RESUMO
This article presents a method for producing hydrogel dressings using high methylated pectin from apples or citrus, doped with the antiseptic agent, octenidine dihydrochloride. Octenidine was incorporated in-situ during the polymer crosslinking. The pectins were characterized by their varying molecular weight characteristics, monosaccharide composition, and degree of esterification (DE). The study assessed the feasibility of producing biologically active hydrogels with pectin and delved into how the polymer's characteristics affect the properties of the resulting dressings. The structure evaluation of hydrogel materials showed interactions between individual components of the system and their dependence on the type of used pectin. Both the antimicrobial properties and cytotoxicity of the dressings were evaluated. The results suggest that the primary determinants of the functional attributes of the hydrogels are the molecular weight characteristics and the DE of the pectin. As these values rise, there is an increase in polymer-polymer interactions, overshadowing polymer-additive interactions. This intensification strengthens the mechanical and thermal stability of the hydrogels and enhances the release of active components into the surrounding environment. Biological evaluations demonstrated the ability of octenidine to be released from the dressings and effectively inhibit the growth of microbial pathogens.
Assuntos
Anti-Infecciosos Locais , Bandagens , Hidrogéis , Iminas , Pectinas , Piridinas , Pectinas/química , Pectinas/farmacologia , Iminas/química , Hidrogéis/química , Hidrogéis/farmacologia , Anti-Infecciosos Locais/química , Anti-Infecciosos Locais/farmacologia , Piridinas/química , Piridinas/farmacologia , Citrus/química , Malus/química , Peso Molecular , Humanos , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , AnimaisRESUMO
An enzyme catalyzed strategy for the synthesis of a chiral hydrazine from 3-cyclopentyl-3-oxopropanenitrile 5 and hydrazine hydrate 2 is presented. An imine reductase (IRED) from Streptosporangium roseum was identified to catalyze the reaction between 3-cyclopentyl-3-oxopropanenitrile 5 and hydrazine hydrate 2 to produce trace amounts of (R)-3-cyclopentyl-3-hydrazineylpropanenitrile 4. We employed a 2-fold approach to optimize the catalytic performance of this enzyme. First, a transition state analogue (TSA) model was constructed to illuminate the enzyme-substrate interactions. Subsequently, the Enzyme_design and Funclib methods were utilized to predict mutants for experimental evaluation. Through three rounds of site-directed mutagenesis, site saturation mutagenesis, and combinatorial mutagenesis, we obtained mutant M6 with a yield of 98% and an enantiomeric excess (ee) of 99%. This study presents an effective method for constructing a hydrazine derivative via IRED-catalyzed reductive amination of ketone and hydrazine. Furthermore, it provides a general approach for constructing suitable enzymes, starting from nonreactive enzymes and gradually enhancing their catalytic activity through active site modifications.
Assuntos
Biocatálise , Nitrilas , Oxirredutases , Pirazóis , Pirimidinas , Nitrilas/química , Nitrilas/metabolismo , Pirimidinas/química , Pirimidinas/biossíntese , Pirimidinas/metabolismo , Oxirredutases/metabolismo , Oxirredutases/genética , Pirazóis/química , Pirazóis/metabolismo , Iminas/química , Iminas/metabolismo , Estrutura Molecular , Hidrazinas/química , Engenharia de ProteínasRESUMO
α,ß-Diamino acids are important structural motifs and building blocks for numerous bioactive natural products, peptidomimetics, and pharmaceuticals, yet efficient asymmetric synthesis to access these stereoarrays remains a challenge. Herein, we report the development of a pyridoxal 5'-phosphate (PLP)-dependent enzyme that is engineered to catalyze stereoselective Mannich-type reactions between free α-amino acids and enolizable cyclic imines. This biocatalyst enabled one-step asymmetric enzymatic synthesis of the unusual pyrrolidine-containing amino acid L-tambroline at gram-scale with high enantio- and diastereocontrol. Furthermore, this enzymatic platform is capable of utilizing a diverse range of α-amino acids as the Mannich donor and various cyclic imines as the acceptor. By coupling with different imine-generating enzymes, we established versatile biocatalytic cascades and demonstrated a general, concise, versatile, and atom-economic approach to access unprotected α,ß-diamino acids, including structurally complex α,α-disubstituted α,ß-diamino acids with contiguous stereocenters.
