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1.
Proc Natl Acad Sci U S A ; 119(17): e2111744119, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-35467978

RESUMO

Human DNA polymerase α (Polα) does not possess proofreading ability and plays an important role in genome replication and mutagenesis. Polα extends the RNA primers generated by primase and provides a springboard for loading other replication factors. Here we provide the structural and functional analysis of the human Polα interaction with a mismatched template:primer. The structure of the human Polα catalytic domain in the complex with an incoming deoxycytidine triphosphate (dCTP) and the template:primer containing a T-C mismatch at the growing primer terminus was solved at a 2.9 Å resolution. It revealed the absence of significant distortions in the active site and in the conformation of the substrates, except the primer 3'-end. The T-C mismatch acquired a planar geometry where both nucleotides moved toward each other by 0.4 Å and 0.7 Å, respectively, and made one hydrogen bond. The binding studies conducted at a physiological salt concentration revealed that Polα has a low affinity to DNA and is not able to discriminate against a mispaired template:primer in the absence of deoxynucleotide triphosphate (dNTP). Strikingly, in the presence of cognate dNTP, Polα showed a more than 10-fold higher selectivity for a correct duplex versus a mismatched one. According to pre-steady-state kinetic studies, human Polα extends the T-C mismatch with a 249-fold lower efficiency due to reduction of the polymerization rate constant by 38-fold and reduced affinity to the incoming nucleotide by 6.6-fold. Thus, a mismatch at the postinsertion site affects all factors important for primer extension: affinity to both substrates and the rate of DNA polymerization.


Assuntos
DNA Polimerase I , Replicação do DNA , Domínio Catalítico , DNA Polimerase I/genética , DNA Polimerase I/metabolismo , Primers do DNA/genética , Humanos , Cinética
2.
Br J Nutr ; 131(12): 2005-2030, 2024 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-38606599

RESUMO

Nitrogen balance (NB), the principal methodology used to derive recommendations for human protein and amino acid requirements, has been widely criticised, and calls for increased protein and amino acid requirement recommendations have been made, often on the basis of post-prandial amino acid tracer kinetic studies of muscle protein synthesis, or of amino acid oxidation. This narrative review considers our knowledge of the homeostatic regulation of the FFM throughout the diurnal cycle of feeding and fasting and what can and has been learnt from post-prandial amino acid tracer studies, about amino acid and protein requirements. Within the FFM, muscle mass in well fed weight-stable adults with healthy lifestyles appears fixed at a phenotypic level within a wide range of habitual protein intakes. However homoeostatic regulation occurs in response to variation in habitual protein intake, with adaptive changes in amino acid oxidation which influence the magnitude of diurnal losses and gains of body protein. Post-prandial indicator amino acid oxidation (IAAO) studies have been introduced as an alternative to NB and to the logistically complex 24 h [13C-1] amino acid balance studies, for assessment of protein and amino acid requirements. However, a detailed examination of IAAO studies shows both a lack of concern for homeostatic regulation of amino acid oxidation and  major flaws in their design and analytical interpretation, which seriously constrain their ability to provide reliable values. New ideas and a much more critical approach to existing work is needed if real progress is to be made in the area.


Assuntos
Aminoácidos , Proteínas Alimentares , Necessidades Nutricionais , Oxirredução , Período Pós-Prandial , Humanos , Aminoácidos/metabolismo , Aminoácidos/administração & dosagem , Proteínas Alimentares/administração & dosagem , Proteínas Alimentares/metabolismo , Homeostase , Músculo Esquelético/metabolismo , Proteínas Musculares/metabolismo , Ritmo Circadiano/fisiologia
3.
Environ Res ; 241: 117551, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-37939801

