RESUMEN
A new class of Ru-sulfonamidate precatalysts for sp3 C-H hydroxylation is described along with a versatile process for assembling unique heteroleptic Ru(II) complexes. The latter has enabled structure-performance studies to identify an optimal precatalyst, 2h, bearing one 4,4'-di-tert-butylbipyridine (dtbpy) and one pyridylsulfonamidate ligand. Single-crystal X-ray analysis confirmed the structure and stereochemistry of this adduct. Catalytic hydroxylation reactions are conveniently performed in an aqueous, biphasic solvent mixture with 1 mol % 2h and ceric ammonium nitrate as the terminal oxidant and deliver oxidized products in yields ranging from 37 to 90%. A comparative mechanistic investigation of 2h against a related homoleptic precatalyst, [Ru(dtbpy)2(MeCN)2](OTf)2, convincingly establishes that the former generates one or more surprisingly long-lived active species under the reaction conditions, thus accounting for the high turnover numbers. Structure-performance, kinetics, mass spectrometric, and electrochemical analyses reveal that ligand oxidation is a prerequisite for catalyst activation. Our findings sharply contrast a large body of prior art showing that ligand oxidation is detrimental to catalyst function. We expect these results to stimulate future innovations in C-H oxidation research.
RESUMEN
Cholangiocarcinoma (CCA) results from the malignant transformation of cholangiocytes. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are chronic diseases in which cholangiocytes are primarily damaged. Although PSC is an inflammatory condition predisposing to CCA, CCA is almost never found in the autoimmune context of PBC. Here, we hypothesized that PBC might favor CCA immunosurveillance. In preclinical murine models of cholangitis challenged with syngeneic CCA, PBC (but not PSC) reduced the frequency of CCA development and delayed tumor growth kinetics. This PBC-related effect appeared specific to CCA as it was not observed against other cancers, including hepatocellular carcinoma. The protective effect of PBC was relying on type 1 and type 2 T cell responses and, to a lesser extent, on B cells. Single-cell TCR/RNA sequencing revealed the existence of TCR clonotypes shared between the liver and CCA tumor of a PBC host. Altogether, these results evidence a mechanistic overlapping between autoimmunity and cancer immunosurveillance in the biliary tract.
Asunto(s)
Autoinmunidad , Neoplasias de los Conductos Biliares/inmunología , Colangiocarcinoma/inmunología , Colangitis/inmunología , Animales , Neoplasias de los Conductos Biliares/patología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Colangiocarcinoma/patología , Colangitis/patología , Citocinas/metabolismo , Femenino , Factores de Transcripción Forkhead/metabolismo , Hígado/inmunología , Hígado/patología , Ratones Endogámicos C57BL , Monitorización Inmunológica , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/patologíaRESUMEN
A Davis-Beirut reaction inspired nitroso Diels-Alder protocol is reported. The starting material for the procedure is a nitrophenyl moiety with the para position appropriately substituted with a 2°-amine (see 5) or 2°-alcohol (see 6). Deprotonation at the benzylic position followed by concomitant oxidation of the benzylic position and reduction of the nitro moiety delivers a nitrosophenyl intermediate, which subsequently undergoes a nitroso Diels-Alder reaction. This one-pot procedure delivers aryldihydro-1,2-oxazines in moderate yields.
RESUMEN
We previously identified a spiro [piperidine-4,1-pyrido [3,4-b]indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770 or GLGP1837 to restore channel activity of a defined subset of minimal function cystic fibrosis transmembrane conductance regulator (CFTR) mutants. Here, structure-activity studies were conducted to improve their potency over the previously identified compound, 20 (originally termed CP-A01). Targeted synthesis of 37 spiro [piperidine-4,1-pyrido [3,4-b]indoles] was generally accomplished using versatile two or three step reaction protocols with each step having high efficiency. Structure-activity relationship studies established that analog 2i, with 6'-methoxyindole and 2,4,5-trifluorobenzyl substituents, had the greatest potency for activation of N1303K-CFTR, with EC50 â¼600 nM representing an â¼17-fold improvement over the original compound identified in a small molecule screen.
Asunto(s)
Agonistas de los Canales de Cloruro/química , Agonistas de los Canales de Cloruro/farmacología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/agonistas , Indoles/química , Indoles/farmacología , Aminofenoles/farmacología , Animales , Línea Celular , Agonistas de los Canales de Cloruro/síntesis química , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Humanos , Indoles/síntesis química , Modelos Moleculares , Mutación , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacología , Quinolonas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
This article presents the catalysis investigation of octanethiolate-capped palladium nanoparticles (C8 PdNP) and phenylethanethiolate-capped palladium nanoparticles (PhC2 PdNP) for chemoselective catalytic hydrogenation reactions of styrene derivatives in the presence of other reducible functionalities. The results show that the C8 PdNP is highly active under mild reaction conditions (room temperature and atmospheric pressure) and selective for hydrogenating monosubstituted alkene groups without reducing other reactive functional groups such as nitro, halo, carbonyls, and so forth. In comparison, the noncovalent interactions between surface phenyl ligands and aromatic substrates are found to hinder the hydrogenation activity of PhC2 PdNP.
