RESUMEN
Titanium alkoxide-based alkyne-alkyne reductive coupling mediated by in situ generated arylamidate is described. A high level of regioselectivity is achieved in 37 examples, where (E,E)-dienes are exclusively formed. To the best of our knowledge, this study represents the first example of an apparent amide and carbamate directing effect in metal-mediated reductive coupling.
RESUMEN
Rheumatoid arthritis (RA) is an inflammatory disease that has been linked to several risk factors, including periodontitis. Identification of new anti-inflammatory compounds to treat arthritis is needed. We had previously demonstrated the beneficial effect of Kava-241, a kavain-derived compound, in the management of Porphyromonas gingivalis-induced periodontitis. The present study evaluated systemic and articular effects of Kava-241 in an infective arthritis murine model triggered by P. gingivalis bacterial inoculation and primed with a collagen antibody cocktail (CIA) to induce joint inflammation and tissular destruction. Clinical inflammation score and radiological analyses of the paws were performed continuously, while histological assessment was obtained at sacrifice. Mice exposed to P. gingivalis and a CIA cocktail and treated concomitantly with Kava-241 exhibited a reduced clinical inflammatory score and a decreased number of inflammatory cells and osteoclasts within joint. Kava-241 treatment also decreased significantly tumor necrosis factor alpha (TNF-α) in serum from mice injected with a Toll-like receptor 2 or 4 (TLR-2/4) ligand, P. gingivalis-lipopolysaccharide (LPS). Finally, bone marrow-derived macrophages infected with P. gingivalis and exposed to Kava-241 displayed reduced TLR-2/4, reduced mitogen-activated protein kinase (MAPK)-related signal elements, and reduced LPS-induced TNF-α factor (LITAF), all explaining the observed reduction of TNF-α secretion. Taken together, these results emphasized the novel properties of Kava-241 in the management of inflammatory conditions, especially TNF-α-related diseases such as infective RA.
Asunto(s)
Antiinflamatorios/farmacología , Artritis/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Articulaciones/microbiología , Porphyromonas gingivalis , Pironas/farmacología , Animales , Artritis/microbiología , Infecciones por Bacteroidaceae/sangre , Infecciones por Bacteroidaceae/tratamiento farmacológico , Modelos Animales de Enfermedad , Inflamación/sangre , Inflamación/microbiología , Articulaciones/citología , Articulaciones/efectos de los fármacos , Lipopolisacáridos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/microbiología , Masculino , Ratones , Osteoclastos/efectos de los fármacos , Receptor Toll-Like 2/sangre , Factor de Necrosis Tumoral alfa/sangreRESUMEN
A modular and diastereodivergent synthesis of tetrahydro-1 H-pyrrolo[1,2 d]diazepine-(2,5)-diones is presented. The tetrahydropyrrolodiazepinedione scaffold is obtained via a base-mediated three-step isomerization/tandem cyclization of amino acid-coupled homoallylic amino esters. Diastereoselectivity of the process is mediated by the interplay of a kinetic cyclization event and a propensity for thermodynamic epimerization at two labile chiral centers, giving rise to two distinct major diastereomers dependent on starting material stereochemistry and reaction conditions selected. Herein, we present a synthetic and computational study for this tandem process on a variety of amino ester substrates.
Asunto(s)
Lactamas/química , Pirroles/química , Pirroles/síntesis química , Técnicas de Química Sintética , Ciclización , Cinética , Modelos Moleculares , Conformación Molecular , Estereoisomerismo , TermodinámicaRESUMEN
Six kava analogues of the structural type 3-oxocyclohex-1-en-1-yl benzoates (and corresponding benzamides) were synthesized and evaluated for their affect on periodontal deconstruction in collagen anti-body primed oral gavage model of periodontitis. The compounds were prepared through an acylation or amidation of the enolizable cyclic 1,3-diketone. We have learned that three of the analogues are responsible for the reduction of inflammatory cell counts within soft tissue. These novel kava-like molecules where the lactone is replaced by an α,ß-unsaturated ketone show promise in the prevention and treatment of inflammation and alveolar bone loss associated with periodontitis.
