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1.
Curr Pharm Des ; 2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-32723252

RESUMO

Xanthine oxidase (EC 1.17.3.2) (XO) is one of the main enzymatic sources that create reactive oxygen species (ROS) in the living system. It is a dehydrogenase enzyme that performs electron transfer to nicotinamide adenine dinucleotide (NAD+ ), while oxidizing hypoxanthin, which is an intermediate compound in purine catabolism, first to xanthine and then to uric acid. XO turns into an oxidant enzyme that oxidizes thiol groups under certain stress conditions in the tissue. The last metabolic step, in which hypoxanthin turns into uric acid, is catalyzed by XO. Uric acid, considered a waste product, can cause kidney stones and gouty-type arthritis as it is crystallized, when present in high concentrations. Thus, XO inhibitors are one of the drug classes used against gout, a purine metabolism disease that causes urate crystal storage in the joint and its surroundings caused by hyperuricemia. Urate-lowering therapy include XO inhibitors that reduce uric acid production as well as uricosuric drugs that increase urea excretion. Current drugs that obstruct uric acid synthesis through XO inhibition are allopurinol, febuxostat, and uricase. However, since the side effects, safety and tolerability problems of some current gout medications still exist; intensive research is ongoing to look for new, effective, and safer XO inhibitors of natural or synthetic origins for the treatment of the disease. In the present review, we aimed to assess in detail XO inhibitory capacities of pure natural compounds along with the extracts from plants and other natural sources via screening Pubmed, Web of Science (WoS), Scopus, and Google Academic. The data pointed out to the fact that natural products, particularly phenolics such as flavonoids (quercetin, apigenin, and scutellarein), tannins (agrimoniin and ellagitannin), chalcones (melanoxethin), triterpenes (ginsenoside Rd and ursolic acid), stilbenes (resveratrol and piceatannol), alkaloids (berberin and palmatin) have a great potential for new XO inhibitors capable of use against gout disease. In addition, not only plants but other biological sources such as microfungi, macrofungi, lichens, insects (silk worms, ants, etc) seem to be the promising sources of novel XO inhibitors.

2.
Clin Infect Dis ; 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32649738

RESUMO

BACKGROUND: The outbreak of coronavirus disease (COVID-19) in 2019 has spread worldwide and continues to cause great threat to peoples' health as well as put pressure on the accessibility of medical systems. Early prediction of survival of hospitalized patients will help the clinical management of COVID-19, but such a prediction model which is reliable and valid is still lacking. METHODS: We retrospectively enrolled 628 confirmed cases of COVID-19 using positive RT-PCR tests for SARS-CoV-2 in Tongji Hospital in Wuhan, China. These patients were randomly grouped into a training cohort (60%) and a validation cohort (40%). In the training cohort, least absolute shrinkage and selection operator (LASSO) regression analysis and multivariate Cox regression analysis were utilized to identify prognostic factors for in-hospital survival of patients with COVID-19. A nomogram based on the three variables was built for clinical use. Areas under the ROC curves (AUC), concordance index (C-index) and calibration curve were used to evaluate the efficiency of the nomogram in both the training and validation cohorts. RESULTS: Hypertension, higher neutrophil-to-lymphocyte ratio and increased NT-proBNP value were found to be significantly associated with poorer prognosis in hospitalized patients with COVID-19. The three predictors were further used to build a prediction nomogram. The C-index of the nomogram in the training and validation cohorts was 0.901 and 0.892, respectively. The AUC in the training cohort was 0.922 for 14- day and 0.919 for 21-day probability of in-hospital survival, while in the validation cohort was 0.922 and 0.881, respectively. Moreover, the calibration curve for 14- day and 21-day survival also showed high coherence between the predicted and actual probability of survival. CONCLUSION: We managed to build a predictive model and constructed a nomogram for predicting in-hospital survival of patients with COVID-19. This model represents good performance and might be utilized clinically in the management of COVID-19.

3.
Nat Prod Bioprospect ; 10(4): 171-186, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32529545

RESUMO

New coronavirus referred to SARS-CoV-2 has caused a worldwide pandemic (COVID-19) declared by WHO. Coronavirus disease 2019 (COVID-19) is an infectious disease with severe acute respiratory syndrome caused by coronavirus-2 (SARS-CoV-2). SARS-CoV-2 is akin to SARS-CoV, which was the causative agent of severe acute respiratory syndrome (SARS) in 2002 as well as to that of Middle East respiratory syndrome (MERS) in 2012. SARS-CoV-2 has been revealed to belong to Coronaviridiae family as a member of ß-coronaviruses. It has a positive-sense single-stranded RNA with the largest RNA genome. Since its genomic sequence has a notable similarity to that of SARS-CoV, antiviral drugs used to treat SARS and MERS are now being also applied for COVID-19 treatment. In order to combat SARS-CoV-2, many drug and vaccine development studies at experimental and clinical levels are currently conducted worldwide. In this sense, medicinal plants and the pure natural molecules isolated from plants have been reported to exhibit significant inhibitory antiviral activity against SARS-CoV and other types of coronaviruses. In the present review, plant extracts and natural molecules with the mentioned activity are discussed in order to give inspiration to researchers to take these molecules into consideration against SARS-CoV-2.

