RESUMEN
Electron-rich diarylamines, exemplified by anisole-derived amines, play pivotal roles in process chemistry, pharmaceuticals, and materials. In this study, homo-diarylamines were synthesized directly from the C-H activation of electron-rich arenes by sodium nitrate/trifluoroacetic acid and the successive treatment of iron powder. Mechanistic investigations reveal that nitrosoarene serves as the reaction intermediate, and the formation of the second C-N bond between the resulting nitrosoarene and electron-rich arene is catalyzed by the nitrosonium ion (NO+). Thus, hetero-diarylamines were synthesized using preformed nitrosoarenes and various electron-rich arenes. This reaction complements a range of cross-coupling reactions catalyzed by transition metal catalysts.
RESUMEN
Enantioselective synthesis of nabscessin C (1), an aminocyclitol amide with antimicrobial activity, is reported. Starting from myo-inositol, (+)-nabscessin C was synthesized in 12 isolation steps. Desymmetrization of 2-deoxygenated 4,6-dibenzylinositol was achieved using lipase from porcine pancreas (PPL), and the stereochemistry was established by X-ray crystallography. This method has the potential for synthesizing other cyclitol-derived compounds.
Asunto(s)
Ciclitoles , Animales , Porcinos , Ciclitoles/química , Estereoisomerismo , Lipasa , InositolRESUMEN
A general method for synthesizing optically active, primary, secondary, and tertiary organofluorides was developed. This chiral pool synthesis utilized the skeleton of arabinose to generate diastereomerically pure 2-oxazolidinone-fused aziridines, which underwent ring opening with a fluoride anion. The adducts, polyoxygenated organofluorides, were useful precursors to various fluorinated compounds, such as fluorinated amino acids.
Asunto(s)
Aziridinas , Oxazolidinonas , Estructura Molecular , Aziridinas/química , Estereoisomerismo , Aminas/químicaRESUMEN
Bromotrimethylsilane (TMSBr)-promoted intramolecular cyclization of (o-arylethynyl)benzyl ethers to form 1H-isochromenes at room temperature is reported. Further studies indicated that vinyl carbocations are the reaction intermediates which are stabilized by the conjugated aryl groups. Thus, O-addition of benzyl ethers/tetrahydropyrans to alkynes was achieved under metal-free, acidic conditions. These reaction conditions were compatible with an alkynyl Prins reaction; therefore, 1H-isochromenes were produced directly from alkynyl benzaldehydes and alkynyl alcohols using a one-pot procedure.
RESUMEN
Acetoxylation of arenes is an important reaction and an unmet need in chemistry. We report a metal-free, direct acetoxylation reaction using sodium nitrate under an anhydrous environment of trifluoroacetic acid, acetic acid, and acetic anhydride. Arenes (31 examples), with oxidation potentials (Eox, in V vs SCE) lower than benzene (2.48 V), were acetoxylated with good yields and regioselectivity. A stepwise, single electron-transfer mechanism is proposed.
RESUMEN
Hydrobromination and oxy-isomerization of (o-arylethynyl)benzyl alcohols to yield brominated aryl ketones were achieved with bromotrimethylsilane. The substrate scope suggested that vinyl carbocations, stabilized by the conjugated aryl groups, are the reaction intermediates. 1H-Isochromene was also detected by 1H NMR, and an isolated 1H-isochromene was converted to the product when retreated with TMSBr. The formation of 1H-isochromene is equivalent to a 6-endo-dig cyclization and contrasts with the corresponding reactions under basic conditions, in which the 5-exo-dig process dominated.
RESUMEN
An enantiomer of nabscessin A (1), an aminocyclitol amide with antimicrobial activity, was synthesized from myo-inositol and dimethyl d-camphor acetal in 14 steps. Formal synthesis of natural nabscessin A was also achieved through the new approach to access both enantiomers of 4,5-di-O-benzyl-myo-inositol, derived from the same set of starting materials. This synthesis features utilizations of the existing framework of myo-inositol and a regioselective esterification.