Asunto(s)
Benzamidas/farmacología , Benzoatos/farmacología , Ciclohexanonas/farmacología , Kava/química , Enfermedades Periodontales/tratamiento farmacológico , Animales , Benzamidas/síntesis química , Benzamidas/química , Benzoatos/síntesis química , Benzoatos/química , Ciclohexanonas/síntesis química , Ciclohexanonas/química , Macrófagos/efectos de los fármacos , Ratones , Enfermedades Periodontales/microbiología , Porphyromonas gingivalis/patogenicidad , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
AIM: The aim of this study was to evaluate the effect of Kava-241, an optimized Piper methysticum Kava compound, on periodontal destruction in a collagen antibody primed oral gavage model of periodontitis. METHODS: Experimental periodontitis was induced by oral gavage of Porphyromonas gingivalis (P. gingivalis) + type II collagen antibody (AB) in mice during 15 days. Mice were treated with Kava-241 concomitantly or prior to P. gingivalis gavage and compared to untreated mice. Comprehensive histomorphometric analyses were performed. RESULTS: Oral gavage with P. gingivalis induced mild epithelial down-growth and alveolar bone loss, while oral gavage with additional AB priming had greater tissular destruction in comparison with gavage alone (p < .05). Kava-241 treatment significantly (p < .05) reduced epithelial down-growth (72%) and alveolar bone loss (36%) in P. gingivalis+AB group. This Kava-241 effect was associated to a reduction in inflammatory cell counts within soft tissues and an increase in fibroblasts (p < .05). CONCLUSION: Priming with type II collagen antibody with oral gavage is a fast and reproducible model of periodontal destruction adequate for the evaluation of novel therapeutics. The effect of Kava-241 shows promise in the prevention and treatment of inflammation and alveolar bone loss associated with periodontitis. Further experiments are required to determine molecular pathways targeted by this therapeutic agent.
Asunto(s)
Kava/química , Periodontitis/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Porphyromonas gingivalis/metabolismo , Animales , Anticuerpos/inmunología , Colágeno/inmunología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Masculino , Ratones , Ratones Endogámicos DBA , Periodontitis/microbiología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Complete details of an asymmetric synthesis of (+)-isatisine A (1) are described. The synthesis highlights the use of a highly diastereoselective Mukaiyama-type [3 + 2]-annulation of allylsilane 5 with the unsaturated aldehyde 9a to assemble the functionalized tetrahydrofuran core of isatisine A. A convergent route to the framework of the natural product was established that employed a substrate-controlled indole coupling that was followed by a late-stage intramolecular copper(I)-mediated amidation to complete the assembly of the tetracyclic framework of (+)-isatisine A. In addition, the scope of the [3 + 2]-annulation was evaluated and enhanced utilizing diastereomeric allylsilanes anti-5 and syn-5 to establish an efficient route to stereochemically well-defined tetrahydrofurans.
Asunto(s)
Alcaloides Indólicos/síntesis química , Isatina/análogos & derivados , Silanos/química , Alcaloides Indólicos/química , Isatina/síntesis química , Isatina/química , Estructura Molecular , EstereoisomerismoRESUMEN
An organosilane-directed alkyne-alkene reductive coupling of readily available propargylsilanes is used to access densely functionalized chiral allylsilanes. The divergent reactivity of the allylsilanes can be controlled to afford a range of novel carbocyclic ring systems through an intramolecular allylation, [3+2] annulation, and Sakurai-like homodimerization.