RESUMO

The present study investigated the sustainable approach for wastewater treatment using waste algal blooms. The current study investigated the removal of toxic metals namely chromium (Cr), nickel (Ni), and zinc (Zn) from aqueous solutions in batch and column studies using biochar produced by the marine algae Ulva reticulata. SEM/EDX, FTIR, and XRD were used to examine the adsorbents' properties and stability. The removal efficiency of toxic metals in batch operations was investigated by varying the parameters, which included pH, biochar dose, initial metal ion concentration, and contact time. Similarly, in the column study, the removal efficiency of heavy metal ions was investigated by varying bed height, flow rate, and initial metal ion concentration. Response Surface Methodology (Central Composite Design (CCD)) was used to confirm the linearity between the observed and estimated values of the adsorption quantity. The packed bed column demonstrated successful removal rates of 90.38% for Cr, 91.23% for Ni, and 89.92% for Zn heavy metals from aqueous solutions, under a controlled environment. The breakthrough analysis also shows that the Thomas and Adams-Bohart models best fit the regression values, allowing prior breakthroughs in the packed bed column to be predicted. Desorption studies were conducted to understand sorption and elution during different regeneration cycles. Adding 0.3 N sulfuric acid over 40 min resulted in the highest desorption rate of the column and adsorbent used for all three metal ions.


Assuntos
Metais Pesados , Alga Marinha , Poluentes Químicos da Água , Metais Pesados/análise , Níquel , Zinco/análise , Cromo/análise , Água , Íons , Adsorção , Poluentes Químicos da Água/análise , Concentração de Íons de Hidrogênio , Cinética
4.
Arch Pharm (Weinheim) ; 357(9): e2400325, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38885529

RESUMO

A library of imidazole-thiadiazole compounds (1-24) was synthesized to explore their therapeutic applications. The compounds were subjected to meticulous in vitro evaluation against α-glucosidase, α-amylase, acetylcholinesterase (AChE), and butylcholinesterase (BChE) enzymes. Compounds were also investigated for antioxidant activities using cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays. Derivatives 5-7, 9-11, 18, and 19 displayed potent inhibitory activities with IC50 values of 1.4 ± 0.01 to 13.6 ± 0.01 and 0.9 ± 0.01 to 12.8 ± 0.02 µM against α-glucosidase, and α-amylase enzymes, respectively, compared to the standard acarbose (IC50 = 14.8 ± 0.01 µM). Compounds 11-13, 16, 20, and 21 exhibited potent activity IC50 = 8.6 ± 0.02 to 34.7 ± 0.03 µM against AChE enzyme, compared to donepezil chloride (IC50 = 39.2 ± 0.05 µM). Compound 21 demonstrated comparable inhibition IC50 = 45.1 ± 0.09 µM against BChE, compared to donepezil chloride (IC50 = 44.2 ± 0.05 µM). All compounds also demonstrated excellent antioxidant activities via CUPRAC, FRAP, and DPPH methods. Complementing the experimental studies, extensive kinetics, ADME/T, and molecular docking analysis were also conducted to unravel the pharmacokinetics and safety profiles of the designed compounds. These studies supported the experimental findings and facilitated the prioritization of hit candidates for subsequent stages of drug development.


Assuntos
Acetilcolinesterase , Antioxidantes , Desenho de Fármacos , Imidazóis , Tiadiazóis , Tiadiazóis/farmacologia , Tiadiazóis/química , Tiadiazóis/síntese química , Imidazóis/farmacologia , Imidazóis/química , Imidazóis/síntese química , Relação Estrutura-Atividade , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/síntese química , Acetilcolinesterase/metabolismo , Estrutura Molecular , Simulação de Acoplamento Molecular , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Simulação por Computador , Butirilcolinesterase/metabolismo , alfa-Glucosidases/metabolismo , Humanos , Relação Dose-Resposta a Droga , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química
5.
Int J Phytoremediation ; 26(9): 1392-1409, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38441053