4.
Med Chem ; 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32520690

RESUMO

BACKGROUND: One of the best methods to treat Alzheimer disease (AD) is through the effective use of cholinesterase inhibitors as vital drugs due to the identification of acetylcholine deficit in the AD patients. OBJECTIVE: The present study aims the investigation of spiro heterocyclic compounds as potential AD agents supported by their metal chelation capacity, POM analyses and DFT studies respectively. METHOD: The cholinesterase inhibition and metal chelation ability was performed on ELISA microtiter assay. Whereas B3LYP method with 6-31+G(d,p) basis set was implemented to study HOMO-LUMO energy calculations. The pharmacokinetic properties of the synthesized molecules were studied through Petra, Osiris and Molinspiration (POM). RESULTS: The six spiro (1-6) skeletons were tested for their inhibitory potential and metal-chelation capacity. Our findings revealed that the tested spiro skeletons exerted none or lower than 50% inhibition against both cholinesterases, while compound 4 proved to be the most active molecule with 57.21±0.89% of inhibition toward BChE. The spiro molecule 3 exhibited the highest metal-chelation capacity (9.12±5.26%). Molecular docking model for the most active molecule exhibited promising bindings with AChE and BChE's active site pertained to hydrophobic hydrogen bonds and positive ionizable interactions. The POM analyses gave the information about the flexibility at the site of coordination of spiro compounds (1-6). CONCLUSION: The screening of spirocompounds (1-6) against cholinesterases revealed that some of them show considerable potential to inhibit AChE and BChE. Herein we propose that the spiro molecules after further derivatization could serve interesting AD inhibitor drugs.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31985374

RESUMO

With respect to the unknowns of the pathophysiology of Alzheimer's Disease (AD)-, and Parkinson's Disease (PD)-like neurodegenerative disorders, natural product research is still one of the valid tools in order to provide alternative and/or better treatment options. At one hand, various extracts of herbals provide a combination of actions targeting multiple receptors, on the other hand, the discovery of active natural products (i.e., secondary metabolites) generally offer alternative chemical structures either ready to be employed in clinical studies or available to be utilized as important scaffolds for the design of novel agents. Regarding the importance of the enzymes, e.g. cholinesterase and monoamine oxidase B, for the treatment of AD and PD, we have surveyed the natural product research in the last decade on this area. Particularly novel natural agents discovered within this period concomitant to novel biological activities displayed for known natural products are harmonized within the present study.

6.
Phytochemistry ; 169: 112162, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31627115

RESUMO

Twelve undescribed triterpenoid pentacyclic glycosides, medicagenic acid (3-O-ß-D-glucuronopyranosyl-28-O-{[ß-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)]-[α-L-rhamnopyranosyl-(1 → 3)]-4-O-acetyl-ß-D-fucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-12-ene-23,28-dioic acid, 3-O-ß-D-glucuronopyranosyl-28-O-{[α-L-rhamnopyranosyl-(1 → 2)]-[ß-D-apiofuranosyl-(1 → 3)]-4-O-acetyl-ß-D-fucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-12-ene-23,28-dioic acid, 3-O-ß-D-glucuronopyranosyl-28-O-{[α-L-rhamnopyranosyl-(1 → 2)]-3,4-O-diacetyl-ß-D-fucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-12-ene-23,28-dioic acid, 28-O-{[6-O-acetyl-ß-D-glucopyranosyl-(1 → 2)]-[2-O-acetyl-α-L-rhamnopyranosyl-(1 → 4)-ß-D-glucopyranosyl-(1 → 6)]-ß-D-glucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-12-ene-23,28-dioic acid, 28-O-{[6-O-acetyl-ß-D-glucopyranosyl-(1 → 2)]-[3-O-acetyl-α-L-rhamnopyranosyl-(1 → 4)-ß-D-glucopyranosyl-(1 → 6)]-ß-D-glucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-12-ene-23,28-dioic acid, 28-O-{[6-O-acetyl-ß-D-glucopyranosyl-(1 → 2)]-[4-O-acetyl-α-L-rhamnopyranosyl-(1 → 4)-ß-D-glucopyranosyl-(1 → 6)]-ß-D-glucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-12-ene-23,28-dioic acid, 28-O-{[6-O-acetyl-ß-D-glucopyranosyl-(1 → 2)]-[ß-D-glucopyranosyl-(1 → 6)]-ß-D-glucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-12-ene-23,28-dioic acid, 28-O-{[ß-D-glucopyranosyl-(1 → 2)]-[ß-D-glucopyranosyl-(1 → 6)]-ß-D-glucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-12-ene-23,28-dioic acid), zanhic acid (3-O-ß-D-glucuronopyranosyl-28-O-{[ß-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)]-[α-L-rhamnopyranosyl-(1 → 3)]-4-O-acetyl-ß-D-fucopyranosyl-(1→)}2ß,3ß,16α-trihydroxyolean-12-ene-23,28-dioic acid, 3-O-ß-D-glucuronopyranosyl-28-O-{[ß-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)]-ß-D-fucopyranosyl-(1→)}-2ß,3ß,16α-trihydroxyolean-12-ene-23,28-dioic acid), 29-hydroxy-medicagenic acid (3-O-ß-D-glucuronopyranosyl-28-O-{[ß-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)]-[α-L-rhamnopyranosyl-(1 → 3)]-4-O-acetyl-ß-D-fucopyranosyl-(1→)}-2ß,3ß,29ß-trihydroxyolean-12-ene-23,28-dioic acid) and herniaric acid (28-O-{[6-O-acetyl-ß-D-glucopyranosyl-(1 → 2)]-[α-L-rhamnopyranosyl-(1 → 4)-ß-D-glucopyranosyl-(1 → 6)]-ß-D-glucopyranosyl-(1→)}-2ß,3ß-dihydroxyolean-18-ene-23,28-dioic acid) were isolated from the whole plant extract of Herniaria glabra L. (Caryophyllaceae), wild growing in the Ukraine. In addition, five known triterpenoid saponins; i.e. herniariasaponins 1, 4, 5, 6, and 7 were also isolated. Their structures were elucidated by HRESIMS, 1D and 2D NMR spectroscopy, as well as by comparison with the literature data. Twelve herniariasaponins, the purified crude extract, and the saponin fraction were evaluated in vitro for their xanthine oxidase, collagenase, elastase, and tyrosinase inhibitory activity. Moreover, herniariasaponins 4, 5, and 7 were screened for their cholinesterase inhibitory potential. As a result, no or low inhibition towards the mentioned enzymes was observed.