Asunto(s)
Alquenos/química , Alquinos/química , Hidrocarburos Cíclicos/síntesis química , Silanos/química , Alquenos/síntesis química , Alquinos/síntesis química , Compuestos Alílicos/síntesis química , Compuestos Alílicos/química , Ciclización , Dimerización , Hidrocarburos Cíclicos/química , Oxidación-Reducción , Silanos/síntesis química , EstereoisomerismoRESUMEN
A stereoselective synthesis of the antibiotic (-)-virginiamycin M(2) is detailed. A convergent strategy was utilized that proceeded in 10 steps (longest linear sequence) from enantioenriched silane (S)-15. This reagent, which was prepared via a Rh(II)- or Cu(I)-catalyzed carbenoid Si-H insertion, was used to introduce the desired olefin geometry and stereocenters of the C1-C5 propionate subunit. A modified Negishi cross-coupling or an efficient alkoxide-directed titanium-mediated alkyne-alkyne reductive coupling strategy was utilized to assemble the trisubstituted (E,E)-diene. An underutilized late-stage SmI(2)-mediated macrocyclization was employed to construct the 23-membered macrocycle scaffold of the natural product.
Asunto(s)
Antibacterianos/síntesis química , Cobre/química , Rodio/química , Silanos/química , Silicio/química , Virginiamicina/análogos & derivados , Alquenos/química , Alquinos/química , Catálisis , Cromatografía Líquida de Alta Presión , Ciclización , Humanos , Hidrógeno/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Oxidación-Reducción , Estereoisomerismo , Virginiamicina/síntesis químicaRESUMEN
A full account of an asymmetric synthesis of reblastatin (1) and the first total synthesis of autolytimycin (2) and related structural compounds is described. The syntheses expand the utility of a highly regio- and diastereoselective hydrometalation aldehyde addition sequence to assemble the fully functionalized ansa chain of the natural products. Also documented is an intramolecular copper-mediated amidation reaction to close the 19-membered macrolactams. The amidation reaction was also employed for the generation of structural derivatives (6-9) of phenolic ansamycins. Ansamycin natural products and selected structural analogues were evaluated in a competitive binding assay to breast cancer cell lysate and a cytotoxicity assay. Both reblastatin (1) and autolytimycin (2) were shown to bind the heat shock protein 90 with enhanced binding activity (approximately 25 nM) than 17-allylamino-17-demethoxygeldanamycin (17-AAG, 4), a geldanamycin (3) derivative currently under evaluation for treatment of cancer (approximately 100 nM).
Asunto(s)
Antineoplásicos/síntesis química , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Lactamas Macrocíclicas/síntesis química , Quinonas/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Benzoquinonas/química , Línea Celular Tumoral , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacología , Estructura Molecular , Fenoles/síntesis química , Quinonas/química , Quinonas/farmacología , Relación Estructura-ActividadRESUMEN
Synthesis and preliminary biological evaluation of a 35-member library of bistramide A stereoisomers are reported. All eight stereoisomers of the C1-C13 tetrahydropyran fragment of the molecule were prepared utilizing crotylsilane reagents 9 and 10 in our [4+2]-annulation methodology. In addition, the four isomers of the C14-C18 gamma-amino acid unit were accessed via a Lewis acid mediated crotylation reaction with use of both enantiomers of organosilane 11. The spiroketal subunit of bistramide A was modified at the C39-alcohol to give another point of stereochemical diversification. The fragments were coupled by using a standard peptide coupling protocol to provide 35 stereoisomers of the natural product. These stereochemical analogues were screened for their effects on cellular actin and cytotoxicity against cancer cell lines (UO-31 renal and SF-295 CNS). The results of these assays identified one analogue, 1.21, with enhanced potency relative to the natural product, bistramide A.
Asunto(s)
Acetamidas/síntesis química , Acetamidas/farmacología , Actinas/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Piranos/síntesis química , Piranos/farmacología , Acetamidas/química , Actinas/química , Antineoplásicos/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Conformación Molecular , Piranos/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Anhydrous FeCl3 in the presence of 2,6-lutidine promotes the substrate-controlled enantioselective [4 + 2]-cycloaddition and crotylation reaction between an enantioenriched ( S, E)-crotyl silane and in situ generated ortho-quinone methides ( oQMs). The reaction produces both the chiral chroman and crotylation products in a ratio reflective of the electronic nature of the parent oQM with overall combined yields up to 96%. A ring-opening and elimination sequence was subsequently developed to provide direct access to the crotylation products, containing two contiguous tertiary carbon stereocenters, in good yields and enantioselectivities.