Assuntos
Aminoácidos , Iminas , Iminas/química , Iminas/metabolismo , Estereoisomerismo , Aminoácidos/química , Aminoácidos/síntese química , Aminoácidos/metabolismo , Biocatálise , Fosfato de Piridoxal/química , Fosfato de Piridoxal/metabolismo , Estrutura MolecularRESUMO
Imine reduction is a useful reaction in the preparation of amine derivatives. Various catalysts have been reported to promote this reaction and photoredox catalysts are promising candidates for sustainable amine synthesis. Improvement of this reaction using biomolecule-based reaction scaffolds is expected to increase the utility of the reaction. In this context, we have recently investigated photoredox Ru complexes with pentapeptide scaffolds via coordination bonds as catalysts for photoreduction of dihydroisoquinoline derivatives. First, Ru bipyridine terpyridine complexes coordinated with five different pentapeptides (XVHVV: X = V, F, W, Y, C) were prepared and characterized by mass spectrometry. Catalytic activities of the Ru complexes with XVHVV were evaluated for photoreduction of dihydroisoquinoline derivatives in the presence of ascorbate and thiol compounds as sacrificial reagents and hydrogen sources. Interestingly, the turnover number of the Ru complex with VVHVV is 531, which is two-fold higher than that of a simple Ru complex with an imidazole ligand. The detailed emission lifetime measurements indicate that the enhanced catalytic activity provided by the peptide scaffold is caused by an efficient reaction with the thiol derivative to accelerate reductive quenching of Ru complex. The quenching behavior suggests formation of an active species such as a Ru(I) complex. These findings reveal that the simple pentapeptide serves as an effective scaffold to enhance the photocatalytic activity of a photoactive Ru complex.
Assuntos
Complexos de Coordenação , Iminas , Oxirredução , Rutênio , Rutênio/química , Iminas/química , Complexos de Coordenação/química , Oligopeptídeos/química , Piridinas/química , Processos Fotoquímicos , CatáliseRESUMO
3,4-disubstituted maleimides find wide applications in various pharmacologically active compounds. This study presents a highly effective approach for synthesizing derivatives of 3,4-disubstituted maleimides through the direct isomerization of α-succinimide-substituted allenoates, followed by a cascade γ'-addition and aryl imines using PR3 as a catalyst. The resulting series of 3,4-disubstituted maleimides exhibited excellent stereoselectivities, achieving yields of up to 86%. To our knowledge, the phosphine-mediated γ'-addition reaction of allenoates is seldom reported.
Assuntos
Iminas , Maleimidas , Fosfinas , Succinimidas , Maleimidas/química , Maleimidas/síntese química , Fosfinas/química , Catálise , Iminas/química , Succinimidas/química , Estereoisomerismo , Estrutura Molecular , IsomerismoRESUMO
Alzheimer's disease (AD), a severe neurodegenerative disorder, imposes socioeconomic burdens and necessitates innovative therapeutic strategies. Current therapeutic interventions are limited and underscore the need for novel inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), enzymes implicated in the pathogenesis of AD. In this study, we report a novel synthetic strategy for the generation of 2-aminopyridine derivatives via a two-component reaction converging aryl vinamidinium salts with 1,1-enediamines (EDAMs) in a dimethyl sulfoxide (DMSO) solvent system, catalyzed by triethylamine (Et3N). The protocol introduces a rapid, efficient, and scalable synthetic pathway, achieving good to excellent yields while maintaining simplistic workup procedures. Seventeen derivatives were synthesized and subsequently screened for their inhibitory activity against AChE and BChE. The most potent derivative, 3m, exhibited an IC50 value of 34.81 ± 3.71 µM against AChE and 20.66 ± 1.01 µM against BChE compared to positive control donepezil with an IC50 value of 0.079 ± 0.05 µM against AChE and 10.6 ± 2.1 µM against BChE. Also, detailed kinetic studies were undertaken to elucidate their modes of enzymatic inhibition of the most potent compounds against both AChE and BChE. The promising compound was then subjected to molecular docking and dynamics simulations, revealing significant binding affinities and favorable interaction profiles against AChE and BChE. The in silico ADMET assessments further determined the drug-like properties of 3m, suggesting it as a promising candidate for further pre-clinical development.