RESUMO

Industries generate hazardous dye wastewater, posing significant threats to public health and the environment. Removing dyes before discharge is crucial. The ongoing study primarily focused on synthesizing, applying, and understanding the mechanism of green nano-biochar composites. These composites, including zinc oxide/biochar, copper oxide/biochar, magnesium oxide/biochar, and manganese oxide/biochar, are designed to effectively remove Actas Pink-2B (Direct Red-31) in conjunction with constructed wetlands. Constructed wetland maintained pH 6.0-7.9. At the 10th week, the copper oxide/biochar treatment demonstrated the highest removal efficiency of total suspended solids (72%), dissolved oxygen (7.2 mg/L), and total dissolved solids (79.90%), followed by other biochar composites. The maximum removal efficiency for chemical oxygen demand (COD) and color was observed at a retention time of 60 days. The electrical conductivity also followed the same order, with a decrease observed up to the 8th week before becoming constant. A comprehensive statistical analysis was conducted, encompassing various techniques including variance analysis, regression analysis, correlation analysis, and principal component analysis. The rate of color and COD removal followed a second-order and first-order kinetics, respectively. A significant negative relationship was observed between dissolved oxygen and COD. The study indicates that employing biochar composites in constructed wetlands improves textile dye removal efficiency.


The novelty of this study is the selection of Cymbopogon as a proper plant for phytoremediation of dye along with green metal oxide coated biochar. These were selected due to their good ability to remove organic pollutant. This study demonstrates the uptake and degradation processes of persistent dye in constructed wetland.


Assuntos
Carvão Vegetal , Corantes , Nanocompostos , Eliminação de Resíduos Líquidos , Poluentes Químicos da Água , Áreas Alagadas , Eliminação de Resíduos Líquidos/métodos , Biodegradação Ambiental , Águas Residuárias/química , Análise da Demanda Biológica de Oxigênio , Compostos Azo
6.
Drug Dev Res ; 85(5): e22240, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39105636

RESUMO

In an effort to develop new and effective therapeutic agents for Alzheimer's disease, a series of hydrazone derivatives bearing piperidine rings have been designed and synthesized. The chemical structures of the compounds were characterized by various spectroscopic techniques. In vitro antioxidant and cholinesterase activities of the compounds were evaluated. Among the compounds, N12 exhibited the most antioxidant activity in all methods (CUPRAC, FRAP, DPPH, ABTS). In vitro acetylcholinesterase (AChE) activity results of the compounds showed good IC50 values between 14.124 ± 0.084 and 49.680 ± 0.110 µM were obtained (IC50 = 38.842 ± 0.053 µM for Donepezil). Among the compounds, N7 and N6 are much more effective derivatives than the standard compound donepezil with IC50 values of 14.124 ± 0.084 and 17.968 ± 0.072 µM, respectively. In vitro, butyrylcholinesterase (BChE) inhibition values of the compounds were between 13.505 ± 0.025 and 52.230 ± 0.027 µm. Among the compounds, N6 has the highest BChE inhibition with an IC50 value of 13.505 µm in the series. The cytotoxicity and AChE inhibitory activity of the compounds on SH-SY5Y cell lines were also evaluated. Kinetic studies were also performed to determine the behavior of the compounds as competitive or noncompetitive inhibitors. The binding modes of N6, which was determined to be highly effective according to in vitro analyses, with AChE and BChE were investigated using molecular docking studies, and the stability of the complexes was determined by molecular dynamics simulations. These findings indicated that AChE and BChE enzymes maintained their overall structural stability and compactness during interactions with compound N6.


Assuntos
Acetilcolinesterase , Butirilcolinesterase , Inibidores da Colinesterase , Desenho de Fármacos , Hidrazonas , Simulação de Acoplamento Molecular , Piperidinas , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Hidrazonas/farmacologia , Hidrazonas/síntese química , Hidrazonas/química , Piperidinas/farmacologia , Piperidinas/química , Piperidinas/síntese química , Butirilcolinesterase/metabolismo , Acetilcolinesterase/metabolismo , Humanos , Antioxidantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Relação Estrutura-Atividade , Modelos Moleculares
7.
J Environ Manage ; 370: 122600, 2024 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-39316881

