RESUMO
CONTEXT: The regioselectivity and diastereoselectivity of the 1,3-dipolar cycloaddition reaction between azomethine ylides and acrolein were investigated. The DFT studies revealed that the favored pathway leads to the formation of cis-cycloadduct pyrrolidine and these computational findings align with experimental observations. The cis-cycloadduct pyrrolidine product serves as an advanced intermediate in the synthesis of a hepatitis C virus inhibitor. For this, the antiviral activity of cis-cycloadduct pyrrolidine against cyclophilin A, the co-factor responsible for hepatitis C virus, was also evaluated through molecular docking simulations which revealed intriguing interactions and a high C-score, which were further confirmed by molecular dynamics simulations, demonstrating stability over a 100-ns simulation period. Furthermore, the cis-cycloadduct pyrrolidine exhibits favorable drug-like properties and a better ADMET profile compared to hepatitis C virus inhibitor. METHODS: Chemical reactivity studies were performed using DFT method by the functional B3LYP at 6-31G (d, p) computational level by GAUSSIAN 16 program. Frontal molecular orbitals theory used to investigate HOMO/LUMO interactions between azomethine ylides and acrolein. Findings of this approach were confirmed by global reactivity indices and electron displacement was investigated based on Fukui functions. Furthermore, the activation energies were determined after frequency calculations using TS Berny algorithm and transition states were confirmed by the presence of a single imaginary frequency. Moreover, antiviral activity of cis-cycloadduct was explored through molecular docking using Surflex-Dock suite SYBYL X 2.0, and molecular dynamics simulation using GROMACS program. Finally, drug-like properties were investigated with SwissADME and ADMETlab 2.0.
Assuntos
Acroleína , Hepacivirus , Simulação de Acoplamento Molecular , Acroleína/farmacologia , Reação de Cicloadição , Pirrolidinas/química , Antivirais/farmacologiaRESUMO
The importance of regioselectivity in 1,3-dipolar cycloadditions (DCs) makes it surprising that no benchmarking study on this problem has appeared. We investigated whether DFT calculations are an accurate tool to predict the regioselectivity of uncatalyzed thermal azide 1,3-DCs. We considered the reaction between HN3 and 12 dipolarophiles, comprising ethynes HC≡C-R and ethenes H2 C=CH-R (R=F, OH, NH2 , Me, CN, CHO), which cover a broad range of electron demand and conjugation ability. We established benchmark data by the W3X protocol [complete-basis-set-extrapolated CCSD(T)-F12 energy with T-(T) and (Q) corrections and MP2-calculated core/valence and relativistic effects] and showed that core/valence effects and high-order excitations are important for accurate regioselectivity. Regioselectivities calculated using an extensive set of density functional approximations (DFAs) were compared with benchmark data. Range-separated and meta-GGA hybrids gave the best results. Good treatment of self-interaction and electron exchange are the key features for accurate regioselectivity. Dispersion correction slightly improves agreement with W3X results. The best DFAs provide the isomeric TS energy difference with an expected error ≈0.7â mh and errors ≈2â mh can occur. The isomer yield provided by the best DFA has an expected error of ±5 %, though errors up to 20 % are not rare. At present, an accuracy of 1-2 % is unfeasible but it seems that we are not far from achieving this goal.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Azidas , Alcenos , Alcinos , Reação de CicloadiçãoRESUMO
Mass spectrometry-based chemoproteomics has enabled functional analysis and small molecule screening at thousands of cysteine residues in parallel. Widely adopted chemoproteomic sample preparation workflows rely on the use of pan cysteine-reactive probes such as iodoacetamide alkyne combined with biotinylation via copper-catalyzed azide-alkyne cycloaddition (CuAAC) or "click chemistry" for cysteine capture. Despite considerable advances in both sample preparation and analytical platforms, current techniques only sample a small fraction of all cysteines encoded in the human proteome. Extending the recently introduced labile mode of the MSFragger search engine, here we report an in-depth analysis of cysteine biotinylation via click chemistry (CBCC) reagent gas-phase fragmentation during MS/MS analysis. We find that CBCC conjugates produce both known and novel diagnostic fragments and peptide remainder ions. Among these species, we identified a candidate signature ion for CBCC peptides, the cyclic oxonium-biotin fragment ion that is generated upon fragmentation of the N(triazole)-C(alkyl) bond. Guided by our empirical comparison of fragmentation patterns of six CBCC reagent combinations, we achieved enhanced coverage of cysteine-labeled peptides. Implementation of labile searches afforded unique PSMs and provides a roadmap for the utility of such searches in enhancing chemoproteomic peptide coverage.
