RESUMO
The inhibition of glutaminase 1 (GLS1) represents a potential treatment of malignant tumors. Structural analysis led to the design of a novel series of macrocyclic GLS1 allosteric inhibitors. Through extensive structure-activity relationship studies, a promising candidate molecule 13b (LL202) was identified with robust GLS1 inhibitory activity (IC50 = 6 nM) and high GLS1 binding affinity (SPR, Kd = 24 nM; ITC, Kd = 37 nM). The X-ray crystal structure of the 13b-GLS1 complex was resolved, revealing a unique binding mode and providing a novel structural scaffold for GLS1 allosteric inhibitors. Importantly, 13b clearly adjusted the cellular metabolites and induced an increase in the ROS level by blocking glutamine metabolism. Furthermore, 13b exhibited a similar in vivo antitumor activity as CB839. This study adds to the growing body of evidence that macrocyclization provides an alternative and complementary approach for the design of small-molecule inhibitors, with the potential to improve the binding affinity to the targets.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Glutaminase/antagonistas & inibidores , Compostos Macrocíclicos/química , Sítio Alostérico , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Glutaminase/metabolismo , Glicólise/efeitos dos fármacos , Meia-Vida , Humanos , Compostos Macrocíclicos/metabolismo , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/uso terapêutico , Camundongos , Camundongos Nus , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
The development of effective respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors against both wild-type and the D486N-mutant F protein is urgently required. We recently reported a 15-membered macrocyclic pyrazolo[1,5-a]pyrimidine derivative 4 that exhibited potent anti-RSV activities against not only wild-type, but also D486N-mutant F protein. However, NMR studies revealed that the 15-membered derivative 4 existed as a mixture of atropisomers. An optimization study of the linker moiety between the 2-position of the benzoyl moiety and the 7-position of the pyrazolo[1,5-a]pyrimidine scaffold identified a 16-membered derivative 42c with an amide linker that showed a rapid interconversion of atropisomers. Subsequent optimization of the 5-position of the pyrazolo[1,5-a]pyrimidine scaffold and the 5-position of the benzoyl moiety resulted in the discovery of a potent clinical candidate 60b for the treatment of RSV infections.
Assuntos
Antivirais/química , Vírus Sincicial Respiratório Humano/metabolismo , Proteínas Virais de Fusão/antagonistas & inibidores , Animais , Antivirais/metabolismo , Antivirais/farmacologia , Sítios de Ligação , Linhagem Celular , Permeabilidade da Membrana Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Isomerismo , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Camundongos , Simulação de Dinâmica Molecular , Mutação , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Proteínas Virais de Fusão/genética , Proteínas Virais de Fusão/metabolismo , Internalização do Vírus/efeitos dos fármacosRESUMO
Oral factor XIa (FXIa) inhibitors may provide a promising new antithrombotic therapy with an improved benefit to bleeding risk profile over existing antithrombotic agents. Herein, we report application of a previously disclosed cyclic carbamate P1 linker which provided improved oral bioavailability in the imidazole-based 13-membered macrocycle to the 12-membered macrocycle. This resulted in identification of compound 4 with desired FXIa inhibitory potency and good oral bioavailability but high in vivo clearance. Further structure-activity relationship (SAR) studies of heterocyclic core modifications to replace the imidazole core as well as various linkers to the P1 group led to the discovery of compound 6f, a potent FXIa inhibitor with selectivity against most of the relevant serine proteases. Compound 6f also demonstrated excellent pharmacokinetics (PK) profile (high oral bioavailability and low clearance) in multiple preclinical species. Compound 6f achieved robust antithrombotic efficacy in a rabbit efficacy model at doses which preserved hemostasis.