Asunto(s)
Ciclitoles , Inositol , Alcanfor , EstereoisomerismoRESUMEN
Non-small cell lung cancer (NSCLC) accounts about 80% of all lung cancers. More than two-thirds of NSCLC patients have inoperable, locally advanced or metastatic tumors. Non-toxic agents that synergistically potentiate cancer-killing activities of chemotherapeutic drugs are in high demand. YL-9 was a novel and non-cytotoxic compound with the structure related to sildenafil but showing much less activity against phosphodiesterase type 5 (PDE5). NCI-H460, an NSCLC cell line with low PDE5 expression, was used as the cell model. YL-9 synergistically potentiated vinorelbine-induced anti-proliferative and apoptotic effects in NCI-H460 cells. Vinorelbine induced tubulin acetylation and Bub1-related kinase (BUBR1) phosphorylation, a necessary component in spindle assembly checkpoint. These effects, as well as BUBR1 cleavage, were substantially enhanced in co-treatment with YL-9. Several mitotic arrest signals were enhanced under combinatory treatment of vinorelbine and YL-9, including an increase of mitotic spindle abnormalities, increased cyclin B1 expression, B-cell lymphoma 2 (Bcl-2) phosphorylation and increased phosphoproteins. Moreover, YL-9 also displayed synergistic activity in combining with vinorelbine to induce apoptosis in A549 cells which express PDE5. In conclusion. the data suggest that YL-9 is a novel agent that synergistically amplifies vinorelbine-induced NSCLC apoptosis through activation of spindle assembly checkpoint and increased mitotic arrest of the cell cycle. YL-9 shows the potential for further development in combinatory treatment against NSCLC.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/genética , Proteínas Serina-Treonina Quinasas/genética , Células A549 , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Microtúbulos/efectos de los fármacos , Microtúbulos/genética , Inhibidores de Fosfodiesterasa 5/farmacología , Huso Acromático/efectos de los fármacos , Vinorelbina/farmacologíaRESUMEN
Because conventional chemotherapy is not sufficiently effective against prostate cancer, various examinations have been performed to identify anticancer activity of naturally occurring components and their mechanisms of action. The (+)-brevipolide H, an α-pyrone-based natural compound, induced potent and long-term anticancer effects in human castration-resistant prostate cancer (CRPC) PC-3 cells. Flow cytofluorometric analysis with propidium iodide staining showed (+)-brevipolide H-induced G1 arrest of cell cycle and subsequent apoptosis through induction of caspase cascades. Since Akt/mTOR pathway has been well substantiated in participating in cell cycle progression in G1 phase, its signaling and downstream regulators were examined. Consequently, (+)-brevipolide H inhibited the signaling pathway of Akt/mTOR/p70S6K. The c-Myc inhibition and downregulation of G1 phase cyclins were also attributed to (+)-brevipolide H action. Overexpression of myristoylated Akt significantly rescued mTOR/p70S6K and downstream signaling under (+)-brevipolide H treatment. ROS and Ca2+, two key mediators in regulating intracellular signaling, were determined, showing that (+)-brevipolide H interactively induced ROS production and an increase of intracellular Ca2+ levels. The (+)-Brevipolide H also induced the downregulation of anti-apoptotic Bcl-2 family proteins (Bcl-2 and Bcl-xL) and loss of mitochondrial membrane potential, indicating the contribution of mitochondrial dysfunction to apoptosis. In conclusion, the data suggest that (+)-brevipolide H displays anticancer activity through crosstalk between ROS production and intracellular Ca2+ mobilization. In addition, suppression of Akt/mTOR/p70S6K pathway associated with downregulation of G1 phase cyclins contributes to (+)-brevipolide H-mediated anticancer activity, which ultimately causes mitochondrial dysfunction and cell apoptosis. The data also support the biological significance and, possibly, clinically important development of natural product-based anticancer approaches.
Asunto(s)
Apoptosis , Ciclopropanos/farmacología , Puntos de Control de la Fase G1 del Ciclo Celular , Estrés Oxidativo/efectos de los fármacos , Neoplasias de la Próstata Resistentes a la Castración/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pironas/farmacología , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Antineoplásicos Fitogénicos/farmacología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa/genética , Transducción de Señal , Serina-Treonina Quinasas TOR/genética , Células Tumorales CultivadasRESUMEN
Various derivatives that mimic ceramide structures by introducing a triazole to connect the aminodiol moiety and long alkyl chain have been synthesized and screened for their anti-leukemia activity. SPS8 stood out among the derivatives, showing cytotoxic selectivity between leukemic cell lines and human peripheral blood mononuclear cells (about ten times). DAPI nuclear staining and H&E staining revealed DNA fragmentation under the action of SPS8. SPS8 induced an increase in intracellular Ca2+ levels and mitochondrial stress in HL-60 cells identified by the loss of mitochondrial membrane potential, transmission electron microscopy (TEM) examination, and altered expressions of Bcl-2 family proteins. SPS8 also induced autophagy through the detection of Atg5, beclin-1, and LC3 II protein expression, as well as TEM examination. Chloroquine, an autophagy inhibitor, promoted SPS8-induced apoptosis, suggesting the cytoprotective role of autophagy in hindering SPS8 from apoptosis. Furthermore, SPS8 was shown to alter the expressions of a variety of genes using a microarray analysis and volcano plot filtering. A further cellular signaling pathways analysis suggested that SPS8 induced several cellular processes in HL-60, including the sterol biosynthesis process and cholesterol biosynthesis process, and inhibited some cellular pathways, in which STAT3 was the most critical nuclear factor. Further identification revealed that SPS8 inhibited the phosphorylation of STAT3, representing the loss of cytoprotective activity. In conclusion, the data suggest that SPS8 induces both apoptosis and autophagy in leukemic cells, in which autophagy plays a cytoprotective role in impeding apoptosis. Moreover, the inhibition of STAT3 phosphorylation may support SPS8-induced anti-leukemic activity.