Assuntos
Química Click , Cisteína , Alcinos/química , Azidas/química , Catálise , Química Click/métodos , Cobre/química , Reação de Cicloadição , Cisteína/química , Humanos , Espectrometria de Massas em TandemRESUMO
Gold(I)-catalyzed [4 + 2] cycloaddition of indolylynamides and cyanamides (aminonitriles) is an efficient redox-neutral and atom-economic route to diversely substituted 1,3-diamino-ß-carbolines. The protocol operates under mild conditions (Ph3PAuNTf2 5 mol %, DCE, 60 °C) with a good tolerance to functional groups (23 examples and yields up to 98%). The obtained ß-carboline systems represent a versatile synthetic platform with modifiable substituents for successive functionalizations. Control experiments indicate the crucial role of both the nature of reactants and the identity of employed catalysts in the developed cycloaddition.
Assuntos
Cianamida , Ouro , Carbolinas , Catálise , Reação de Cicloadição , OxirreduçãoRESUMO
A recent strong trend toward green and sustainable chemistry has promoted the intensive use of renewable carbon sources for the production of polymers, biofuels, chemicals, monomers and other valuable products. The Diels-Alder reaction is of great importance in the chemistry of renewable resources and provides an atom-economic pathway for fine chemical synthesis and for the production of materials. The biobased furans furfural and 5-(hydroxymethyl)furfural, which can be easily obtained from the carbohydrate part of plant biomass, were recognized as "platform chemicals" that will help to replace the existing oil-based refining to biorefining. Diels-Alder cycloaddition of furanic dienes with various dienophiles represents the ideal example of a "green" process characterized by a 100% atom economy and a reasonable E-factor. In this review, we first summarize the literature data on the regio- and diastereoselectivity of intermolecular Diels-Alder reactions of furfural derivatives with alkenes with the aim of establishing the current progress in the efficient production of practically important low-molecular-weight products. The information provided here will be useful and relevant to scientists in many fields, including medical and pharmaceutical research, polymer development and materials science.
Assuntos
Cicloparafinas/síntese química , Furanos/síntese química , Reação de Cicloadição , Cicloparafinas/química , Furanos/química , Química Verde , EstereoisomerismoRESUMO
Voltage-gated sodium (NaV) channels are pore-forming transmembrane proteins that play essential roles in excitable cells, and they are key targets for antiepileptic, antiarrhythmic, and analgesic drugs. We implemented a heterobivalent design strategy to modulate the potency, selectivity, and binding kinetics of NaV channel ligands. We conjugated µ-conotoxin KIIIA, which occludes the pore of the NaV channels, to an analogue of huwentoxin-IV, a spider-venom peptide that allosterically modulates channel gating. Bioorthogonal hydrazide and copper-assisted azide-alkyne cycloaddition conjugation chemistries were employed to generate heterobivalent ligands using polyethylene glycol linkers spanning 40-120 Å. The ligand with an 80 Å linker had the most pronounced bivalent effects, with a significantly slower dissociation rate and 4-24-fold higher potency compared to those of the monovalent peptides for the human NaV1.4 channel. This study highlights the power of heterobivalent ligand design and expands the repertoire of pharmacological probes for exploring the function of NaV channels.