Assuntos
Fator XIa/antagonistas & inibidores , Fibrinolíticos/administração & dosagem , Fibrinolíticos/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Avaliação Pré-Clínica de Medicamentos , Fator XIa/química , Fator XIa/metabolismo , Fibrinolíticos/química , Fibrinolíticos/farmacocinética , Humanos , Interações Hidrofóbicas e Hidrofílicas , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacocinética , Compostos Macrocíclicos/farmacologia , Modelos Moleculares , Coelhos , Relação Estrutura-AtividadeRESUMO
Capture and activation of the water-soluble uranyl dication (UO22+) remains a challenging problem, as few rational approaches are available for modulating the reactivity of this species. Here, we report the divergent synthesis of heterobimetallic complexes in which UO22+ is held in close proximity to a range of redox-inactive metals by a tailored macrocyclic ligand. Crystallographic and spectroscopic studies confirm assembly of homologous UVI(µ-OAr)2Mn+ cores with a range of mono-, di-, and trivalent Lewis acids (Mn+). Cyclic voltammetry data demonstrate that the UVI/UV reduction potential in these complexes is modulated over a span of 600 mV, depending linearly on the Lewis acidity of the redox-inactive metal with a sensitivity of 61 ± 9 mV/pKa unit. These findings suggest that interactions with Lewis acids could be effectively leveraged for rational tuning of the electronic and thermochemical properties of the 5f elements, reminiscent of strategies more commonly employed with 3d transition metals.
Assuntos
Compostos Macrocíclicos/química , Metais/química , Urânio/química , Cátions , Ácidos de Lewis/química , Oxirredução , Elementos de Transição/químicaRESUMO
A new macrocyclic diterpenoid, 4ß,5ß-dihydroxyovatodiolide (1), together with twenty-two known compounds (2-23) were isolated from the MeOH extract of the dried aerial parts of Anisomeles indica (L.) O. Kuntze (Labiatae). The structure of 1 was established on the basis of spectral evidence. Phenylethanoids, acteoside (5) and isoacteoside (6) showed significant inhibitory to IL-2 secretion of with respect to phorbol myristate acetate and anti-CD28 monoclonal antibody co-stimulated activation of human peripheral blood T cells.
Assuntos
Diterpenos/química , Diterpenos/farmacologia , Lamiaceae/química , Anticorpos Monoclonais/farmacologia , Antígenos CD28/imunologia , Antígenos CD28/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Medicamentos de Ervas Chinesas/química , Humanos , Interleucina-2/metabolismo , Compostos Macrocíclicos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
Manipulation of the emerging anion-π interactions in a highly cooperative manner through sophisticated host design represents a very challenging task. In this work, unprecedented tetrahedral anion-π receptors have been successfully constructed for complementary accommodation of tetrahedral and relevant anions. The synthesis was achieved by a macrocycle-directed approach by using large macrocycle precursors bearing four reactive sites, which enabled a kinetic-favored pathway and afforded the otherwise inaccessible tetrahedral cages in considerable yields. Crystal structure suggested that the tetrahedral cages have an enclosed three-dimensional cavity surrounded by four electron-deficient triazine faces in a tetrahedral array. The complementary accommodation of a series of tetrahedral and relevant anions including BF4 - , ClO4 - , H2 PO4 - , HSO4 - , SO4 2- and PF6 - was revealed by ESI-MS and DFT calculations. Crystal structures of ClO4 - and PF6 - complexes showed that the anion was nicely encapsulated within the tetrahedral cavity with up to quadruple cooperative anion-π interactions by an excellent shape and size match. The strong anion-π binding was further confirmed by negative ion photoelectron spectroscopy measurements.
Assuntos
Compostos Macrocíclicos/química , Triazinas/química , Ânions/química , Boratos/química , Reagentes de Ligações Cruzadas/química , Cristalização , Teoria da Densidade Funcional , Estrutura Molecular , Percloratos/química , Espectrometria de Massas por Ionização por Electrospray , Sulfatos/químicaRESUMO
Synthesis of 1,11-dithia-4,8-diazacyclotetradecane (L1), a constitutional isomer of the macrocyclic [14]aneN2S2 series, is accompanied with reaction and method optimization. Chelation of L1 with copper(II) provided assessment of lattice packing, ring contortion, and evidence of conformational fluxionality in solution through two unique crystal structures: L1Cu(ClO4)2 and [(L1Cu)2µ-Cl](ClO4)3. Multiple synthetic approaches are presented, supplemented with reaction methodology and reagent screening to access [14]aneN2S2 L1. Reductive alkylation of bis-tosyl-cystamine was integrated into the synthetic route, eliminating the use and isolation of volatile thiols and streamlining the synthetic scale-up. Late-stage cleavage of protecting sulfonamides was addressed using reductive N-S cleavage to furnish macrocyclic freebase L1.