RESUMO

The presence of fluoride in drinking water can cause various diseases, such as dental fluorosis and skeletal fluorosis. The present study aims to intensify the fluoride removal using a rotating anode electro-coagulation (EC) reactor with providing the proper hydrodynamics conditions. This fluoride removal is modeled and optimized using Response Surface Methodology (RSM) and central composite design (CCD) with varying operational parameters (rotation speed: 20-80 RPM, current: 0.2-1.0 A, initial fluoride concentration: 8-40 mg/L and time: 15-75 min). The maximum fluoride removal is obtained as 96.87% (predicted) and 95.40% (experimental) for the optimized process parameters, initial concentration of 32 mg/L, 0.8 A current, 60 min, and 60 RPM of rotating speed. Kinetic analysis reveals that the removal process adheres to a second-order kinetic model, suggesting that the rate of fluoride removal is dependent on the concentration of fluoride ions present. Isothermal studies indicate that the effective sorption of fluoride onto the generated flocs follows a sips isotherm. The optimal cost analysis is carried out to determine the operational cost as 0.256 USD/m3 for F removal of 93.49% at initial concentration 24 mg/L, time 50 min, current 0.7 A, and rotation 70 rpm and presenting a cost-effective solution for fluoride mitigation. Further, characterizations of the resultant sludge through X-Ray Diffraction (XRD), Fourier-Transform Infrared Spectroscopy (FTIR), and the Toxicity Characteristic Leaching Procedure (TCLP) confirmed the safe disposal potential of the sludge. The findings show a promising approach for fluoride removal, combining high efficiency, economic viability, and environmental safety.

8.
Environ Geochem Health ; 46(9): 308, 2024 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-39001890

RESUMO

This study introduces a new biosorbent derived from Delonix regia bark-activated carbon to efficiently remove Chromium Cr(VI) metal ions from aqueous systems. The biosorbent was synthesized from the bark powder of the plant species and chemically activated with phosphoric acid. The biosorbent was characterized using FTIR, SEM, and BET to determine its functional properties and structural morphology. The batch adsorption experiments examined the optimal conditions for Cr(VI) metal ion adsorption, identifying that the highest removal efficiency occurred at pH levels of 2. The ideal adsorbent dosage was determined to be 2.5 g/L, with equilibrium achieved at a contact time of 60 min at the optimal temperature of about 303 K for a Cr(VI) metal ion concentration of 20 mg/L. Various isotherm models were applied to the adsorption equilibrium values, revealing that the adsorbent had a maximum removal capacity of approximately 224.8 mg/g for Cr(VI) metal ions. The adsorption process of Cr(VI) on the DAC biosorbent was best described by the Freundlich isotherm, indicating multilayer adsorption. The kinetic data fit well with the pseudo-second-order model. Thermodynamic parameters suggested that the adsorption process was spontaneous, exothermic, and feasible across different temperatures. Furthermore, the desorption studies showed that the DAC biosorbent can easily be rejuvenated and utilized several cycles with high adsorption capacity. These findings indicate that the developed adsorbent is environmentally friendly and effective for removing Cr(VI) from water systems.


Assuntos
Carvão Vegetal , Cromo , Casca de Planta , Poluentes Químicos da Água , Cromo/química , Adsorção , Casca de Planta/química , Poluentes Químicos da Água/química , Carvão Vegetal/química , Concentração de Íons de Hidrogênio , Purificação da Água/métodos , Cinética , Sapotaceae/química , Termodinâmica , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura
9.
Chembiochem ; 24(12): e202200731, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-36944581

RESUMO

Kinetic studies revealed that nitrate radicals (NO3 ⋅), which are formed through reaction of the noxious air pollutants nitrogen dioxide (NO2 ⋅) and ozone (O3 ), very rapidly oxidize phenylalanine residues in an aqueous environment, with overall rate coefficients in the 108 -109  M-1 s-1 range. With amino acids and dipeptides as model systems, the data suggest that the reaction proceeds via a π-complex between NO3 ⋅ and the aromatic ring in Phe, which subsequently decays into a charge transfer (CT) complex. The stability of the π-complex is sequence-dependent and is increased when Phe is at the N terminus of the dipeptide. Computations revealed that the considerably more rapid radical-induced oxidation of Phe residues in both neutral and acidic aqueous environments, compared to acetonitrile, can be attributed to stabilization of the CT complex by the protic solvent; this clearly highlights the health-damaging potential of exposure to combined NO2 ⋅ and O3 .