Assuntos
Ligantes , Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Potenciais de Ação/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Sítios de Ligação , Conotoxinas/química , Conotoxinas/metabolismo , Reação de Cicloadição , Humanos , Concentração Inibidora 50 , Cinética , Simulação de Acoplamento Molecular , Canal de Sódio Disparado por Voltagem NAV1.4/química , Canal de Sódio Disparado por Voltagem NAV1.7/química , Técnicas de Patch-Clamp , Polietilenos/química , Venenos de Aranha/síntese química , Venenos de Aranha/química , Venenos de Aranha/metabolismo , Aranhas/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologiaRESUMO
We report a biocompatible and rapid reaction between cysteine thiols and 2,4-difluoro-6-hydroxy-1,3,5-benzenetricarbonitrile (DFB), which enables the efficient cyclization of peptides in neutral aqueous solutions. The reaction was further applied to cyclize peptides displayed on the phage surface without reducing phage infectivity, thus affording high-quality cyclic peptide libraries useful for screening of cyclic peptide ligands. Using the DFB-cyclic peptide library, we identified ligands that can distinguish the pro-survival protein Bcl-xl from its close relative Bcl-2. Therefore, this study on one hand reports a useful reaction for the construction of cyclic peptide libraries, and on the other hand presents valuable hits for further design of selective Bcl-xl ligands.
Assuntos
Derivados de Benzeno/química , Reação de Cicloadição , Nitrilas/química , Peptídeos Cíclicos/química , Derivados de Benzeno/síntese química , Reação de Cicloadição/economia , Reação de Cicloadição/métodos , Halogenação , Ligantes , Modelos Moleculares , Nitrilas/síntese química , Biblioteca de Peptídeos , Peptídeos Cíclicos/síntese químicaRESUMO
A collection of small molecules has been synthesized by composing photo-cycloaddition, C-H functionalization, and N-capping strategies. Multidimensional biological fingerprints of molecules comprising this collection have been recorded as changes in cell and organelle morphology. This untargeted, phenotypic approach allowed for a broad assessment of biological activity to be determined. Reproducibility and the magnitude of measured fingerprints revealed activity of several treatments. Reactive functional groups, such as imines, dominated the observed activity. Two non-reactive candidate compounds with distinct bioactivity fingerprints were identified, as well.
Assuntos
Pirrolidinas/síntese química , Pirrolidinas/metabolismo , Aminas/química , Linhagem Celular , Ciclização , Reação de Cicloadição , Humanos , Iminas/química , Imagem Óptica , Organelas/metabolismo , Organelas/ultraestrutura , Processos Fotoquímicos , Reprodutibilidade dos Testes , EstereoisomerismoRESUMO
Fludioxonil has been proven valuable as a broad-spectrum fungicide. However, there are concerns about its risk posed to non-target organisms in aquatic environments. In this paper, the mechanism, photoproducts transformation and eco-toxicity of fludioxonil during â¢OH/1O2-initiated process were systematically studied using quantum chemistry and computational toxicology. The results indicate that the two favorable pathways of â¢OH/1O2-initiated reactions are both occurred in pyrrole ring. It can conclude that the rate constants of â¢OH and 1O2 are 1.23 × 1010 and 3.69 × 107 M-1 s-1 at 298K, respectively, which results in half-lives of <2 days in surface waters under sunlit near-surface conditions. Based on toxicity assessments, these photoproducts showed a decreased aquatic toxicity but the majority products are still toxic. This study gives more insight into the chemical transformation mechanism of fludioxonil in aquatic environments.