Assuntos
Quelantes/química , Quelantes/síntese química , Cobre/química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/síntese química , Técnicas de Química Sintética , Modelos Moleculares , Conformação MolecularRESUMO
Bifunctional supramolecular prodrug vesicles have been successfully constructed based on the complexation between a glutathione (GSH)-responsive prodrug guest molecule (DNS-CPT) and a water-soluble pillar[5]arene (WP5) for cancer diagnosis and therapy. Under the microenvironment of cancer cells with high GSH concentration, 7-ethyl-10-hydroxycamptothecin (SN-38) with strong yellow fluorescence can be efficiently released from the prodrug DNS-CPT for drug location and cancer therapy.
Assuntos
Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Portadores de Fármacos/química , Compostos Macrocíclicos/química , Pró-Fármacos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Camptotecina/farmacologia , Camptotecina/toxicidade , Linhagem Celular Tumoral , Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos , Feminino , Glutationa/química , Humanos , Compostos Macrocíclicos/síntese química , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Nanopartículas/química , Tamanho da Partícula , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Pró-Fármacos/toxicidade , Solubilidade , Água , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The nano-encapsulation of Periploca angustifolia phenolic extract using the macrocyclic carbohydrate polymers (ßcyclodextrins) is a most approach compared with other encapsulation methods. In this work, the ßCyclodextrins-PAE complex stability has been evaluated by advanced analytical methods and techniques including HPLC, FTIR and XRD. The results showed that CdCl2 treatment caused a significant decrease in cell viability. The CdCl2-induced damage in the HepG2 cells were significantly ameliorated (pâ¯<â¯0.001) by treatment of the PAE and ßCyclodextrins-PAE complex. Thus, pretreatment with 100⯵gâ¯mL-1 of ßCyclodextrins-PAE complex significantly protect HepG2 cells against cytotoxicity induced by cadmium exposure more effectively than PAE only. However, Cd-intoxication significantly (pâ¯<â¯0.001) increased these enzymes activity. Additionally, reactive oxygen species generation was significantly decreased when cells were treated with nano-encapsulation PAE. The levels of supernatant antioxidant parameters including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and GSH were significantly (pâ¯<â¯0.001) decreased in Cd-treated cells with concomitant enhancement of lipid peroxidation. In addition, ßCyclodextrins-PAE pretreatment significantly (pâ¯<â¯0.01) inhibited Cd-exposure activated the apoptotic pathway caspace-3 and caspace-9. This effect may be due to the ability of ßCyclodextrins molecules to enhance stability and permeability properties.
Assuntos
Cádmio/farmacologia , Compostos Macrocíclicos/química , Nanopartículas/química , Periploca/química , Extratos Vegetais/química , Substâncias Protetoras/química , beta-Ciclodextrinas/química , Antioxidantes/metabolismo , Catalase/metabolismo , Linhagem Celular Tumoral , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Células Hep G2 , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Polímeros/química , Substâncias Protetoras/farmacologia , Superóxido Dismutase/metabolismoRESUMO
Type 2 diabetes is characterized by hyperglycemia derived from insulin resistance in periphery tissue. Effects of skeletal muscle on glucose disposal are closely related to insulin resistance. The potential effects on mitochondrial function of loesenerine, a macrocyclic spermidine alkaloid from the aerial part of Euonymus fortunei (TURCZ.) HAND.-MAZZ were observed after a high-throughout screening based on mitochondrial membrane potential (MMP) assay. Further pharmacological studies revealed that loesenerine activates AMP-activated protein kinase (AMPK) pathway through increasing ADP/ATP ratio by inhibiting mitochondrial respiration. In addition, loesenerine induced 1.07-, 1.14-, and 1.22-fold increment of glucose uptake in C2C12 cells at the concentrations of 20, 40 and 80 µmol/L, respectively. Meanwhile, incubated with loesenerine for 12 h increased glucose consumption in a dose-dependent manner in C2C12 cells. This is the first report that macrocyclic spermidine alkaloid possesses potential hypoglycemic activity in vitro.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Alcaloides/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Compostos Macrocíclicos/farmacologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Espermidina/análogos & derivados , Espermidina/farmacologia , Alcaloides/química , Animais , Linhagem Celular , Ativação Enzimática , Euonymus/química , Humanos , Hipoglicemiantes/química , Insulina/metabolismo , Resistência à Insulina , Compostos Macrocíclicos/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Espermidina/químicaRESUMO
The application of chalcogen bonding (ChB) to anion recognition is an underdeveloped area of host-guest supramolecular chemistry. The chemical instability of heavier chalcogen derivatives may in part be responsible for the lack of progress. Herein, the synthesis of a new structurally simple, tellurium-based ChB binding motif is reported, the robust stability of which has enabled the thermodynamic properties for ChB halide anion binding in polar aprotic and wet protic organic solvent media to be elucidated. The thermodynamic data reveals how the subtle interplay between ChB host, anion guest and solvent dictates halide binding selectivity and affinity trends. These findings help to provide a deeper insight into the nature of the ChB-anion interaction.