Assuntos
Acetilcolinesterase , Doença de Alzheimer , Aminopiridinas , Butirilcolinesterase , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Doença de Alzheimer/tratamento farmacológico , Aminopiridinas/química , Aminopiridinas/síntese química , Aminopiridinas/farmacologia , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Humanos , Relação Estrutura-Atividade , Iminas/química , Iminas/farmacologia , Iminas/síntese químicaRESUMO
The synthesis, antioxidant capacity, and anti-inflammatory activity of four novel N-benzyl-2-[4-(aryl)-1H-1,2,3-triazol-1-yl]ethan-1-imine oxides 10a-d are reported herein. The nitrones 10a-d were tested for their antioxidant properties and their ability to inhibit soybean lipoxygenase (LOX). Four diverse antioxidant tests were used for in vitro antioxidant assays, namely, interaction with the stable free radical DPPH (1,1-diphenyl-2-picrylhydrazyl radical) as well as with the water-soluble azo compound AAPH (2,2'-azobis(2-amidinopropane) dihydrochloride), competition with DMSO for hydroxyl radicals, and the scavenging of cationic radical ABTSâ¢+ (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) radical cation). Nitrones 10b, 10c, and 10d, having the 4-fluorophenyl, 2,4-difluorophenyl, and 4-fluoro-3-methylphenyl motif, respectively, exhibited high interaction with DPPH (64.5-81% after 20 min; 79-96% after 60 min), whereas nitrone 10a with unfunctionalized phenyl group showed the lowest inhibitory potency (57% after 20 min, 78% after 60 min). Nitrones 10a and 10d, decorated with phenyl and 4-fluoro-3-methylphenyl motif, respectively, appeared the most potent inhibitors of lipid peroxidation. The results obtained from radical cation ABTSâ¢+ were not significant, since all tested compounds 10a-d showed negligible activity (8-46%), much lower than Trolox (91%). Nitrone 10c, bearing the 2,4-difluorophenyl motif, was found to be the most potent LOX inhibitor (IC50 = 10 µM).
Assuntos
Antioxidantes , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/síntese química , Lipoxigenase/metabolismo , Glycine max/enzimologia , Glycine max/química , Inibidores de Lipoxigenase/farmacologia , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/síntese química , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Iminas/química , Iminas/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/antagonistas & inibidores , Picratos/química , Picratos/antagonistas & inibidores , Óxidos de Nitrogênio/química , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Sequestradores de Radicais Livres/síntese químicaRESUMO
With the increased occurrence of bacteria resistance to conventional antibiotics, the development of novel antimicrobials is urgently needed. Traditional biomaterials used for delivering these agents often struggle to achieve sustained release while maintaining non-cytotoxic properties. In this study, we present an innovative approach using bacterial polyhydroxyalkanoates (PHA) as a carrier for antimicrobial delivery, specifically designed for wound healing applications. Octenidine dihydrochloride (OCT), a widely used antimicrobial agent, served as our model drug. To achieve the desired balance of OCT release and low cytotoxicity, we introduced a novel bio-derived additive, 3-hydroxy-pentadecanoic acid (3OHC15), extracted from bacteria. This additive significantly improved the hydrophilicity of PHA films, resulting in enhanced and sustained release of OCT. Importantly, the additive did not adversely affect the material's tensile strength or thermal properties. The increased OCT release led to improved antibacterial activity against both Gram-negative and -positive strains. Most notably, the incorporation of 3OHC15 in PHA mitigated the cytotoxic effects of the released drug on human fibroblasts, ensuring biocompatibility. This work represents a novel strategy in the design of biomaterials for the delivery of bioactive compounds, achieving a critical balance between efficacy and cytocompatibility, and marks a significant advancement in the field of antimicrobial delivery systems.
