RESUMEN
Schisandra chinensis (Turcz.) Baill. (S. chinensis) and Schisandra sphenanthera Rehd. et Wils (S. sphenanthera) are called "Wuweizi" in traditional Chinese medicine, and they have distinct clinical applications. To systematically compare the differential characteristics of S. chinensis and S. sphenanthera, this study employed ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) and gas chromatography-mass spectrometry (GC-MS) to construct chemical profiles of these two species from different regions. In total, 31 non-volatiles and 37 volatiles were identified in S. chinensis, whereas 40 non-volatiles and 34 volatiles were detected in S. sphenanthera. A multivariate statistical analysis showed that the non-volatiles tigloygomisin P, schisandrol A, schisantherin C, and 6-O-benzoylgomisin O and the volatiles ylangene, γ-muurolene, and ß-pinene distinguish these species. Additionally, the metabolism of oxygen free radicals can contribute to the development of various diseases, including cardiovascular and neurodegenerative diseases. Therefore, antioxidant activities were evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) scavenging assays. The results showed that S. sphenanthera exhibited significantly higher antioxidant potential. A gray relational analysis indicated that the key contributors to the antioxidant activity of S. chinensis were schisandrol A, gomisin G, schisantherin C, pregomisin, gomisin J, and schisantherin B. For S. sphenanthera, the key contributors included gomisin K2, schisantherin B, gomisin J, pregomisin, schisantherin C, schisandrin, gomisin G, schisantherin A, schisanhenol, and α-pinene. The identification of the differential chemical markers and the evaluation of the antioxidant activities provide a foundation for further research into the therapeutic applications of these species. This innovative study provides a robust framework for the quality control and therapeutic application of S. chinensis and S. sphenanthera, offering new insights into their medicinal potential.
Asunto(s)
Antioxidantes , Cromatografía de Gases y Espectrometría de Masas , Schisandra , Schisandra/química , Antioxidantes/química , Antioxidantes/farmacología , Antioxidantes/análisis , Cromatografía de Gases y Espectrometría de Masas/métodos , Lignanos/química , Lignanos/análisis , Ciclooctanos/química , Ciclooctanos/análisis , Cromatografía Líquida de Alta Presión/métodos , Compuestos Policíclicos/química , Compuestos Policíclicos/análisis , Monoterpenos Bicíclicos/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Monoterpenos/química , Monoterpenos/análisis , Compuestos Bicíclicos con Puentes/análisis , Compuestos Bicíclicos con Puentes/química , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacologíaRESUMEN
Anthranilic acids, salicylaldehydes and arylboronic acids reacted in EtOH/H2O (1/3) at 150 °C under microwave irradiation for 1 h to give, in excellent yields and purity, twenty-three bridgehead bicyclo[4.4.0]boron heterocycles via one-pot, three-component green synthesis. The scope and the limitations of the reactions are discussed in terms of the substitution of ten different anthranilic acids, three salicylaldehydes and three arylboronic acids. The replacement of salicylaldehyde with o-hydroxyacetophenone demanded a lipophilic solvent for the reaction to occur. Eight novel derivatives were isolated following crystallization in a toluene-containing mixture that included molecular sieves. The above one-pot, three-component reactions were completed under microwave irradiation at 180 °C within 1.5 h, thus avoiding the conventional prolonged heating reaction times and the use of a Dean-Stark apparatus. All derivatives were studied for their affinity to calf thymus DNA using proper techniques like viscosity and UV-vis spectroscopy, where DNA-binding constants were found in the range 2.83 × 104-8.41 × 106 M-1. Ethidium bromide replacement studies using fluorescence spectroscopy indicated Stern-Volmer constants between 1.49 × 104 and 5.36 × 104 M-1, whereas the corresponding quenching constants were calculated to be between 6.46 × 1011 and 2.33 × 1012 M-1 s-1. All the above initial experiments show that these compounds may have possible medical applications for DNA-related diseases.