Assuntos
Nitratos , Dióxido de Nitrogênio , Nitratos/química , Dióxido de Nitrogênio/química , Fenilalanina/química , Cinética , Oxirredução , Dipeptídeos/química
10.
Bioorg Chem ; 140: 106805, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37634269

RESUMO

Enzymes are the biological macromolecules that have emerged as an important drug target as their upregulation/imbalance leads to various pathological conditions, such as inflammation, parasitic infection, Alzheimer's, cancer, and many others. Here, we designed and synthesized some morpholine tethered novel aurones and evaluated them as potential inhibitors for CTSB, α-amylase, lipase and activator for trypsin. All the newly synthesized compounds were fully characterized by various spectroscopic techniques (1H NMR, 13C NMR, HRMS) and the Z-configuration to them was assigned based on single crystal XRD data and 1H NMR chemical shift values. Further, the hybrids were evaluated for their intracellular (cathepsin B) and extracellular (trypsin, lipase, amylase) enzyme inhibition potencies. The in-vitro inhibition screening against cathepsin B revealed that most of the synthesized compounds are good competitive inhibitors (% inhibition = 22.91-75.04), with 6q (% inhibition = 75.04) and 6r (% inhibition = 71.13) as the eminent inhibitors of the series. At the same time, they exhibited weak to moderate inhibition towards amylase (% inhibition = 7.22-22.48) and lipase (% inhibition = 16.29-54.83). A significant trypsin activation (% activation = 107.42-196.47) was observed even at the micromolar concentration of the compounds. Furthermore, the drug-modeling studies showed a good correlation between the in-vitro experimental results and the calculated binding affinity of the screened compounds with all the tested enzymes. These findings are expected to provide a new lead in drug development for different pathological disorders wherever these enzymes are involved.


Assuntos
Catepsina B , Morfolinas , Simulação de Acoplamento Molecular , Tripsina , Morfolinas/farmacologia , Amilases , Lipase
11.
Molecules ; 28(3)2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36771076

RESUMO

Supercritical CO2 extraction is a green method that combines economic and environmental benefits. Microalgae, on the other hand, is a biomass in abundance, capable of providing a vast variety of valuable compounds, finding applications in the food industry, cosmetics, pharmaceuticals and biofuels. An extensive study on the existing literature concerning supercritical fluid extraction (SFE) of microalgae has been carried out focusing on carotenoids, chlorophylls, lipids and fatty acids recovery, as well as the bioactivity of the extracts. Moreover, kinetic models used to describe SFE process and experimental design are included. Finally, biomass pretreatment processes applied prior to SFE are mentioned, and other extraction methods used as benchmarks are also presented.


Assuntos
Cromatografia com Fluido Supercrítico , Microalgas , Dióxido de Carbono , Ácidos Graxos , Carotenoides , Biomassa , Cromatografia com Fluido Supercrítico/métodos
12.
Molecules ; 28(5)2023 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-36903593