Assuntos
Poli-Hidroxialcanoatos , Poli-Hidroxialcanoatos/química , Poli-Hidroxialcanoatos/farmacologia , Humanos , Fibroblastos/efeitos dos fármacos , Iminas/química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Piridinas/química , Piridinas/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Testes de Sensibilidade Microbiana , Interações Hidrofóbicas e Hidrofílicas , Sobrevivência Celular/efeitos dos fármacosRESUMO
Four new copper(II) complexes were synthesized and characterized with the general formula [Cu(N-N)(Th)(NO3)], where N-N corresponds to the N-heterocyclic ligands 1,10-phenanthroline (phen), 2,2'-bipyridine (bipy), 4,7-diphenyl-1,10-phenanthroline (dpp), and 4,4-dimethyl-2,2'-bipyridine (dmbp) and Th represents the N,N-dibenzyl-N'-benzoylthiourea. Cytotoxic activities of the complexes against HCT116 (human colon carcinoma), HepG2 (human hepatocellular carcinoma), and non-tumor MRC-5 (human lung fibroblast) cells were investigated. The copper(II) complexes 1-4 were characterized by spectroscopic techniques while complexes 1 and 2 were studied using single-crystal X-ray diffraction as well. The complexes possessed a five-coordinated structure with one nitrate ligand as a monodentate at the axial position and two bidentate ligands N-heterocyclic and N,N-dibenzyl-N'-benzoylthiourea. The complexes showed promising IC50 values, ranging from 0.3 to 9.0 µM. Furthermore, interaction studies with biomolecules such as calf thymus DNA (ct-DNA) and Bovine Serum Albumin (BSA), which can act as possible biological targets of the complexes, were carried out. The studies suggested that the compounds interact moderately with ct-DNA and BSA. Complexes 1, 2, and 4 did not lead to cell accumulation at any stage of the cell cycle but caused a significant increase in internucleosomal DNA fragmentation. Whereas, compound 3 caused cell cycle arrest in the S phase while doxorubicin caused cell cycle arrest in the G2/M phase. The effect of structural modifications on the metal compounds was correlated with their biological properties and it was concluded that an increase in biological activity occurred with increasing the extension of the diimine ligands. Thus, complex 3 was the most promising one.
Assuntos
Antineoplásicos , Ciclo Celular , Complexos de Coordenação , Cobre , DNA , Soroalbumina Bovina , Tioureia , Cobre/química , Cobre/farmacologia , Humanos , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , DNA/metabolismo , DNA/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Bovinos , Tioureia/química , Tioureia/farmacologia , Ciclo Celular/efeitos dos fármacos , Animais , Iminas/química , Iminas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células/efeitos dos fármacos , Estrutura MolecularRESUMO
DNA-encoded library (DEL) technologies enable the fast exploration of gigantic chemical space to identify ligands for the target protein of interest and have become a powerful hit finding tool for drug discovery projects. However, amenable DEL chemistry is restricted to a handful of reactions, limiting the creativity of drug hunters. Here, we describe a new on-DNA synthetic pathway to access sulfides and sulfoximines. These moieties, usually contemplated as challenging to achieve through alkylation and oxidation, can now be leveraged in routine DEL selection campaigns.