Asunto(s)
ADN , Microondas , ADN/química , Tecnología Química Verde/métodos , Ácidos Borónicos/química , ortoaminobenzoatos/química , Animales , Aldehídos/química , Técnicas de Química Sintética , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis química , Estructura Molecular , Bovinos , Compuestos Bicíclicos con Puentes/químicaRESUMEN
While natural terpenoid cyclases generate complex terpenoid structures via cationic mechanisms, alternative radical cyclization pathways are underexplored. The metal-catalysed H-atom transfer reaction (M-HAT) offers an attractive means for hydrofunctionalizing olefins, providing access to terpenoid-like structures. Artificial metalloenzymes offer a promising strategy for introducing M-HAT reactivity into a protein scaffold. Here we report our efforts towards engineering an artificial radical cyclase (ARCase), resulting from anchoring a biotinylated [Co(Schiff-base)] cofactor within an engineered chimeric streptavidin. After two rounds of directed evolution, a double mutant catalyses a radical cyclization to afford bicyclic products with a cis-5-6-fused ring structure and up to 97% enantiomeric excess. The involvement of a histidine ligation to the Co cofactor is confirmed by crystallography. A time course experiment reveals a cascade reaction catalysed by the ARCase, combining a radical cyclization with a conjugate reduction. The ARCase exhibits tolerance towards variations in the dienone substrate, highlighting its potential to access terpenoid scaffolds.
Asunto(s)
Terpenos , Terpenos/química , Terpenos/metabolismo , Ciclización , Modelos Moleculares , Compuestos Bicíclicos con Puentes/química , Ingeniería de ProteínasRESUMEN
The great variety and fascinating complexity of terpenoid skeletons are achieved through different cyclizations catalyzed by terpene cyclases. Here, we report a sesquiterpene cyclase (MfdS) from Aspergillus ustus for the formation of malfilanol D, a member of the group of biochemically less investigated sesquiterpenes with a bicyclo[5.4.0]undecane skeleton. Feeding 13C-labeled acetates in Aspergillus nidulans with the mfdS sequence provides evidence for a C-1 to C-10 cyclization with subsequent 1,2-alkyl and 1,2-hydride shifts in the formation of the 6/7-fused rings.
Asunto(s)
Aspergillus , Sesquiterpenos , Aspergillus/química , Aspergillus/metabolismo , Sesquiterpenos/química , Sesquiterpenos/metabolismo , Estructura Molecular , Ciclización , Alcanos/química , Alcanos/metabolismo , Aspergillus nidulans/metabolismo , Aspergillus nidulans/química , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/metabolismoAsunto(s)
Odorantes , Perfumes , Humanos , Perfumes/toxicidad , Perfumes/química , Animales , Medición de Riesgo , Benzoatos/toxicidad , Benzoatos/química , Pruebas de Toxicidad , Determinación de Punto Final , Compuestos Bicíclicos con Puentes/toxicidad , Compuestos Bicíclicos con Puentes/química , Seguridad de Productos para el Consumidor , Nivel sin Efectos Adversos Observados , Bases de Datos de Compuestos QuímicosRESUMEN
Inhibition of human ornithine aminotransferase interferes with glutamine and proline metabolism in hepatocellular carcinoma, depriving tumors of essential nutrients. A proposed mechanism-based inhibitor containing a bicyclo[3.1.1]heptanol warhead is reported herein. The proposed inactivation mechanism involves a novel α-iminol rearrangement. The synthesis of the proposed inhibitor features an asymmetric intramolecular Mannich reaction, utilizing a chiral sulfinamide. This study presents a novel approach toward the synthesis of functionalized bicyclo[3.1.1]heptanes and highlights an underutilized method to access enantiopure exocyclic amines.
Asunto(s)
Ácidos Carboxílicos , Estereoisomerismo , Ácidos Carboxílicos/química , Estructura Molecular , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/síntesis química , HumanosAsunto(s)
Perfumes , Humanos , Perfumes/toxicidad , Perfumes/química , Animales , Medición de Riesgo , Odorantes , Pruebas de Toxicidad , Determinación de Punto Final , Seguridad de Productos para el Consumidor , Compuestos Bicíclicos con Puentes/toxicidad , Compuestos Bicíclicos con Puentes/química , Bases de Datos de Compuestos QuímicosRESUMEN
Medicinal compounds from plants include bicyclo[3.3.1]nonane derivatives, the majority of which are polycyclic polyprenylated acylphloroglucinols (PPAPs). Prototype molecules are hyperforin, the antidepressant constituent of St. John's wort, and garcinol, a potential anticancer compound. Their complex structures have inspired innovative chemical syntheses, however, their biosynthesis in plants is still enigmatic. PPAPs are divided into two subclasses, named type A and B. Here we identify both types in Hypericum sampsonii plants and isolate two enzymes that regiodivergently convert a common precursor to pivotal type A and B products. Molecular modelling and substrate docking studies reveal inverted substrate binding modes in the two active site cavities. We identify amino acids that stabilize these alternative binding scenarios and use reciprocal mutagenesis to interconvert the enzymatic activities. Our studies elucidate the unique biochemistry that yields type A and B bicyclo[3.3.1]nonane cores in plants, thereby providing key building blocks for biotechnological efforts to sustainably produce these complex compounds for preclinical development.