Assuntos
Compostos Macrocíclicos/química , Compostos Organometálicos/química , Selênio/química , Telúrio/química , Ânions/química , Modelos Moleculares , Solventes , Temperatura , TermodinâmicaRESUMO
The disulfide bond (-S-S-) is an enormously valuable functional group in a variety of chemical and biological agents that display effective reactivity or biological activities (e.g., antitumor activities). The disulfide bonds prevalent in proteins are somewhat oxidizing in the extracellular space; however, such disulfide bonds can rarely be found inside cells because of disulfide cleavage reactions facilitated by abundant free cellular thiols, including glutathione (GSH), which is the most important common thiol-containing small molecule. Interestingly, intracellular GSH concentrations are considerably higher in cancer cells than in analogous normal cells; this feature may prove to be significant in the development of anticancer drug delivery systems (DDS). Moreover, upconversion nanoparticles (UCNPs) have been extensively investigated in multimodal imaging, photodynamic therapy (PDT) and photothermal therapy. UCNPs exploit near-infrared excitation instead of ultraviolet excitation and possess exclusive properties, which include greatly increased penetration depth in biological samples and reductions in background autofluorescence, photobleaching and photodamage to biological specimens. These fascinating optical features of UCNPs may broaden their prospects in the fields of imaging and therapy. Graphene has emerged as a flat monolayer of carbon atoms that are tightly embedded in a two-dimensional (2D) honeycomb lattice. Widespread research has been carried out on graphene in recent years owing to its exclusive shape and size, as well as innumerable fascinating physical and chemical properties. Owing to their high optical absorption in the near-infrared (NIR) region, graphene and GO have been extensively employed for photothermal therapy (PTT). In this study, we attempted to merge the properties of these compounds by conjugating UCNPs and NGO-PEG-BPEI-DOX into a single platform for chemotherapy and photothermal therapy.
Assuntos
Doxorrubicina/química , Doxorrubicina/farmacologia , Grafite/química , Compostos Macrocíclicos/química , Nanopartículas/química , Óxidos/química , Fototerapia/métodos , Polietilenoglicóis/química , Polietilenoimina/análogos & derivados , Animais , Doxorrubicina/uso terapêutico , Células HeLa , Humanos , Camundongos , Oxirredução , Polietilenoimina/químicaRESUMO
The enzymes hydroxylamine oxidoreductase and cytochrome (cyt) P460 contain related unconventional "heme P460" cofactors. These cofactors are unusual in their inclusion of nonstandard cross-links between amino acid side chains and the heme macrocycle. Mutagenesis studies performed on the Nitrosomonas europaea cyt P460 that remove its lysine-heme cross-link show that the cross-link is key to defining the spectroscopic properties and kinetic competence of the enzyme. However, exactly how this cross-link confers these features remains unclear. Here we report the 1.45 Å crystal structure of cyt P460 from Nitrosomonas sp. AL212 and conclude that the cross-link does not lead to a change in hybridization of the heme carbon participating in the cross-link but rather enforces structural distortions to the macrocycle away from planarity. Time-dependent density functional theory coupled to experimental structural and spectroscopic analysis suggest that this geometric distortion is sufficient to define the spectroscopic properties of the heme P460 cofactor and provide clues toward establishing a relationship between heme P460 electronic structure and function.