Assuntos
DNA , Sulfetos , DNA/química , Sulfetos/química , Sulfetos/síntese química , Estrutura Molecular , Iminas/química , Oxirredução , Alquilação , Descoberta de DrogasRESUMO
Asymmetric catalysis enables the synthesis of optically active compounds, often requiring the differentiation between two substituents on prochiral substrates1. Despite decades of development of mainly noble metal catalysts, achieving differentiation between substituents with similar steric and electronic properties remains a notable challenge2,3. Here we introduce a class of Earth-abundant manganese catalysts for the asymmetric hydrogenation of dialkyl ketimines to give a range of chiral amine products. These catalysts distinguish between pairs of minimally differentiated alkyl groups bound to the ketimine, such as methyl and ethyl, and even subtler distinctions, such as ethyl and n-propyl. The degree of enantioselectivity can be adjusted by modifying the components of the chiral manganese catalyst. This reaction demonstrates a wide substrate scope and achieves a turnover number of up to 107,800. Our mechanistic studies indicate that exceptional stereoselectivity arises from the modular assembly of confined chiral catalysts and cooperative non-covalent interactions between the catalyst and the substrate.
Assuntos
Técnicas de Química Sintética , Hidrogenação , Iminas , Nitrilas , Estereoisomerismo , Aminas/química , Aminas/síntese química , Catálise , Iminas/química , Manganês/química , Nitrilas/química , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química , Especificidade por Substrato , AlquilaçãoRESUMO
The multicomponent etiology, complex clinical implications, dose-based side effect and degree of pain mitigation associated with the current pharmacological therapy is incapable in complete resolution of chronic neuropathic pain patients which necessitates the perpetual requirement of novel medication therapy. Therefore, this study explored the ameliorative aptitude of two novel methanimine imitative like (E)-N-(4-nitrobenzylidene)-4chloro-2-iodobenzamine (KB 09) and (E)-N-(4-methylbenzylidene)-4chloro-2-iodobenzamine (KB 10) in chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rat model. Standard behavioral tests like dynamic and static allodynia, cold, thermal and mechanical hyperalgesia along with rotarod activity were performed at various experimental days like 0, 3, 7, 14 and 21. Enzyme linked immunosorbent assay (ELISA) on spinal tissue and antioxidant assays on sciatic nerve were executed accompanied by molecular docking and simulation studies. Prolonged ligation of sciatic nerve expressively induced hyperalgesia as well as allodynia in rats. KB 09 and KB 10 substantially attenuated the CCI elicited hyperalgesia and allodynia. They significantly reduced the biomarkers of pain and inflammation like Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in ELISA and while enhanced the GSH, SOD and CAT and diminished the MDA levels during antioxidant assays. KB 09 displayed -9.62 kcal/mol with TNF-α and -7.68 kcal/mol binding energy with IL-6 whereas KB 10 exhibited binding energy of -8.20 kcal/mol with IL-6 while -11.68 kcal/mol with TNF-α and hence both trial compounds ensured stable interaction with IL-6 and TNF-α during computational analysis. The results advocated that both methanimine derivatives might be novel candidates for attenuation of CCI-induced neuropathic pain prospects via anti-nociceptive, anti-inflammatory and antioxidant mechanisms.
Assuntos
Hiperalgesia , Simulação de Acoplamento Molecular , Neuralgia , Nervo Isquiático , Animais , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Masculino , Hiperalgesia/tratamento farmacológico , Nervo Isquiático/lesões , Nervo Isquiático/efeitos dos fármacos , Ratos , Ratos Wistar , Modelos Animais de Doenças , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Analgésicos/química , Antioxidantes/farmacologia , Antioxidantes/química , Simulação por Computador , Constrição , Iminas/química , Iminas/farmacologiaRESUMO
Four Pt(II) bis(pyrrole-imine) Schiff base chelates (1-4) were synthesised by previously reported methods, through a condensation reaction, and the novel crystal structure of 2,2'-{propane-1,3-diylbis[nitrilo(E)methylylidene]}bis(pyrrol-1-ido)platinum(II) (1) was obtained. Pt(II) complexes 1-4 exhibited phosphorescence, with increased luminescence in anaerobic solvents or when bound to human serum albumin (HSA). One of the complexes shows a 15.6-fold increase in quantum yield when bound to HSA and could be used to detect HSA concentrations as low as 5 nM. Pt(II) complexes 1-3 was investigated as potential theranostic agents in MCF-7 breast cancer cells, but only complex 3 exhibited cytotoxicity when irradiated with UV light (λ355nmExcitation). Interestingly, the cytotoxicity of complex 1 was unresponsive to UV light irradiation. This indicates that only complex 3 can be considered a potential photosensitising agent.