Asunto(s)
Hypericum , Hypericum/metabolismo , Hypericum/genética , Hypericum/química , Compuestos Bicíclicos con Puentes/metabolismo , Compuestos Bicíclicos con Puentes/química , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Simulación del Acoplamiento Molecular , Floroglucinol/metabolismo , Floroglucinol/análogos & derivados , Floroglucinol/química , Alcanos/metabolismo , Alcanos/química , Dominio Catalítico , Terpenos/metabolismo , Terpenos/química , Modelos MolecularesRESUMEN
Thirteen new sirenin derivatives named eupenicisirenins C-O (1-13), along with a biosynthetically related known one (14), were isolated from the mangrove sediment-derived fungus Penicillium sp. SCSIO 41410. The structures, which possessed a rare cyclopropane moiety, were confirmed by extensive analyses of the spectroscopic data, quantum chemical calculations, and X-ray diffraction. Among them, eupenicisirenin C (1) exhibited the strongest NF-κB inhibitory activities, as well as suppressing effects on cGAS-STING pathway. Moreover, 1 showed the significant inhibitory effect on RANKL-induced osteoclast differentiation in bone marrow macrophages cells, and also displayed the therapeutic potential on prednisolone-induced zebrafish osteoporosis. Transcriptome analysis and the following verification tests suggested that its anti-osteoporotic mechanism is related to the extracellular matrix receptor interaction-related pathways. This study provided a promising marine-derived anti-osteoporotic agent for the treatment of skeletal disease.
Asunto(s)
Osteoporosis , Penicillium , Animales , Hongos/metabolismo , Macrófagos , FN-kappa B/metabolismo , Osteoporosis/tratamiento farmacológico , Penicillium/química , Pez Cebra/metabolismo , Compuestos Bicíclicos con Puentes/químicaRESUMEN
The development of synthetic strategies for the preparation of bioisosteric compounds is a demanding undertaking in medicinal chemistry. Numerous strategies have been developed for the synthesis of bicyclo[1.1.1]pentanes (BCPs), bridge-substituted BCPs, and bicyclo[2.1.1]hexanes. However, progress on the synthesis of bicyclo[3.1.1]heptanes, which serve as meta-substituted arene bioisosteres, has not been previously explored. Herein, we disclose the first photoinduced [3σ + 2σ] cycloaddition for the synthesis of trisubstituted bicyclo[3.1.1]heptanes using bicyclo[1.1.0]butanes and cyclopropylamines. This transformation not only uses mild and operationally simple conditions but also provides unique meta-substituted arene bioisosteres. The applicability of this method is showcased by simple derivatization reactions.
Asunto(s)
Compuestos Bicíclicos con Puentes , Heptanos , Compuestos Bicíclicos con Puentes/química , Heptanos/química , Reacción de Cicloadición , Hexanos/química , ButanosRESUMEN
The organocatalytic enantioselective Michael addition of functionalized prochiral cyclic hemiacetals and nitroolefins has been developed under cooperative enamine and hydrogen bond catalysis. The obtained chiral hemiacetal intermediates could be used in the subsequent diastereocontrolled cyclization/desymmetrization divergent process to access (1) 9-oxabicyclo[3.3.1]nonane or 8-oxabicyclo[3.2.1]octane frameworks via oxocarbenium ion-mediated Friedel-Crafts cyclization, and (2) 2,9-dioxabicyclo[3.3.1]nonane frameworks via intramolecular nucleophilic cyclization. Experimental results suggest that there is neighboring group participation controlling the diastereoselectivities of the desymmetrization process.