Assuntos
Amônia/metabolismo , Proteínas de Bactérias/metabolismo , Coenzimas/metabolismo , Citocromos/metabolismo , Ferro/química , Compostos Macrocíclicos/metabolismo , Metaloporfirinas/metabolismo , Nitrosomonas europaea/enzimologia , Proteínas de Bactérias/química , Coenzimas/química , Cristalografia por Raios X , Citocromos/química , Espectroscopia de Ressonância de Spin Eletrônica , Compostos Macrocíclicos/química , Metaloporfirinas/química , Estrutura Molecular , Oxirredução , Espectrofotometria UltravioletaRESUMO
Naphthalene-linked P2-P4 macrocycles within a tri-peptide-based acyl sulfonamide chemotype have been synthesized and found to inhibit HCV NS3 proteases representing genotypes 1a and 1b with single digit nanomolar potency. The pharmacokinetic profile of compounds in this series was optimized through structural modifications along the macrocycle tether as well as the P1 subsite. Ultimately a compound with oral bioavailability of 100% in rat, and a long half-life in plasma was obtained. However, compounds in this macrocyclic series exhibited cardiac effects in an isolated rabbit heart model and for this reason further optimization efforts were discontinued.
Assuntos
Antivirais/química , Compostos Macrocíclicos/química , Naftalenos/química , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Antivirais/farmacologia , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Coração/efeitos dos fármacos , Coração/fisiologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Compostos Macrocíclicos/farmacocinética , Compostos Macrocíclicos/farmacologia , Microssomos Hepáticos/metabolismo , Conformação Molecular , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Coelhos , Ratos , Proteínas não Estruturais Virais/metabolismoRESUMO
Research within the field of photodynamic therapy has escalated over the past 20 years. The required conjunctional use of photosensitizers, particularly of the macrocycle structure, has lead to a vast repertoire of derivatives that branch classes and subclasses thereof. Each exhibits a differential range of physiochemical properties that influence their potential applications within the larger phototherapy field for use in either diagnostics, photodynamic therapy, both or none. Herein, we provide an overview of these properties as they relate to photodynamic therapy and to a lesser extent diagnostics. By summarizing the mechanistics of photodynamic therapy coupled to the photo-energetics displayed by macrocycle photosensitizers, we aimed to highlight the critical aspects any researcher should be aware of and consider when selecting and performing research for therapeutic application purposes. These include photosensitizer, photophysical and structural properties, synthesis design and subsequent attributes, main applications within research, common shortcomings exhibited and the current methods practiced to overcome them.
Assuntos
Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Corantes/química , Humanos , Luz , Metais/química , Estrutura Molecular , Processos FotoquímicosRESUMO
Biotin/(strept)avidin self-assembly is a powerful platform for nanoscale fabrication and capture with many different applications in science, medicine, and nanotechnology. However, biotin/(strept)avidin self-assembly has several well-recognized drawbacks that limit performance in certain technical areas and there is a need for synthetic mimics that can either become superior replacements or operational partners with bio-orthogonal recognition properties. The goal of this tutorial review is to describe the recent progress in making high affinity synthetic association partners that operate in water or biological media. The review starts with a background summary of biotin/(strept)avidin self-assembly and the current design rules for creating synthetic mimics. A series of case studies are presented that describe recent success using synthetic derivatives of cyclodextrins, cucurbiturils, and various organic cyclophanes such as calixarenes, deep cavitands, pillararenes, and tetralactams. In some cases, two complementary partners associate to produce a nanoscale complex and in other cases a ditopic host molecule is used to link two partners. The article concludes with a short discussion of future directions and likely challenges.
Assuntos
Avidina/química , Biotina/química , Calixarenos/síntese química , Ciclodextrinas/síntese química , Compostos Macrocíclicos/síntese química , Estreptavidina/química , Calixarenos/química , Ciclodextrinas/química , Humanos , Compostos Macrocíclicos/químicaRESUMO
This paper reports a method for evaluating antioxidant capacity based on the inhibitory effects of a macrocyclic Ni(II) complex-catalysed Briggs-Rauscher reaction. The macrocyclic Ni(II) complex NiL(ClO4)2, in which L is 5,7,7,12,14,14-hexamethyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene, is a porphyrin-like compound, the structure of which can be found in certain enzymes. The experiments indicated that three natural compounds could temporarily quench the oscillations for a period of time prior to regeneration of oscillations. The inhibition time was related to the compound type and concentration; thus, procedures for evaluating the antioxidant activities of polyphenolic compounds were successfully established. Three polyphenolic compounds were tested to evaluate their antioxidant activities: protocatechuic acid, rutin hydrate and procyanidin. Of these three naturally occurring compounds, procyanidin was found to be the most efficient antioxidant. We have also discussed the reaction of the antioxidant with the hydroperoxyl radical (HOO) present in the oscillating system.