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder, for which there is no effective cure. Current drugs only slow down the course of the disease, and, therefore, there is an urgent need to find effective therapies that not only treat, but also prevent it. Acetylcholinesterase inhibitors (AChEIs), among others, have been used for years to treat AD. Histamine H3 receptors (H3Rs) antagonists/inverse agonists are indicated for CNS diseases. Combining AChEIs with H3R antagonism in one structure could bring a beneficial therapeutic effect. The aim of this study was to find new multitargetting ligands. Thus, continuing our previous research, acetyl- and propionyl-phenoxy-pentyl(-hexyl) derivatives were designed. These compounds were tested for their affinity to human H3Rs, as well as their ability to inhibit cholinesterases (acetyl- and butyrylcholinesterases) and, additionally, human monoamine oxidase B (MAO B). Furthermore, for the selected active compounds, their toxicity towards HepG2 or SH-SY5Y cells was evaluated. The results showed that compounds 16 (1-(4-((5-(azepan-1-yl)pentyl)oxy)phenyl)propan-1-one) and 17 (1-(4-((6-(azepan-1-yl)hexyl)oxy)phenyl)propan-1-one) are the most promising, with a high affinity for human H3Rs (Ki: 30 nM and 42 nM, respectively), a good ability to inhibit cholinesterases (16: AChE IC50 = 3.60 µM, BuChE IC50 = 0.55 µM; 17: AChE IC50 = 1.06 µM, BuChE IC50 = 2.86 µM), and lack of cell toxicity up to 50 µM.


Assuntos
Doença de Alzheimer , Neuroblastoma , Receptores Histamínicos H3 , Humanos , Histamina , Acetilcolinesterase/metabolismo , Relação Estrutura-Atividade , Agonismo Inverso de Drogas , Receptores Histamínicos H3/química , Inibidores da Colinesterase/química , Receptores Histamínicos , Monoaminoxidase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Inibidores da Monoaminoxidase/farmacologia , Ligantes
13.
Artigo em Inglês | MEDLINE | ID: mdl-36840367

RESUMO

In recent times, ground water contamination by toxic elements is of great concern and it is to be addressed for consumption of human, animal, and plant growth. In this context, we have synthesized an adsorbent by modifying commercially available activated carbon with aluminum and tested for de-fluoridation studies. The activity results suggested that the optimized adsorbent is highly efficient in removing the fluoride from ground water. Adsorption maxima are obtained over a wide pH range from 4 to 9, with a contact time of 15 minutes at a dosage of 4 g/L. The results also revealed that the synthesized adsorbent is suitable for application in ground water without any pH adjustment and has exhibited 85%-95% tolerance for common anions in the range of 100-500 mg/L. Equilibrium adsorption isotherm models as well as kinetics of adsorption were applied for the system. An adsorption capacity of 20.4 mg/g and fast kinetics observed are most favorable for defluoridation. Reuse of adsorbent over repeated cycles was investigated. Residual amount of aluminum in treated water is found to be negligible. The removal of toxic elements like Pb, Cd, Cr, Cu, Ni, Zn, As, and Se under the optimized experimental conditions has also been investigated. Al-AC found to be a highly promising material for removal of fluoride and toxic metals from drinking water.


Assuntos
Água Potável , Água Subterrânea , Poluentes Químicos da Água , Purificação da Água , Humanos , Fluoretos/química , Alumínio/química , Carvão Vegetal , Adsorção , Cinética , Concentração de Íons de Hidrogênio , Poluentes Químicos da Água/análise , Purificação da Água/métodos
14.
Angew Chem Int Ed Engl ; 62(33): e202307826, 2023 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-37309734

RESUMO

A ligand-controlled regiodivergence in Ni-catalyzed rearrangement of vinylcyclopropanes to 1,4- or 1,5-disubstituted cyclopentenes is reported. The 1,4- or 1,5-disubstituted cyclopentene is selectively obtained depending on the choice of ligands. Detailed kinetic studies and density functional theory calculations on the catalytic cycle revealed that the product selectivity is determined at the reductive elimination step from the six-membered η1 -allyl intermediate.

15.
Chembiochem ; 23(2): e202100270, 2022 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-34494353

RESUMO

Proteolysis-targeting chimeras (PROTACs), an emerging paradigm-shifting technology, hijacks the ubiquitin-proteasome system for targeted protein degradation. PROTACs induce ternary complexes between an E3 ligase and POI, and this induced proximity leads to polyUb chain formation on substrates and eventual proteasomal-mediated POI degradation. PROTACs have shown great therapeutic potential by degrading many disease-causing proteins, such as the androgen receptor and BRD4. The PROTAC technology has advanced significantly in the last two decades, with the repertoire of PROTAC targets increased tremendously. Herein, we describe recent developments of PROTAC technology, focusing on mechanistic and kinetic studies, pharmacokinetic study, spatiotemporal control of PROTACs, covalent PROTACs, resistance to PROTACs, and new E3 ligands.