Asunto(s)
Compuestos Bicíclicos con Puentes , Oxígeno , Ciclización , Estereoisomerismo , Compuestos Bicíclicos con Puentes/química , CatálisisRESUMEN
Among the valuable saturated bicyclic structures incorporated in newly developed bio-active compounds, bicyclo[2.1.1]hexanes are playing an increasingly important role, while being still underexplored from a synthetic accessibility point of view. Here, we disclose an efficient and modular approach toward new 1,2-disubstituted bicyclo[2.1.1]hexane modules. Our strategy is based on the use of photochemistry to access new building blocks via [2 + 2] cycloaddition. The system can readily be derivatized with numerous transformations, opening the gate to sp3-rich new chemical space.
Asunto(s)
Compuestos Bicíclicos con Puentes , Hexanos , Hexanos/química , Compuestos Bicíclicos con Puentes/química , Reacción de CicloadiciónRESUMEN
Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes.
Asunto(s)
Compuestos Bicíclicos con Puentes , Diseño de Fármacos , Heptanos , Aniones/química , Benceno/química , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/química , Descubrimiento de Drogas , Heptanos/síntesis química , Heptanos/química , Pentanos/síntesis química , Pentanos/química , SolubilidadRESUMEN
Acyl bicyclobutanes are shown to engage in strain-promoted cycloaddition reactions with a diverse array of triazolinedione reagents. The synthesis of an orthogonally protected urazole building block enabled the facile preparation of amino acid- and peptide-derived triazolinediones that undergo cycloaddition reactions to afford novel peptide conjugates. The additive-free and fully atom-economical nature of the transformation is a promising starting point for the generalization of this cycloaddition reaction for the functionalization of biomolecules.
Asunto(s)
Compuestos Bicíclicos con Puentes/química , Péptidos/química , Triazoles/química , Aminoácidos/química , Reacción de Cicloadición , Estructura MolecularRESUMEN
Owing to its roles in human health and disease, the modification of nuclear, cytoplasmic, and mitochondrial proteins with O-linked N-acetylglucosamine residues (O-GlcNAc) has emerged as a topic of great interest. Despite the presence of O-GlcNAc on hundreds of proteins within cells, only two enzymes regulate this modification. One of these enzymes is O-GlcNAcase (OGA), a dimeric glycoside hydrolase that has a deep active site cleft in which diverse substrates are accommodated. Chemical tools to control OGA are emerging as essential resources for helping to decode the biochemical and cellular functions of the O-GlcNAc pathway. Here we describe rationally designed bicyclic thiazolidine inhibitors that exhibit superb selectivity and picomolar inhibition of human OGA. Structures of these inhibitors in complex with human OGA reveal the basis for their exceptional potency and show that they extend out of the enzyme active site cleft. Leveraging this structure, we create a high affinity chemoproteomic probe that enables simple one-step purification of endogenous OGA from brain and targeted proteomic mapping of its post-translational modifications. These data uncover a range of new modifications, including some that are less-known, such as O-ubiquitination and N-formylation. We expect that these inhibitors and chemoproteomics probes will prove useful as fundamental tools to decipher the mechanisms by which OGA is regulated and directed to its diverse cellular substrates. Moreover, the inhibitors and structures described here lay out a blueprint that will enable the creation of chemical probes and tools to interrogate OGA and other carbohydrate active enzymes.