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Triazoles/química , Triazoles/farmacología , Calcio/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Redes Reguladoras de Genes , Células HL-60 , Humanos , Leucemia , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Modelos Biológicos , Estructura Molecular , Transducción de Señal/efectos de los fármacos , Estrés Fisiológico , Transcripción Genética , TranscriptomaRESUMEN
Allylic oxidation of 2-allylbenzoic acids to phthalides, instead of Wacker-type isocoumarins, was achieved with 1,2-bis(phenylsulfinyl)ethane palladium(ii) acetate (White catalyst) and oxygen in DMSO. The selective formation of 3-ethylidenephthalides or 3-vinylphthalides was controlled by the addition of acids or bases, and the reaction conditions were applied to substituted 2-allylbenzoic acids to generate corresponding phthalides selectively. Mechanistic studies, including the corresponding reaction of (E)-2-(1-propenyl)benzoic acid to 3-methylisocoumarin, isomerization reaction of 3-vinylphthalide to 3-ethylidenephthalide, and the kinetic isotope effect using 2-(1,1-d2-allyl)benzoic acid, revealed the competition between Wacker-type oxidation and allylic C-H cleavage, which is the key step to generating phthalides. A natural product, 3-ethyl-6-hydroxyphthalide, was prepared by this method.
RESUMEN
Kijanose is one of the most highly functionalized deoxysugars found in nature and a challenging synthetic target. We found that the ring opening of trisubstituted, 2-oxazolidinone-fused aziridines is regio- and stereoselective, and the azide adduct has the same stereochemistry as that of kijanose after converting the azido to a nitro group. Therefore, both α- and ß-methyl l-kijanosides were prepared from ethyl l-lactate in 14% total yield.
RESUMEN
A new and efficient protocol to prepare indenes is reported. Assisted by boron trifluoride diethyl etherate, the one-pot reaction of aryl homopropargyl alcohols and aldehydes in the presence of arenes yielded indene derivatives. The reaction was studied with various substrates, which suggests a cascade reaction including a sequence of Prins, Friedel-Crafts, ring-opening reactions, and Friedel-Crafts to form three C-C bonds leading to indenes.
RESUMEN
Cannabinoid-1 (CB1) receptors are broadly distributed in the central and peripheral nervous systems; among others, they are located in the enteric nervous system. In the gastrointestinal (GI) system, they participate in regulation of intestinal motility or ion transport. The aim of our study was to assess the effect of 1,2,3-triazole derivatives (compound 1: 2-[4,5-bis(2,4-dichlorophenyl)-2H-1,2,3-triazol-2-yl]-N-(2-fluorobenzyl)acetamide, compound 2: 2-[4,5-bis(2,4-dichlorophenyl)-2H-1,2,3-triazol-2-yl]-N-(4-fluorobenzyl)acetamide, compound 3: N-benzyl-2-[4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2H-1,2,3-triazol-2-yl]acetamide]), characterized in vitro as CB1 antagonists with high CB1 over CB2 selectivity, in the mouse GI tract. The action of compounds 1-3 was assessed in vitro (electrical field stimulated smooth muscle contractility of the mouse ileum and colon) and in vivo (whole GI transit time). Compound 1 decreased ileal (10-6 M) and colonic (10-7-10-6 M) smooth muscles contractility. Moreover, it prolonged whole GI transit. Compound 2 (10-10-10-8 M) slightly increased the amplitude of muscle contractions in the ileum, but at a higher concentration (10-6 M), the amplitude was decreased. Compound 2 reduced colonic contractility but accelerated GI transit. Compound 3 decreased the amplitude of intestinal muscle contractions in the ileum (10-6 M) and colon (10-10-10-6 M). Moreover, it increased the GI transit time in vivo. Triazole derivatives possess easily modifiable structure and interesting pharmacological action in the GI tract; further, alterations may enhance their efficacy at CB receptors and provide low side effect profile in clinical conditions.
Asunto(s)
Antagonistas de Receptores de Cannabinoides/farmacología , Motilidad Gastrointestinal/efectos de los fármacos , Receptor Cannabinoide CB1/antagonistas & inhibidores , Triazoles/farmacología , Animales , Colon/efectos de los fármacos , Colon/fisiología , Íleon/efectos de los fármacos , Íleon/fisiología , Técnicas In Vitro , Ligandos , Masculino , Ratones , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiologíaRESUMEN
A one-pot synthesis of thioesters directly from carboxylic acids, N,N'-diphenylthiourea, triethylamine, and primary alkyl halides is described. Microwave-assisted heating and a catalytic amount of 4-(dimethylamino)pyridine (DMAP) further improved the yields. Both aromatic and aliphatic carboxylic acids were converted to the corresponding thioesters, and many functional groups were compatible with this reaction. Several possible reaction intermediates were investigated, and the quaternary ammonium salts, derived from alkyl halides and tertiary amines, were the intermediates to yield thioesters. A new reaction mechanism for this thioesterification is proposed.