Asunto(s)
Indolquinonas/química , Silanos/química , Reacción de Cicloadición , Estructura Molecular , EstereoisomerismoRESUMEN
Kavain, a compound derived from Piper methysticum, has demonstrated anti-inflammatory properties. To optimize its drug properties, identification and development of new kavain-derived compounds was undertaken. A focused library of analogs was synthesized and their effects on Porphyromonas gingivalis (P. gingivalis) elicited inflammation were evaluated in vitro and in vivo. The library contained cyclohexenones (5,5-dimethyl substituted cyclohexenones) substituted with a benzoate derivative at the 3-position of the cyclohexanone. The most promising analog identifed was a methylated derivative of kavain, Kava-205Me (5,5-dimethyl-3-oxocyclohex-1-en-1-yl 4-methylbenzoate.) In an in vitro assay of anti-inflammatory effects, murine macrophages (BMM) and THP-1 cells were infected with P. gingivalis (MOI = 20:1) and a panel of cytokines were measured. Both cell types treated with Kava-205Me (10 to 200 µg/ml) showed significantly and dose-dependently reduced TNF-α secretion induced by P. gingivalis. In BMM, Kava-205Me also reduced secretion of other cytokines involved in the early phase of inflammation, including IL-12, eotaxin, RANTES, IL-10 and interferon-γ (p < 0.05). In vivo, in an acute model of P. gingivalis-induced calvarial destruction, administration of Kava-205Me significantly improved the rate of healing associated with reduced soft tissue inflammation and osteoclast activation. In an infective arthritis murine model induced by injection of collagen-antibody (ArthriomAb) + P. gingivalis, administration of Kava-205Me was able to reduce efficiently paw swelling and joint destruction. These results highlight the strong anti-inflammatory properties of Kava-205Me and strengthen the interest of testing such compounds in the management of P. gingivalis elicited inflammation, especially in the management of periodontitis.
Asunto(s)
Antiinflamatorios/farmacología , Artritis Experimental/tratamiento farmacológico , Resorción Ósea/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Kava/química , Extractos Vegetales/farmacología , Cráneo/efectos de los fármacos , Animales , Artritis Experimental/inducido químicamente , Resorción Ósea/inducido químicamente , Resorción Ósea/patología , Citocinas/metabolismo , Inflamación/inducido químicamente , Inflamación/patología , Lipopolisacáridos/toxicidad , Macrófagos/efectos de los fármacos , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos DBA , Porphyromonas gingivalis/aislamiento & purificación , Cráneo/patologíaRESUMEN
Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential base excision repair enzyme that is upregulated in a number of cancers, contributes to resistance of tumors treated with DNA-alkylating or -oxidizing agents, and has recently been identified as an important therapeutic target. In this work, we identified hot spots for binding of small organic molecules experimentally in high resolution crystal structures of APE1 and computationally through the use of FTMAP analysis ( http://ftmap.bu.edu/ ). Guided by these hot spots, a library of drug-like macrocycles was docked and then screened for inhibition of APE1 endonuclease activity. In an iterative process, hot-spot-guided docking, characterization of inhibition of APE1 endonuclease, and cytotoxicity of cancer cells were used to design next generation macrocycles. To assess target selectivity in cells, selected macrocycles were analyzed for modulation of DNA damage. Taken together, our studies suggest that macrocycles represent a promising class of compounds for inhibition of APE1 in cancer cells.