Assuntos
Pirróis , Humanos , Células MCF-7 , Pirróis/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Bases de Schiff/química , Iminas/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/efeitos da radiação , Complexos de Coordenação/síntese química , Substâncias Luminescentes/química , Substâncias Luminescentes/toxicidade , Substâncias Luminescentes/síntese química , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismoRESUMO
As trimethylamine (TMA) is widely used in agriculture and industry, inhalation of TMA can cause very serious negative effects on human health. However, most of the current gas sensors for detecting TMA are commonly performed at high temperatures and cannot meet market needs. Inspired by this, we prepared imine covalent organic frameworks (TB-COF) synthesized from two monomers, 1,3,5-tris(4-aminophenyl)benzene (TAPB) and 1,3,5-benzotricarboxaldehyde (BTCA), using acetic acid as a catalyst at room temperature. Based on this, three sensors were prepared for gas sensitivity testing, namely, TA, BT, and TB-COF sensors. The three sensors were tested for 15 different gases at room temperature. From the whole gas sensitivity data, the TB-COF sensor made by compositing TA and BT has a higher sensitivity (6845.9%) to TMA at 500 ppm, which is 6.1 and 5.4 times higher than the response of TA and BT sensors, respectively. The TB-COF sensor adsorbs and desorbs TMA in a controlled 23 s cycle with a low detection limit of 28.6 ppb. This result indicates that TB-COF prepared at room temperature can be used as a gas-sensitive sensing material for real-time monitoring of TMA. The gas sensing results demonstrate the great potential of COFs for sensor development and application and provide ideas for further development of COFs-based gas sensors.
Assuntos
Iminas , Estruturas Metalorgânicas , Metilaminas , Metilaminas/análise , Metilaminas/química , Iminas/química , Estruturas Metalorgânicas/química , Limite de Detecção , Gases/química , Gases/análiseRESUMO
(S)-1-(4-Methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline ((S)-1-(4-methoxybenzyl)-OHIQ) is the key intermediate of the nonopioid antitussive dextromethorphan. In this study, (S)-IR61-V69Y/P123A/W179G/F182I/L212V (M4) was identified with a 766-fold improvement in catalytic efficiency compared with wide-type IR61 through enzyme engineering. M4 could completely convert 200 mM of 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline into (S)-1-(4-methoxybenzyl)-OHIQ in 77% isolated yield, with >99% enantiomeric excess and a high space-time yield of 542 g L-1 day-1, demonstrating a great potential for the synthesis of dextromethorphan intermediate in industrial applications.
Assuntos
Dextrometorfano , Dextrometorfano/química , Dextrometorfano/síntese química , Estrutura Molecular , Oxirredutases/metabolismo , Oxirredutases/química , Iminas/química , Estereoisomerismo , Antitussígenos/química , Antitussígenos/síntese química , Engenharia de ProteínasRESUMO
Nitric oxide (NO) acts in different physiological processes, such as blood pressure control, antiparasitic activities, neurotransmission, and antitumor action. Among the exogenous NO donors, ruthenium nitrosyl/nitro complexes are potential candidates for prodrugs, due to their physicochemical properties, such as thermal and physiological pH stability. In this work, we proposed the synthesis and physical characterization of the new nitro terpyridine ruthenium (II) complexes of the type [RuII(L)(NO2)(tpy)]PF6 where tpy = 2,2':6',2â³-terpyridine; L = 3,4-diaminobenzoic acid (bdq) or o-phenylenediamine (bd) and evaluation of influence of diimine bidentate ligand NH.NHq-R (R = H or COOH) in the HSA/DNA interaction as well as antiviral activity. The interactions between HSA and new nitro complexes [RuII(L)(NO2)(tpy)]+ were evaluated. The Ka values for the HSA-[RuII(bdq)(NO2)(tpy)]+ is 10 times bigger than HSA-[RuII(bd)(NO2)(tpy)]+. The sites of interaction between HSA and the complexes via synchronous fluorescence suppression indicate that the [RuII(bdq)(NO2)(tpy)]+ is found close to the Trp-241 residue, while the [RuII(bd)(NO2)(tpy)]+ complex is close to Tyr residues. The interaction with fish sperm fs-DNA using direct spectrophotometric titration (Kb) and ethidium bromide replacement (KSV and Kapp) showed weak interaction in the system fs-DNA-[RuII(bdq)(NO)(tpy)]+. Furthermore, fs-DNA-[RuII(bd)(NO2)(tpy)]+ and fs-DNA-[RuII(bd)(NO)(tpy)]3+ system showed higher intercalation constant. Circular dichroism spectra for fs-DNA-[RuII(bd)(NO2)(tpy)]+ and fs-DNA-[RuII(bd)(NO)(tpy)]3+, suggest semi-intercalative accompanied by major groove binding interaction modes. The [RuII(bd)(NO2)(tpy)]+ and [RuII(bd)(NO)(tpy)]3+ inhibit replication of Zika and Chikungunya viruses based in the nitric oxide release under S-nitrosylation reaction with cysteine viral.