RESUMEN
Photoswitches capable of accessing two geometric states are highly desirable, especially if their design is modular and incorporates a pharmacophore tethering site. We describe a redox isomerization strategy for synthesizing p-formylazobenzenes from p-nitrobenzyl alcohol. The resulting azo-aldehydes can be readily converted to photoswitchable compounds with excellent photophysical properties using simple hydrazide click chemistry. As a proof of principle, we synthesized a photoswitchable surfactant enabling the photocontrol of an emulsion with exceptionally high spatiotemporal precision.
Asunto(s)
Compuestos Azo/química , Procesos Fotoquímicos , Dimetilsulfóxido/química , Isomerismo , Modelos Moleculares , Conformación Molecular , Oxidación-ReducciónRESUMEN
Pendrin is a transmembrane chloride/anion antiporter that is strongly upregulated in the airways in rhinoviral infection, asthma, cystic fibrosis and chronic rhinosinusitis. Based on its role in the regulation of airway surface liquid depth, pendrin inhibitors have potential indications for treatment of inflammatory airways diseases. Here, a completely regioselective route to tetrahydro-pyrazolopyridine pendrin inhibitors based on 1,3-diketone and substituted hydrazine condensation was been developed. Structure-activity relationships at the tetrahydropyridyl nitrogen were investigated using a focused library, establishing the privileged nature of N-phenyl ureas and improving inhibitor potency by greater than 2-fold.
Asunto(s)
Pirazoles/farmacología , Piridinas/farmacología , Transportadores de Sulfato/antagonistas & inhibidores , Animales , Ratones , Estructura Molecular , Pirazoles/síntesis química , Piridinas/síntesis química , Ratas Endogámicas F344 , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-ActividadRESUMEN
Indazoles are an important class of nitrogen heterocycles because of their excellent performance in biologically relevant applications, such as in chemical biology and medicinal chemistry. In these applications, convenient synthesis using commercially available and diverse building blocks is highly desirable. Within this broad class, 2H-indazoles are relatively underexploited when compared to 1H-indazole, perhaps because of regioselectivity issues associated with the synthesis of 2H-indazoles. This Account describes our unfolding of the synthetic utility of the Davis-Beirut reaction (DBR) for the construction of 2H-indazoles and their derivatives; parallel unfoldings of mechanistic models for these interrelated N-N bond forming reactions are also summarized. The Davis-Beirut reaction is a robust method that exploits the diverse chemistries of a key nitroso imine or nitroso benzaldehyde intermediate generated in situ under redox neutral conditions. The resulting N-N bond-forming heterocyclization between nucleophilic and electrophilic nitrogens can be leveraged for the synthesis of multiple classes of indazoles and their derivatives, such as simple or fused indazolones, thiazolo-indazoles, 3-alkoxy-2H-indazoles, 2H-indazole N-oxides, and 2H-indazoles with various substitutions on the ring system or the nitrogens. These diverse products can all be synthesized under alkaline conditions and the various strategies for accessing these heterocycles are discussed. Alternatively, we have also developed methods involving mild photochemical conditions for the nitrobenzyl â aci-nitro â nitroso imine sequence. Solvent consideration is especially important for modulating the chemistry of the reactive intermediates in these reactions; the presence of water is critically important in some cases, but water's beneficial effect has a ceiling because of the alternative reaction pathways it enables. Fused 2H-indazoles readily undergo ring opening reactions to give indazolones when treated with nucleophiles or electrophiles. Furthermore, palladium-catalyzed cross coupling, the Sonagashira reaction, EDC amide coupling, 1,3-dipolar cycloadditions with nitrile oxides, copper-catalyzed alkyne-azide cycloadditions (click reaction), as well as copper-free click reactions, can all be used late-stage to modify 2H-indazoles and indazolones. The continued development and applications of the Davis-Beirut reaction has provided many insights for taming the reactivity of highly reactive nitro and nitroso groups, which still has a plethora of underexplored chemistries and challenges. For example, there is currently a limited number of nonfused 2H-indazole examples containing an aryl substitution at nitrogen. This is caused by relatively slow N-N bond formation between N-aryl imine and nitroso reactants, which allows water to add to the key nitroso imine intermediate causing imine bond cleavage to be a competitive reaction pathway rather than proceeding through the desired N-N bond-forming heterocyclization.