Asunto(s)
ADN-(Sitio Apurínico o Apirimidínico) Liasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Lactamas Macrocíclicas/farmacología , Lactonas/farmacología , Dominio Catalítico , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , ADN-(Sitio Apurínico o Apirimidínico) Liasa/química , ADN-(Sitio Apurínico o Apirimidínico) Liasa/metabolismo , Descubrimiento de Drogas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Humanos , Lactamas Macrocíclicas/síntesis química , Lactamas Macrocíclicas/metabolismo , Lactonas/síntesis química , Lactonas/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-ActividadRESUMEN
An enantioselective synthesis of the Hsp90 inhibitor geldanamycin was achieved in 20 linear steps and 2.0% overall yield from 2-methoxyhydroquinone. The synthesis is highlighted by a regio- and stereoselective hydroboration reaction; a Sc(OTf)(3)/Et(3)SiH-mediated pyran ring-opening reaction; an enantioselective crotylation to simultaneously install the C8-C9 (E) -trisubstituted olefin, the C10 and C11 stereocenters; a chelation-controlled asymmetric metallated acetylide addition; and an intramolecular copper(I)-mediated aryl amidation reaction to close the 19-membered macrolactam.
Asunto(s)
Benzoquinonas/síntesis química , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Hidroquinonas/química , Lactamas Macrocíclicas/síntesis química , Benzoquinonas/química , Benzoquinonas/farmacología , Catálisis , Cobre/química , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacología , Estructura Molecular , EstereoisomerismoRESUMEN
A convergent enantioselective synthesis of herboxidiene/GEX 1A (1) is described that features a double stereodifferentiating crotylation, [4 + 2] annulation, and a silicon-based sp2-sp2 cross-coupling to assemble the conjugated diene.
Asunto(s)
Antineoplásicos/síntesis química , Alcoholes Grasos/síntesis química , Piranos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Alcoholes Grasos/química , Alcoholes Grasos/farmacología , Estructura Molecular , Piranos/química , Piranos/farmacología , Estereoisomerismo , Streptomyces/químicaRESUMEN
A convenient procedure for the synthesis of highly enantioenriched allenylsilanes by Johnson orthoester Claisen rearrangement of 1-silyl propargylic alcohols is described. Allenylsilanes are then used as carbon nucleophiles in three-component, Lewis acid mediated additions to in situ generated oxonium ions, resulting in enantioenriched homopropargylic ethers.
Asunto(s)
Alcadienos/química , Alcadienos/síntesis química , Pargilina/análogos & derivados , Pargilina/síntesis química , Silanos/química , Silanos/síntesis química , Aldehídos/química , Cromatografía Líquida de Alta Presión , Indicadores y Reactivos , Cinética , Lipasa/química , Solventes , EstereoisomerismoRESUMEN
Alkylidene indane and ring-expanded scaffolds have been prepared using an enantioselective crotylation/Heck cyclization sequence. Further diversification using consecutive cyclopropanation-Cope rearrangement affords novel chemotypes including spiroindane frameworks.
Asunto(s)
Indanos/química , Indanos/clasificación , Alquilación , Compuestos Azo/síntesis química , Compuestos Azo/química , Ciclización , Indanos/síntesis química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Estereoisomerismo , Compuestos de Vinilo/síntesis química , Compuestos de Vinilo/químicaRESUMEN
[structure: see text] The stereocontrolled synthesis of pyridooxazinones by Mg(OTf)2-promoted epoxide ring-opening with use of chiral pipecolates as nucleophiles is described. Pyridooxazinone products derived from azido-epoxides can be further rearranged to seven-membered pyridodiazepinones by azide reduction. The sequence of functional group interconversions generates diversity through topological and stereochemical variation.
Asunto(s)
Ésteres/química , Ácidos Pipecólicos/química , Compuestos Aza/química , Catálisis , Compuestos Epoxi/química , Ésteres/síntesis química , Estructura Molecular , Oxazinas/química , EstereoisomerismoRESUMEN
An asymmetric synthesis of the marine metabolite bistramide A is reported. The synthesis relies on the utility of three different organosilane reagents to construct all principle fragments and 8 of the 11 stereogenic centers of the natural product. [structure: see text].