Assuntos
Proteínas/metabolismo , Células HeLa , Humanos , Imunoconjugados/metabolismo , Cinética , Ligantes , Luz , Conformação Proteica , Proteínas/química , Proteólise , Fatores de Transcrição/metabolismo
16.
Mol Divers ; 26(2): 849-868, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33650031

RESUMO

A variety of dihydroquinazolin-4(1H)-one derivatives (1-37) were synthesized via "one-pot" three-component reaction scheme by treating aniline and different aromatic aldehydes with isatoic anhydride in the presence of acetic acid. Chemical structures of compounds were deduced by different spectroscopic techniques including EI-MS, HREI-MS, 1H-, and 13C-NMR. Compounds were subjected to α-amylase and α-glucosidase inhibitory activities. A number of derivatives exhibited significant to moderate inhibition potential against α-amylase (IC50 = 23.33 ± 0.02-88.65 ± 0.23 µM) and α-glucosidase (IC50 = 25.01 ± 0.12-89.99 ± 0.09 µM) enzymes, respectively. Results were compared with the standard acarbose (IC50 = 17.08 ± 0.07 µM for α-amylase and IC50 = 17.67 ± 0.09 µM for α-glucosidase). Structure-activity relationship (SAR) was rationalized by analyzing the substituents effects on inhibitory potential. Kinetic studies were implemented to find the mode of inhibition by compounds which revealed competitive inhibition for α-amylase and non-competitive inhibition for α-glucosidase. However, in silico study identified several important binding interactions of ligands (synthetic analogues) with the active site of both enzymes.


Assuntos
Diabetes Mellitus , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Cinética , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , alfa-Amilases/metabolismo , alfa-Glucosidases/química
17.
Arch Pharm (Weinheim) ; 355(6): e2100481, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35355329

RESUMO

Diabetes mellitus is one of the most prevalent diseases nowadays. Several marketed drugs are available for the cure and treatment of diabetes, but there is still a dire need of introducing compatible drug molecules with lesser side effects. The current study is based on the synthesis of isatin thiazole derivatives 4-30 via the Hantzsch reaction. The synthetic compounds were characterized using different spectroscopic techniques and evaluated for their α-amylase and α-glucosidase inhibition potential. Of 27 isatin thiazoles, five (4, 5, 10, 12, and 16) displayed good activities against the α-amylase enzyme with IC50 values in the range of 22.22 ± 0.02-27.01 ± 0.06 µM, and for α-glucosidase, the IC50 values of these compounds were in the range of 20.76 ± 0.17-27.76 ± 0.17 µM, respectively. The binding interactions of the active molecules within the active site of enzymes were studied with the help of molecular docking studies. In addition, kinetic studies were carried out to examine the mechanism of action of the synthetic molecules as well. Compounds 3a, 4, 5, 10, 12, and 16 were also examined for their cytotoxic effect and were found to be noncytotoxic. Thus, several molecules were identified as good antihyperglycemic agents, which can be further modified to enhance inhibition ability and to find the lead molecule that can act as a potential antidiabetic agent.