Assuntos
Antivirais , DNA , Rutênio , Humanos , DNA/metabolismo , DNA/química , Rutênio/química , Rutênio/farmacologia , Antivirais/farmacologia , Antivirais/química , Antivirais/metabolismo , Ligantes , Animais , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo , Piridinas/química , Piridinas/farmacologia , Iminas/química , Iminas/farmacologia , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/metabolismoRESUMO
Helicase-primase is an interesting target for the therapy of herpes simplex virus (HSV) infections. Since amenamevir is already approved for varicella-zoster virus (VZV) and HSV in Japan and pritelivir has received breakthrough therapy status for the treatment of acyclovir-resistant HSV infections in immunocompromised patients, the target has sparked interest in me-too approaches. Here, we describe the attempt to improve nervous tissue penetration in Phaeno Therapeutics drug candidate HN0037 to target the latent reservoir of HSV by installing less polar moieties, mainly a difluorophenyl instead of a pyridyl group, and replacing the primary sulfonamide with a methyl sulfoximine moiety. However, all obtained stereoisomers exhibited a weaker inhibitory activity on HSV-1 and HSV-2.
Assuntos
Antivirais , DNA Primase , Sulfonamidas , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , DNA Primase/antagonistas & inibidores , DNA Primase/metabolismo , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Relação Estrutura-Atividade , DNA Helicases/antagonistas & inibidores , DNA Helicases/metabolismo , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Humanos , Estrutura Molecular , Testes de Sensibilidade Microbiana , Relação Dose-Resposta a Droga , Iminas/química , Iminas/farmacologia , Iminas/síntese químicaRESUMO
Macrocyclic imine phycotoxins are an emerging class of chemical compounds associated with harmful algal blooms and shellfish toxicity. Earlier binding and electrophysiology experiments on nAChR subtypes and their soluble AChBP surrogates evidenced common trends for substantial antagonism, binding affinities, and receptor-subtype selectivity. Earlier, complementary crystal structures of AChBP complexes showed that common determinants within the binding nest at each subunit interface confer high-affinity toxin binding, while distinctive determinants from the flexible loop C, and either capping the nest or extending toward peripheral subsites, dictate broad versus narrow receptor subtype selectivity. From these data, small spiroimine enantiomers mimicking the functional core motif of phycotoxins were chemically synthesized and characterized. Voltage-clamp analyses involving three nAChR subtypes revealed preserved antagonism for both enantiomers, despite lower subtype specificity and binding affinities associated with faster reversibility compared with their macrocyclic relatives. Binding and structural analyses involving two AChBPs pointed to modest affinities and positional variability of the spiroimines, along with a range of AChBP loop-C conformations denoting a prevalence of antagonistic properties. These data highlight the major contribution of the spiroimine core to binding within the nAChR nest and confirm the need for an extended interaction network as established by the macrocyclic toxins to define high affinities and marked subtype specificity. This study identifies a minimal set of functional pharmacophores and binding determinants as templates for designing new antagonists targeting disease-associated nAChR subtypes.