Asunto(s)
Indazoles/síntesis química , Compuestos Nitrosos/química , Aminas/química , Ciclización , Modelos QuímicosRESUMEN
The Davis-Beirut reaction provides access to 2H-indazoles from aromatic nitro compounds. However, N-aryl targets have been traditionally challenging to access due to competitive alternate reaction pathways. Previously, the key nitroso imine intermediate was generated under alkaline conditions, but as reported here, the photochemistry of o-nitrobenzyl alcohols empowered Brønsted acid catalyzed conditions for accessing N-aryl targets. Anilines and alkyl amines give different outcomes under optimized conditions; the proposed mechanism was studied using quantum chemical calculations.
Asunto(s)
Indazoles/química , Nitrocompuestos/química , Aminas/química , Alcoholes Bencílicos/química , Catálisis , Iminas/químicaRESUMEN
The Cadogan cyclization is a robust but harsh method for the synthesis of 2 H-indazoles, a valuable class of nitrogen heterocycles. Although nitrene generation by exhaustive deoxygenation is widely accepted as the operating mechanism in the reductive cyclization of nitroaromatics, non-nitrene pathways have only been theorized previously. Here, 2 H-indazole N-oxides were synthesized through an interrupted Cadogan/Davis-Beirut reaction and are presented as direct evidence of competent oxygenated intermediates; mechanistic implications for both reactions are discussed. Isolation and characterization of these N-oxides enabled a formal Cadogan cyclization at room temperature for 2 H-indazole synthesis.
Asunto(s)
Indazoles/síntesis química , Ciclización , Indazoles/química , Estructura MolecularRESUMEN
Chemotherapy has been shown to be effective in reducing the progression and development of cancer in metastatic patients. However, drug selectivity is still a major issue for most chemotherapeutics. In this study, we synthesized four novel heterocyclic compounds having similarity in structure with quinone systems whereby nitrogen atoms replace the oxygen atoms. The anticancer activity of these compounds (DIQ3-6) was tested against HCT116 human colon cancer cells. We showed that all four heterocycles caused significant reduction in colon cancer cell viability at doses as low as 4 µM, a concentration that was not cytotoxic to normal human FHs74Int intestinal cell lines. Interestingly, these heterocycles inhibited colon sphere formation in 3D cultures at first generation (G1), mainly because of inhibition of proliferation as evidenced by Ki67 staining. Thus, DIQ3 causes sufficient eradication of the self-renewal ability of the highly resistant cancer stem cells. This study represents the first documentation of the activity of these novel heterocyclic compounds, particularly compound DIQ3, and their potential therapeutic use in targeting colon cancer self-renewal capacity. Our findings provide the basis for proposing these nontoxic and stable compounds for additional testing against cancer.
RESUMEN
o-Nitrosobenzaldehyde is a reactive intermediate useful in the synthesis of nitrogen heterocycles. Previous strategies for using o-nitrosobenzaldehyde involve its isolation via chromatography and/or formation under harsh conditions. Herein, this intermediate was photochemically generated in situ from o-nitrobenzyl alcohols in a mild, efficient manner for the construction of 1,2-dihydro-3 H-indazol-3-ones using an aqueous solvent at room temperature. This convenient reaction offers several advantages over reported methods. The commercially available photoreactor employed 3 × 18 W bulbs outputting broad emission above 365 nm.
Asunto(s)
Indazoles/química , Procesos Fotoquímicos , Solventes/química , Temperatura , Agua/química , CatálisisRESUMEN
A concise, one-step route to indazolones from primary alkyl amines and o-nitrobenzyl alcohols is reported. The key step in this readily scalable indazolone forming process involves base-mediated in situ o-nitrobenzyl alcohol â o-nitrosobenzaldehyde conversion. Although this functional group interconversion is known to be useful for 2 H-indazole synthesis, its reactivity was modulated for indazolone formation.
Asunto(s)
Aminas/química , Alcoholes Bencílicos/química , Indazoles/síntesis química , Compuestos Nitrosos/química , Catálisis , Ciclización , Oxidación-ReducciónRESUMEN
Reaction options, alkoxide vs hydroxide vs amine addition to the key intermediate (o-nitrosoimine) generated in the Davis-Beirut reaction of an o-nitrobenzylamine substrate, are reported to explain the nucleophilic addition selectivity of this one-pot indazole-forming process. The hydroxide addition/deprotection pathway as well as the fate of the resulting o-nitrosobenzaldehyde were both uncovered with several o-nitrobenzylamine substrates, and design elements required for an efficient double Davis-Beirut reaction, inspired by new mechanistic insights, were defined.
Asunto(s)
Hidróxidos/química , Aminas , Iminas , Indazoles , Estructura MolecularRESUMEN
The discovery of a new variation on the Davis-Beirut reaction is described in which an atypical heterocyclic framework (the anthranil or benzo[c]isoxazole framework) is formed as the result of diversion of a key reactive intermediate away from its expected reactivity-a potentially general approach to reaction design and development. Experimental and computational support for the proposed mechanism and origins of altered reactivity are described.