Asunto(s)
Antígenos de Neoplasias/metabolismo , Compuestos Bicíclicos con Puentes/química , Inhibidores Enzimáticos/química , Histona Acetiltransferasas/metabolismo , Hialuronoglucosaminidasa/metabolismo , Secuencia de Aminoácidos , Encéfalo/metabolismo , Compuestos Bicíclicos con Puentes/metabolismo , Dominio Catalítico , Cromatografía Líquida de Alta Presión , Inhibidores Enzimáticos/metabolismo , Histona Acetiltransferasas/antagonistas & inhibidores , Humanos , Hialuronoglucosaminidasa/antagonistas & inhibidores , Espectrometría de Masas , Péptidos/análisis , Péptidos/química , Procesamiento Proteico-Postraduccional , Proteómica/métodos , Relación Estructura-Actividad , Tiazolidinas/química , Tiazolidinas/metabolismo , Cadena alfa de beta-Hexosaminidasa/antagonistas & inhibidores , Cadena alfa de beta-Hexosaminidasa/metabolismoRESUMEN
Chiral sp3-rich bicyclo[3.3.1]nonane scaffolds 10-12 were synthesized as single diastereomers from aldehyde 9, which was prepared from 4,4-dimethoxycyclohexa-2,5-dienone through a copper-catalyzed enantioselective reduction. Three different types of intramolecular addition reactions were studied: SmI2-mediated reductive cyclization, base-promoted aldol reaction, and one-pot Mannich reaction. We succeeded in introducing three side-chains to scaffold 11 and construct an sp3-rich compound library in both enantiomeric variants by simply changing the chirality of the ligands. The biological evaluation revealed that all synthesized compounds exhibited a concentration-dependent inhibition of hypoxia-inducible factor-1 (HIF-1) transcriptional activity, with IC50 values in the range of 17.2-31.7 µM, whereas their effects on cell viability were varied (IC50 = 3.5 to > 100 µM). The most active compound 16f inhibits the accumulation of HIF-1α protein and mRNA in hypoxia, indicating that it has a mechanism of action distinctly different from other known compounds bearing the common bicyclo[3.3.1]nonane skeleton.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/química , Hipoxia de la Célula/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ligandos , Modelos Moleculares , Estructura Molecular , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/metabolismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Amines containing bridged bicyclic carbon skeletons are desirable building blocks for medicinal chemistry. Herein, we report the conversion of bicyclo[1.1.1]pentan-1-amines to a wide range of polysubstituted bicyclo[3.1.1]heptan-1-amines through a photochemical, formal (4 + 2)-cycloaddition of an intermediate imine diradical. To our knowledge, this is the first reported method to convert the bicyclo[1.1.1]pentane skeleton to the bicyclo[3.1.1]heptane skeleton. Hydrolysis of the imine products gives complex, sp3-rich primary amine building blocks.
Asunto(s)
Alquenos/química , Compuestos Bicíclicos con Puentes/química , Iminas/química , Reacción de Cicloadición , Hidrólisis , Pentanos/química , EstereoisomerismoRESUMEN
Novel innovative catalytic systems such as hydrogen-bond donors and thiourea hybrid catalysts have been developed for the asymmetric synthesis of biologically important pharmaceuticals and natural products. Benzothiadiazines possess a stronger hydrogen-bond donor ability compared to thioureas and exhibit remarkable catalytic performance for the activation of α,ß-unsaturated amides. Hybrid thioureas (bearing an arylboronic acid and an ammonium salt) efficiently promote the hetero-Michael addition to α,ß-unsaturated carboxylic acids and the O-alkylation of keto enols with 5-chlorofuran-2(5H)-one. These hybrid catalysts enable the first total synthesis of non-racemic avenaol, a noncanonical strigolactone, as well as the asymmetric synthesis of several pharmaceuticals. In addition, this study discovers unique chemical phenomena (i.e., the dual role of benzoic acid as a boron ligand and a proton shuttle, the chirality switch of products by solvent used, and the dynamic kinetic resolution of a racemic electrophile in an SN2-type reaction).
Asunto(s)
Compuestos Bicíclicos con Puentes/síntesis química , Ciclopropanos/síntesis química , Tiourea/química , Ácido Benzoico/química , Boro/química , Compuestos Bicíclicos con Puentes/química , Catálisis , Ciclopropanos/química , Enlace de Hidrógeno , Cinética , Ligandos , Estructura MolecularRESUMEN
Much hope in drug development comes from the discovery of positive allosteric modulators (PAM) that display target subtype selectivity and act by increasing agonist potency and efficacy. How such compounds can allosterically influence agonist action remains unclear. Metabotropic glutamate receptors (mGlu) are G protein-coupled receptors that represent promising targets for brain diseases, and for which PAMs acting in the transmembrane domain have been developed. Here, we explore the effect of a PAM on the structural dynamics of mGlu2 in optimized detergent micelles using single molecule FRET at submillisecond timescales. We show that glutamate only partially stabilizes the extracellular domains in the active state. Full activation is only observed in the presence of a PAM or the Gi protein. Our results provide important insights on the role of allosteric modulators in mGlu activation, by stabilizing the active state of a receptor that is otherwise rapidly oscillating between active and inactive states.