Assuntos
Iminas , Toxinas Marinhas , Antagonistas Nicotínicos , Receptores Nicotínicos , Toxinas Marinhas/química , Toxinas Marinhas/farmacologia , Toxinas Marinhas/toxicidade , Iminas/química , Iminas/farmacologia , Antagonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/química , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/efeitos dos fármacos , Animais , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/química , Relação Estrutura-AtividadeRESUMO
Reactive metabolite formation is a major mechanism of hepatotoxicity. Although reactive electrophiles can be soft or hard in nature, screening strategies have generally focused on the use of glutathione trapping assays to screen for soft electrophiles, with many data sets available to support their use. The use of a similar assay for hard electrophiles using cyanide as the trapping agent is far less common, and there is a lack of studies with sufficient supporting data. Using a set of 260 compounds with a defined hepatotoxicity status by the FDA, a comprehensive literature search yielded cyanide trapping data on an unbalanced set of 20 compounds that were all clinically hepatotoxic. Thus, a further set of 19 compounds was selected to generate cyanide trapping data, resulting in a more balanced data set of 39 compounds. Analysis of the data demonstrated that the cyanide trapping assay had high specificity (92%) and a positive predictive value (83%) such that hepatotoxic compounds would be confidently flagged. Structural analysis of the adducts formed revealed artifactual methylated cyanide adducts to also occur, highlighting the importance of full structural identification to confirm the nature of the adduct formed. The assay was demonstrated to add the most value for compounds containing typical structural alerts for hard electrophile formation: half of the severe hepatotoxins with these structural alerts formed cyanide adducts, while none of the severe hepatotoxins with no relevant structural alerts formed adducts. The assay conditions used included cytosolic enzymes (e.g., aldehyde oxidase) and an optimized cyanide concentration to minimize the inhibition of cytochrome P450 enzymes by cyanide. Based on the demonstrated added value of this assay, it is to be initiated for use at GSK as part of the integrated hepatotoxicity strategy, with its performance being reviewed periodically as more data is generated.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Cianetos , Cianetos/metabolismo , Cianetos/química , Humanos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Iminas/química , Iminas/metabolismo , Fígado/metabolismo , Fígado/efeitos dos fármacos , Estrutura MolecularRESUMO
BACKGROUND AND PURPOSE: The analgesic action of paracetamol involves KV7 channels, and its metabolite N-acetyl-p-benzo quinone imine (NAPQI), a cysteine modifying reagent, was shown to increase currents through such channels in nociceptors. Modification of cysteine residues by N-ethylmaleimide, H2O2, or nitric oxide has been found to modulate currents through KV7 channels. The study aims to identify whether, and if so which, cysteine residues in neuronal KV7 channels might be responsible for the effects of NAPQI. EXPERIMENTAL APPROACH: To address this question, we used a combination of perforated patch-clamp recordings, site-directed mutagenesis, and mass spectrometry applied to recombinant KV7.1 to KV7.5 channels. KEY RESULTS: Currents through the cardiac subtype KV7.1 were reduced by NAPQI. Currents through all other subtypes were increased, either by an isolated shift of the channel voltage dependence to more negative values (KV7.3) or by such a shift combined with increased maximal current levels (KV7.2, KV7.4, KV7.5). A stretch of three cysteine residues in the S2-S3 linker region of KV7.2 was necessary and sufficient to mediate these effects. CONCLUSION AND IMPLICATION: The paracetamol metabolite N-acetyl-p-benzo quinone imine (NAPQI) modifies cysteine residues of KV7 subunits and reinforces channel gating in homomeric and heteromeric KV7.2 to KV7.5, but not in KV7.1 channels. In KV7.2, a triple cysteine motif located within the S2-S3 linker region mediates this reinforcement that can be expected to reduce the excitability of nociceptors and to mediate antinociceptive actions of paracetamol.