Assuntos
Dioxóis/análise , Radical Hidroxila/química , Fotólise , Pirróis/análise , Oxigênio Singlete/química , Poluentes Químicos da Água/análise , Reação de Cicloadição , Dioxóis/química , Dioxóis/efeitos da radiação , Ecotoxicologia , Cinética , Pirróis/química , Pirróis/efeitos da radiação , Poluentes Químicos da Água/química , Poluentes Químicos da Água/efeitos da radiaçãoRESUMO
We introduced a regioselective and atom-economical procedure for the synthesis of 3-substituted indoles by annulation of nitrosoarenes with ethynyl ketones. The reactions were carried out achieving indoles without any catalyst and with excellent regioselectivity. No traces of 2-aroylindole products were detected. Working with 4-nitronitrosobenzene as starting material, the 3-aroyl-N-hydroxy-5-nitroindole products precipitated from the reaction mixtures and were isolated by filtration without any further purification technique. Differently from the corresponding N-hydroxy-3-aryl indoles that, spontaneously in solution, give dehydrodimerization products, the N-hydroxy-3-aroyl indoles are stable and no dimerization compounds were observed.
Assuntos
Reação de Cicloadição/métodos , Catálise , IndóisRESUMO
The study of Diels-Alder reactions in materials science is of increasing interest. The main reason for that is the potential thermoreversibility of the reaction. Aiming to predict the behavior of a material modified with maleimido and furyl moieties, 1H NMR and UV-Vis solution studies of the Diels-Alder reaction between furfuryl alcohol and two N-hydroxymaleimides are explored in the present study. Rate constants, activation energy, entropy, and enthalpy of formation were determined from each technique for both reacting systems. Endo and exo isomers were distinguished in 1H NMR, and the transition from a kinetic, controlled Diels-Alder reaction to a thermodynamic one could be observed in the temperature range studied. A discussion on the effect of that on the application in a material was performed. The approach selected considers a simplified equilibrium of the Diels-Alder reaction as the kinetic model, allowing materials scientists to evaluate the suitability of using the reacting molecules for the creation of thermoresponsive materials. The proposed approach determines the kinetic constants without the direct influence of the equilibrium constant value, thereby allowing a more objective data analysis. The effects of the selection of kinetic model, analytical method, and data treatment are discussed.
Assuntos
Furanos/química , Maleimidas/química , Reação de Cicloadição , Entropia , Cinética , Espectroscopia de Ressonância Magnética , Ciência dos Materiais , Modelos Moleculares , Estereoisomerismo , Temperatura , TermodinâmicaRESUMO
While studying the environmental fate of potent endocrine-active steroid hormones, we observed the formation of an intramolecular [2 + 2] photocycloaddition product (2) with a novel hexacyclic ring system following the photolysis of altrenogest (1). The structure and absolute configuration were established by X-ray diffraction analysis. Theoretical computations identified a barrierless two-step cyclization mechanism for the formation of 2 upon photoexcitation. 2 exhibited progesterone, estrogen, androgen, and pregnane X receptor activity, albeit generally with reduced potency relative to 1.
Assuntos
Processos Fotoquímicos , Acetato de Trembolona/análogos & derivados , Reação de Cicloadição , Teoria da Densidade Funcional , Humanos , Receptores Citoplasmáticos e Nucleares/metabolismo , Acetato de Trembolona/síntese química , Acetato de Trembolona/química , Acetato de Trembolona/metabolismoRESUMO
Improving oligonucleotide delivery is critical for the further development of oligonucleotide-based therapeutics. Covalent attachment of reporter molecules is one of the most promising approaches toward efficient oligonucleotide-based therapies. An efficient methods for the attachment of a variety of reporter groups is Cu(I)-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition. However, the majority of potential oligonucleotide (ON) therapeutics in clinical trials are carrying phosphorothioate (PS) linkages, and this robust conjugation method is not yet established for these ONs due to a general concern of Cu-S interaction. Here, we developed a method allowing for efficient conjugation of peptides to PS oligonucleotides. The method utilizes solid supported oligonucleotides that can be readily transformed into "clickable ONs" by simple linker conjugation and further reacted with an azido containing moiety (e.g., a peptide) using the CuBr × Me2S complex as a superior catalyst in that reaction. This study opens the way for further development of PS oligonucleotide-conjugates by means of efficient Cu(I)-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition.
