated carboxylic esters and ketones. Under the new catalytic system, alpha,beta-unsaturated carboxylic esters were found to be superior to their ketone counterparts, which is opposite to the previous (C(3)F(7)CO(2))(2)Rh](2)-catalyzed diamination. The reaction employs readily available N,N-dichloro-p-toluenesulfonamide (TsNCl(2)) and acetonitrile as the nitrogen sources and is very easy to perform at room temperature without the special protection of inert gases. The resulting diamino products belong to imidazolidine analogue and can further strengthen the importance of the new reaction. Modest to good yields (52-84%) and high regio- and stereoselectivity have been achieved for 10 examples.
Assuntos
Alcenos/química , Compostos Férricos/química , Aminas/química , Catálise , Técnicas de Química Combinatória , Ciclização , Ésteres/química , Imidazóis/química , Cetonas/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , EstereoisomerismoRESUMO
alpha,beta-Differentiated 1,2-vicinal diamines have been efficiently synthesized by using new electrophilic imidazolination reaction of alkenes. The hydrolysis of imidazolines was performed by treatment with 6 M HCl in THF at 70 degrees C without epimerization. Eight examples were examined to give good to excellent yields (87-96%).
Assuntos
Alcenos/química , Diaminas/síntese química , Imidazóis/química , Diaminas/química , HidróliseRESUMO
N,N-dichloro-o-nitrobenzenesulfonamide (2-NsNCl2) was found to be an effective electrophilic nitrogen source for the direct diamination of alpha,beta-unsaturated ketones without the use of any metal catalysts. The reaction is very convenient to carry out without the protection of inert gases. Molecular sieves (4 A) and temperature were found to play key roles in controlling the formations of 3-trichloromethyl and dichloromethyl imidazoline products (16 examples). The 2-Ns-protection group of the resulting diamine products can be easily cleaved under mild Fukuyama's conditions. A new mechanism hypothesis of [2+3] cyclization and N-chlorination has been proposed to explain the product structures, particularly their regio- and stereochemistry.
Assuntos
Cloro/química , Cetonas/química , Nitrobenzenos/química , Nitrogênio/química , Sulfonamidas/síntese química , Catálise , Ciclização , Desaminação , Imidazóis/química , Metais/química , Modelos Químicos , Conformação Molecular , EstereoisomerismoRESUMO
A novel generation of 1-iodo-3-siloxy-1,3-butadienes has been developed by reacting trimethylsilyl iodide (TMS-I) with alpha, beta-unsaturated ketones in dichloromethane at 0 degrees C without the use of any catalyst. The halo aldol reaction of these butadiene intermediates with aldehydes was efficiently carried out by using magnesium iodide as the catalyst. Twelve beta-iodo-alpha,beta-unsaturated-beta'-hydroxyketones (halo aldols) have been synthesized under the new condition with excellent geometric selectivity and good chemical yields (>80% chemical yields for 11 examples).