Asunto(s)
Isoxazoles/síntesis química , Isoxazoles/química , Estructura Molecular , Teoría CuánticaRESUMEN
We previously identified phenylquinoxalinone CFTRact-J027 (4) as a cystic fibrosis transmembrane conductance regulator (CFTR) activator with an EC50 of â¼200 nM and demonstrated its therapeutic efficacy in mouse models of constipation. Here, structure-activity studies were done on 36 synthesized phenylquinoxalinone analogs to identify compounds with improved potency and altered metabolic stability. Synthesis of the phenylquinoxalinone core was generally accomplished by condensation of 1,2-phenylenediamines with substituted phenyloxoacetates. Structure-activity studies established, among other features, the privileged nature of a properly positioned nitro moiety on the 3-aryl group. Synthesized analogs showed improved CFTR activation potency compared to 4 with EC50 down to 21 nM and with greater metabolic stability. CFTR activators have potential therapeutic indications in constipation, dry eye, cholestatic liver diseases, and inflammatory lung disorders.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/agonistas , Quinoxalinas/química , Quinoxalinas/farmacología , Enfermedad Aguda , Animales , Línea Celular , Estreñimiento/tratamiento farmacológico , Estreñimiento/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Descubrimiento de Drogas , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Quinoxalinas/metabolismo , Quinoxalinas/uso terapéuticoRESUMEN
Constipation is a common condition for which current treatments can have limited efficacy. By high-throughput screening, we recently identified a phenylquinoxalinone activator of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel that stimulated intestinal fluid secretion and normalized stool output in a mouse model of opioid-induced constipation. Here, we report phenylquinoxalinone structure-activity analysis, mechanism of action, animal efficacy data in acute and chronic models of constipation, and functional data in ex vivo primary cultured human enterocytes. Structure-activity analysis was done on 175 phenylquinoxalinone analogs, including 15 synthesized compounds. The most potent compound, CFTRact-J027, activated CFTR with EC50 â¼ 200 nM, with patch-clamp analysis showing a linear CFTR current-voltage relationship with direct CFTR activation. CFTRact-J027 corrected reduced stool output and hydration in a mouse model of acute constipation produced by scopolamine and in a chronically constipated mouse strain (C3H/HeJ). Direct comparison with the approved prosecretory drugs lubiprostone and linaclotide showed substantially greater intestinal fluid secretion with CFTRact-J027, as well as greater efficacy in a constipation model. As evidence to support efficacy in human constipation, CFTRact-J027 increased transepithelial fluid transport in enteroids generated from normal human small intestine. Also, CFTRact-J027 was rapidly metabolized in vitro in human hepatic microsomes, suggesting minimal systemic exposure upon oral administration. These data establish structure-activity and mechanistic data for phenylquinoxalinone CFTR activators, and support their potential efficacy in human constipation.
Asunto(s)
Líquidos Corporales/metabolismo , Estreñimiento/tratamiento farmacológico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Quinoxalinas/uso terapéutico , Enfermedad Aguda , Animales , Líquidos Corporales/efectos de los fármacos , Línea Celular , Enfermedad Crónica , Estreñimiento/genética , Estreñimiento/patología , Modelos Animales de Enfermedad , Duodeno/efectos de los fármacos , Duodeno/metabolismo , Femenino , Ácido Gástrico/metabolismo , Humanos , Yeyuno/efectos de los fármacos , Yeyuno/metabolismo , Lubiprostona/farmacología , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Técnicas de Placa-Clamp , Péptidos/farmacología , Quinoxalinas/síntesis química , Quinoxalinas/química , Quinoxalinas/farmacología , Ratas , Escopolamina/farmacología , Relación Estructura-ActividadRESUMEN
Unsupported thiolate-capped palladium nanoparticle catalysts are found to be highly substrate-selective for alkene hydrogenation and isomerization. Steric and poisoning effects from thiolate ligands on the nanoparticle surface control reactivity and selectivity by influencing alkene adsorption and directing either di-σ or mono-σ bond formation. The presence of overlapping p orbitals and α protons in alkenes greatly influences the catalytic properties of deactivated palladium nanoparticles leading to easily predictable hydrogenation or isomerization products.
Asunto(s)
Alquenos/química , Nanopartículas del Metal/química , Paladio/química , Catálisis , Hidrogenación , Isomerismo , Ligandos , Espectroscopía de Resonancia MagnéticaRESUMEN
Highly substituted indoles were synthesized by a palladium-catalyzed reaction involving three independent components in a one-pot reaction. Two distinct palladium-catalyzed coupling reactions occur with a single catalytic system: a Buchwald-Hartwig reaction and an arene-alkene coupling. Quantum chemical computations provide insight into the mechanism of the latter coupling step.