Assuntos
Hipoglicemiantes , Isatina , Tiazóis , Diabetes Mellitus , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Isatina/síntese química , Isatina/farmacologia , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologia , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/metabolismo
18.
Int J Phytoremediation ; 24(2): 110-117, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34251916

RESUMO

Biosorption potential of Pennisetum glaucum has elaborated by investigating its kinetic behavior in nonlinear fashion. RMSE values supported the pseudo second order (PSO) and elovich model, but correlation coefficient (R2) values supported the PSO only. Study of intra-particle diffusion model (IPDM) and Boyd plots revealed the multi-linear diffusion pattern of the studied metal ions toward biosorbent. Initially, IPDM was found to be the rate-determining step, however boundary layer diffusion was found to be the slowest step later on. There was no correlation between calculated and experimental values of intercept, calculated by applying mass transfer model. Conclusive findings of Boyd plot supported the governing of biosorption process by film diffusion.Novelty StatementIn this work, biosorption potential of Pennisetum glaucum has been investigating in terms of kinetic studies in nonlinear fashion.Biosorbent is obtained from indigenous sources and its processing is easy, which in turns leads to its cost-effectiveness for better removal of toxic materials from waste water streams.All related theoretical investigations were summarized for showing biosorption efficiency of this novel material.


Assuntos
Pennisetum , Poluentes Químicos da Água , Adsorção , Biodegradação Ambiental , Cádmio/análise , Cátions , Concentração de Íons de Hidrogênio , Cinética , Chumbo , Termodinâmica , Poluentes Químicos da Água/análise
19.
Int J Mol Sci ; 23(23)2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36499576

RESUMO

Ceftobiprole is a novel ß-lactam antibiotic, active against methicillin-resistant Staphylococcus aureus, vancomycin-resistant S. aureus and penicillin-resistant Streptococcus pneumoniae. To artificially generate potential degradation products (DPs) of ceftobiprole that may be formed under relevant storage conditions, acidic, alkaline, oxidative, photolytic and thermolytic stress tests were performed in both solution and solid state. A novel selective HPLC method was developed for the separation of ceftobiprole from its DPs and synthesis by-products (SBPs) using Kinetex Biphenyl column, ammonium acetate buffer pH 5.8 and acetonitrile. The kinetic studies demonstrated the low stability of ceftobiprole in alkaline solution, in the presence of an oxidising agent and under irradiation with near UV. In the solid state, ceftobiprole underwent oxidation when the powder was irradiated with visible light and UV. Based on mass spectroscopic analysis, 13 new structural formulas of SBPs and DPs were proposed, along with molecular formulas for three other DPs obtained in solution and four oxidative DPs characteristic of solid-state degradation.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Cinética , Cefalosporinas , Estabilidade de Medicamentos
20.
J Environ Manage ; 310: 114731, 2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35189556

RESUMO

Additives, such as iron oxides, have been used in anaerobic digestion (AD) to promote direct interspecies electron transfer and to boost methane yield. However, the function of additives in the AD of antibiotic-contaminated organic wastes remained unclear. In this study, the effects of ferric hydroxide and (semi) conductive iron oxides, namely hematite and magnetite, on the AD of oxytetracycline (OTC)-contaminated dairy manure were investigated. Each iron oxide was assigned to a set of experiment where 0.25 g/L of OTC was added to 1 L batch digesters, while the concentration of iron oxide was varied from 0.08 to 0.34 g/L. Generally, magnetite was the most effective iron oxide to enhance methane yield in OTC-free dairy manure followed by ferric hydroxide and hematite. However, when the manure was contaminated with OTC, higher methane yield was observed in ferric hydroxide followed by hematite, while the lowest was with magnetite. In all digesters, the highest methane yield was observed with ferric hydroxide at 0.08 g/L, which was 1.43-fold of that with OTC and without iron oxides. The kinetic studies of methane yield demonstrated that the addition of iron oxides in the AD of OTC-contaminated dairy manure did not shorten the lag phase period despite the increase of methane yield. Thus, the increase of methane yield with ferric hydroxide was attributed to the possible formation of Fe-OTC complex, which attenuated the inhibition of OTC. A strategy to recover OTC residue in the AD was proposed using magnetite, a ferromagnetic particle, and high gradient magnetic separator.


Assuntos
Esterco , Oxitetraciclina , Anaerobiose , Reatores Biológicos , Compostos Férricos , Ferro , Cinética , Metano , Óxidos
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