Assuntos
Antioxidantes/farmacologia , Compostos Macrocíclicos/química , Níquel/química , Polifenóis/farmacologia , Biflavonoides , Catálise , Catequina , Hidroxibenzoatos , Radical Hidroxila/química , Extratos Vegetais/química , Proantocianidinas , RutinaRESUMO
A copper-mediated macrocyclization involving the reaction of a vinyl iodide and a terminal alkyne followed by an in situ reduction of the enyne intermediate is reported. The reaction generates a conjugated Z-double bond within a strained medium-size lactone, lactam, or ether macrocycle. A variety of macrocyclic compounds bearing different ring sizes and functionalities were synthesized. A complementary stepwise procedure was also developed for less strained ring systems.
Assuntos
Alcinos/química , Cobre/química , Compostos Macrocíclicos/síntese química , Catálise , Técnicas de Química Combinatória , Ciclização , Compostos Macrocíclicos/química , Estrutura MolecularRESUMO
Actinyl(VI, V) (An = U, Np and Pu) complexes of the recently reported hybrid macrocycle, cyclo[1]furan[1]pyridine[4]pyrrole (denoted as H4L), have been studied using density functional theory in combination with the small-core scalar-relativistic effective core potentials and corresponding (14s13p10d8f6g)/[ 10s9p5d4f3g] basis sets in the segmented contraction scheme. On the basis of our calculations, the pyrrole nitrogen atoms that possess the shortest An-L bonds and strongest basicity are the main donor atoms that contribute to the formation of actinyl(VI, V) complexes. The natural population analysis (NPA) suggests higher ligand-to-actinyl charge transfer in the actinyl(VI) complexes than in their actinyl(V) analogues, which account for the higher decomposition energies of the former. A significant actinide-to-ligand spin density delocalization in the uranyl(V) and neptunyl(V) complexes was observed owing to the redistribution of spin density caused by complexation. A thermodynamic analysis indicates that the formation of the actinyl(VI, V) complexes are exothermic reactions in CH2Cl2 solvent, where the uranyl cations show the highest selectivity. In aqueous solution containing chloride ions, for complexing with macrocycle H4L, the plutonyl(VI) and uranyl(V) cations possess the highest selectivity among actinyl(VI) and (V) cations, respectively. This work can shed light on the design of macrocycle complexes for actinide recognition and extraction in the future.
Assuntos
Compostos Macrocíclicos/química , Compostos Organometálicos/química , Teoria Quântica , Elétrons , Furanos/química , Ligantes , Cloreto de Metileno/química , Modelos Moleculares , Conformação Molecular , Netúnio/química , Plutônio/química , Piridinas/química , Pirróis/química , Solventes/química , Urânio/química , Água/químicaRESUMO
We report here a series of heteroatom-substituted macrocycles containing an anthraquinone moiety as a fluorescent signaling unit and a cyclic polyheteroether chain as the receptor. Sulfur, selenium, and tellurium derivatives of 1,8-anthraquinone-18-crown-5 (1) were synthesized by reacting sodium sulfide (Na2S), sodium selenide (Na2Se) and sodium telluride (Na2Te) with 1,8-bis(2-bromoethylethyleneoxy)anthracene-9,10-dione in a 1 : 1 ratio. The optical properties of the new compounds are examined and the sulfur and selenium analogues produce an intense green emission enhancement upon association with Pb(II) in acetonitrile. Selectivity for Pb(II) is markedly improved as compared to the oxygen analogue 1 which was also competitive for Ca(II) ion. UV-Visible and luminescence titrations reveal that 2 and 3 form 1 : 1 complexes with Pb(II), confirmed by single-crystal X-ray studies where Pb(II) is complexed within the macrocycle through coordinate covalent bonds to neighboring carbonyl, ether and heteroether donor atoms. Cyclic voltammetry of 2-8 showed classical, irreversible oxidation potentials for sulfur, selenium and tellurium heteroethers in addition to two one-electron reductions for the anthraquinone carbonyl groups. DFT calculations were also conducted on 1, 2, 3, 6, 6 + Pb(II) and 6 + Mg(II) to determine the trend in energies of the HOMO and the LUMO levels along the series.