RESUMEN
Hydroamination of 3-butynamine derivatives to give non-aromatic 2,3-dihydropyrroles was achieved by using PdCl2 or AuCl as the catalyst. With microwave-assisted heating, up to 92% isolated yield was obtained from this intramolecular 5-endo-dig cyclisation. The cyclopentane- and cyclohexane-fused 2,3-dihydropyrroles were transformed into the corresponding N-tosyl-pyrrolidine-2-carboxylic acids.
RESUMEN
Long-range olefin isomerization of 2-alkenylbenzoic acid derivatives going through two to five sp3-carbon atoms to give (E)-alkenes was achieved with palladium(0) nanoparticles. The substrate scope of this reaction includes carboxylic acid, ester, and primary to tertiary amides and tolerates various substituents on the benzene ring. This isomerization reaction was catalyzed by recyclable Pd(0) nanoparticles, prepared in situ from PdCl2 and characterized by X-ray powder diffraction and scanning electron microscopy analyses. 1H NMR studies and kinetic modeling supported a stepwise process. This new process was applied to synthesize a natural dihydroisocoumarin with good efficiency.
RESUMEN
Cyclopropanation using dimethylsulfoxonium methylide (Corey-Chaykovsky reaction) was examined with a series of linear α,ß-unsaturated ketones, and the results showed that the major trajectory for the addition of the sulfur ylide to the enones is anti, related to the γ-substituent. The stereochemical assignment for the generated cyclopropanes was achieved by X-ray crystallography or comparing with the reported spectroscopic data. We found that the diastereoselectivity was influenced by several factors, including the protecting groups, solvents, and temperatures, and good anti/syn ratios (>10:1) were often obtained using the tert-butyldimethylsilyl and tert-butyldiphenylsilyl-protected substrates. The method was applied to a formal synthesis of a natural eicosanoid with good efficiency.
RESUMEN
A series of triazole-based small molecules that mimic FTY720-mediated anticancer activity but minimize its immunosuppressive effect have been produced. SPS-7 is the most effective derivative displaying higher activity than FTY720 in anti-proliferation against human hormone-refractory prostate cancer (HRPC). It induced G1 arrest of cell cycle and subsequent apoptosis in thymidine block-mediated synchronization model. The data were supported by a decrease of cyclin D1 expression, a dramatic increase of p21 expression and an associated decrease in RB phosphorylation. c-Myc overexpression replenished protein levels of cyclin D1 indicating that c-Myc was responsible for cell cycle regulation. PI3K/Akt/mTOR signaling pathways through p70S6K- and 4EBP1-mediated translational regulation are critical to cell proliferation and survival. SPS-7 significantly inhibited this translational pathway. Overexpression of Myr-Akt (constitutively active Akt) completely abolished SPS-7-induced inhibitory effect on mTOR/p70S6K/4EBP1 signaling and c-Myc protein expression, suggesting that PI3K/Akt serves as a key upstream regulator. SPS-7 also demonstrated substantial anti-tumor efficacy in an in vivo xenograft study using PC-3 mouse model. Notably, FTY720 but not SPS-7 induced a significant immunosuppressive effect as evidenced by depletion of marginal zone B cells, down-regulation of sphingosine-1-phosphate receptors and a decrease in peripheral blood lymphocytes. In conclusion, the data suggest that SPS-7 is not an immunosuppressant while induces anticancer effect against HRPC through inhibition of Akt/mTOR/p70S6K pathwaysthat down-regulate protein levels of both c-Myc and cyclin D1, leading to G1 arrest of cell cycle and subsequent apoptosis. The data also indicate the potential of SPS-7 since PI3K/Akt signalingis responsive for the genomic alterations in prostate cancer.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Triazoles/administración & dosificación , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Clorhidrato de Fingolimod/administración & dosificación , Clorhidrato de Fingolimod/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Triazoles/química , Triazoles/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The enantioselective synthesis of natural brevipolide H is reported for the first time. By way of Sharpless epoxidation of penta-1,4-dien-3-ol, both enantiomerically pure epoxides were converted to the corresponding olefins for cross metathesis. Subsequent transformations, including epoxide ring opening, esterifications, cyclopropanation, oxidation and ring-closing metathesis, provided the target molecule. This synthesis successfully addresses previous shortcomings in preparing brevipolides.