Assuntos
Cobre/química , Reação de Cicloadição/métodos , Peptídeos/química , Oligonucleotídeos Fosforotioatos/química , Alcinos/síntese química , Alcinos/química , Azidas/síntese química , Azidas/química , Catálise , Reação de Cicloadição/economia , Peptídeos/síntese química , Oligonucleotídeos Fosforotioatos/síntese químicaRESUMO
As the applications of CRISPR-Cas9 technology diversify and spread beyond the laboratory to diagnostic and therapeutic use, the demands of gRNA synthesis have increased and access to tailored gRNAs is now restrictive. Enzymatic routes are time-consuming, difficult to scale-up and suffer from polymerase-bias while existing chemical routes are inefficient. Here, we describe a split-and-click convergent chemical route to individual or pools of sgRNAs. The synthetic burden is reduced by splitting the sgRNA into a variable DNA/genome-targeting 20-mer, produced on-demand and in high purity, and a fixed Cas9-binding chemically-modified 79-mer, produced cost-effectively on large-scale, a strategy that provides access to site-specific modifications that enhance sgRNA activity and in vivo stability. Click ligation of the two components generates an artificial triazole linkage that is tolerated in functionally critical regions of the sgRNA and allows efficient DNA cleavage in vitro as well as gene-editing in cells with no unexpected off-target effects.
Assuntos
Sistemas CRISPR-Cas/genética , Química Click/métodos , Edição de Genes/métodos , RNA Guia de Cinetoplastídeos/química , Triazóis/química , Catálise , Linhagem Celular Tumoral , Química Click/economia , Cobre/química , Reação de Cicloadição/métodos , DNA/química , DNA/genética , Clivagem do DNA , Edição de Genes/economia , Humanos , Oligonucleotídeos/química , Oligonucleotídeos/genética , RNA Guia de Cinetoplastídeos/genéticaRESUMO
Synthesis of novel triazole fused iminocyclitol-δ-lactams is described. The synthetic sequence involves the intermolecular [3 + 2] cycloaddition reaction of five-membered iminocyclitol derived azides with diethylacetylene dicarboxylate followed by intramolecular lactamisation, decarboxylation/reduction and final deprotection. Compound 3 is found to be a selective inhibitor of α-glucosidase from baker's yeast while two other compounds (2 and 4) that possess an additional hydroxymethyl group in the triazole ring are selective against ß-galactosidase from E. coli. Docking studies suggest the significance of the lactam carbonyl group for effective binding of these inhibitors with the active sites through hydrogen bonding.
Assuntos
Ciclitóis/química , Desenho de Fármacos , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Iminas/química , Lactamas/química , Lactamas/farmacologia , Triazóis/química , alfa-Glucosidases/efeitos dos fármacos , Domínio Catalítico , Simulação por Computador , Reação de Cicloadição , Descarboxilação , Escherichia coli/enzimologia , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Método de Monte Carlo , Saccharomyces cerevisiae/enzimologiaRESUMO
1,3-Dipolar cycloaddition between a chiral nitrone and N-substituted maleimides afforded unprecedented enantiopure spiro-fused heterocycles in good yields with a high enantio- and diastereoselectivity. The reaction was taking place on the less hindered face of the nitrone. The obtaining heterocycles were screened for their in vitro antioxidant properties and the results revealed that the potent antioxidant activity was generally recorded to compounds (3g) and (3e). The in vitro antibacterial activities of these two compounds were also investigated and the results demonstrated the strongest potential of compound (3g) against all the tested bacteria. Molecular properties were analyzed and showed good oral drug candidate like properties and that could be exploited as a potential antioxidant and antimicrobial agent. Finally, the preliminary results obtained from this investigation attempted to clarify if the structurally different side chains of active compounds interfere with their biological properties.
Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Reação de Cicloadição , Concentração Inibidora 50 , Pirrolidinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Click chemistry is an approach that uses efficient and reliable reactions, such as Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), to bind two molecular building blocks. CuAAC has broad applications in medicinal chemistry and other fields of chemistry. This review describes the general features and applications of CuAAC in solid-phase synthesis (CuAAC-SP), highlighting the suitability of this kind of reaction for peptides, nucleotides, small molecules, supramolecular structures, and polymers, among others. This versatile reaction is expected to become pivotal for meeting future challenges in solid-phase chemistry.
Assuntos
Química Click/métodos , Técnicas de Síntese em Fase Sólida/métodos , Alcinos/síntese química , Alcinos/química , Azidas/síntese química , Azidas/química , Catálise , Química Click/economia , Cobre/química , Reação de Cicloadição/economia , Reação de Cicloadição/métodos , Nucleotídeos/síntese química , Nucleotídeos/química , Peptídeos/síntese química , Peptídeos/química , Polímeros/síntese química , Polímeros/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Técnicas de Síntese em Fase Sólida/economiaRESUMO
A concise and flexible synthesis of fully substituted 2-aminopyrroles via gold-catalyzed formal [3+2] cycloaddition between ynamides and isoxazoles has been developed. Under mild reaction conditions, various 2-aminopyrrole derivatives were obtained in good to excellent yields, thus providing an efficient and atom-economic way for the construction of fully substituted 2-aminopyrroles.
Assuntos
Alcinos/química , Ouro/química , Isoxazóis/química , Pirróis/síntese química , Alcinos/síntese química , Catálise , Reação de Cicloadição , Isoxazóis/síntese química , Modelos Moleculares , Pirróis/químicaRESUMO
New reactions and reagents that allow for multiple bond-forming events per synthetic operation are required to achieve structural complexity and thus value with step-, time-, cost-, and waste-economy. Here we report a new class of reagents that function like tetramethyleneethane (TME), allowing for back-to-back [4 + 2] cycloadditions, thereby amplifying the complexity-increasing benefits of Diels-Alder and metal-catalyzed cycloadditions. The parent recursive reagent, 2,3-dimethylene-4-trimethylsilylbutan-1-ol (DMTB), is readily available from the metathesis of ethylene and THP-protected 4-trimethylsilylbutyn-1-ol. DMTB and related reagents engage diverse dienophiles in an initial Diels-Alder or metal-catalyzed [4 + 2] cycloaddition, triggering a subsequent vinylogous Peterson elimination that recursively generates a new diene for a second cycloaddition. Overall, this multicomponent catalytic cascade produces in one operation carbo- and heterobicyclic building blocks for the synthesis of a variety of natural products, therapeutic leads, imaging agents, and materials. Its application to the three step synthesis of a new solvatochromic fluorophore, N-ethyl(6-N,N-dimethylaminoanthracene-2,3-dicarboximide) (6-DMA), and the photophysical characterization of this fluorophore are described.
Assuntos
Alcenos/química , Antracenos/síntese química , Reação de Cicloadição/métodos , Etano/análogos & derivados , Corantes Fluorescentes/síntese química , Antracenos/química , Catálise , Reação de Cicloadição/economia , Etano/química , Corantes Fluorescentes/química , Indicadores e Reagentes/química , Metais/químicaRESUMO
We describe diverse approaches to various dienes and their utilization in the Diels-Alder reaction to produce a variety of polycycles. The dienes covered here are prepared by simple alkylation reaction or via the Claisen rearrangement or by enyne metathesis of alkyne or enyne building blocks. Here, we have also included the Diels-Alder chemistry of dendralenes, a higher analog of cross-conjugated dienes. The present article is inclusive of o-xylylene derivatives that are generated in situ starting with benzosultine or benzosulfone derivatives. The Diels-Alder reaction of these dienes with various dienophiles gave diverse polycyclic systems and biologically important targets.