Assuntos
Caryophyllaceae/química , Inibidores Enzimáticos/farmacologia , Extratos Vegetais/farmacologia , Saponinas/farmacologia , Animais , Colinesterases/metabolismo , Colagenases/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Conformação Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Elastase Pancreática/antagonistas & inibidores , Elastase Pancreática/metabolismo , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Saponinas/química , Saponinas/isolamento & purificação , Estereoisomerismo , Ucrânia , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo
7.
Molecules ; 24(22)2019 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-31744162

RESUMO

The ethyl acetate fraction of the methanolic extract of Yucca schidigera Roezl ex Ortgies bark exhibited moderate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity (IC50 47.44 and 47.40 µg mL-1, respectively). Gel filtration on Sephadex LH-20 and further RP-C18 preparative HPLC of EtOAc fraction afforded 15 known and 3 new compounds, stereoisomers of larixinol. The structures of the isolated spirobiflavonoids 15, 26, and 29 were elucidated using 1D and 2D NMR and MS spectroscopic techniques. The relative configuration of isolated compounds was assigned based on coupling constants and ROESY (rotating-frame Overhauser spectroscopy) correlations along with applying the DP4+ probability method in case of ambiguous chiral centers. Determination of absolute configuration was performed by comparing calculated electronic circular dichroism (ECD) spectra with experimental ones. Compounds 26 and 29, obtained in sufficient amounts, were evaluated for activities against AChE and BChE, and they showed a weak inhibition only towards AChE (IC50 294.18 µM for 26, and 655.18 µM for 29). Furthermore, molecular docking simulations were performed to investigate the possible binding modes of 26 and 29 with AChE.


Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Yucca/química , Cromatografia Líquida de Alta Pressão , Ativação Enzimática/efeitos dos fármacos , Flavonoides/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Compostos de Espiro/química
8.
Life Sci ; 235: 116797, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472146

RESUMO

Chrysin is a promising phytochemical that is categorized under the class of flavonoids based on its chemical structure. Naturally, it is widely present in propolis, honey, passion fruit, and even in mushrooms and other plant sources, whereas its synthetic counterparts are also being employed for pharmacological purposes. It has widely been employed in treatment of various degenerative disorders and provides cytotoxic and anti-inflammatory functions. Its antioxidant and disease preventing abilities are attributed to its structural diversity arising in ring-A and absence of oxygenation in B and C ring. In this review, the scientific studies are being reported emphasizing benefits and its allied health claims on chrysin in numerous metabolic malfunctions.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Antivirais/farmacologia , Flavonoides/farmacologia , Humanos
9.
Food Chem Toxicol ; 134: 110822, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31536753

RESUMO

Phosphodiesterases (PDEs) consisted of 11 subtypes (PDE1 to PDE11) and over 40 isoforms that regulate levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP), the second messengers in cell functions. PDE inhibitors (PDEIs) have been attractive therapeutic targets due to their involvement in diverse medical conditions, e.g. cardiovascular diseases, autoimmune diseases, Alzheimer's disease (AD), etc. Among them; AD with a complex pathology is a progressive neurodegenerative disorder which affect mostly senile people in the world and only symptomatic treatment particularly using cholinesterase inhibitors in clinic is available at the moment for AD. Consequently, novel treatment strategies towards AD are still searched extensively. Since PDEs are broadly expressed in the brain, PDEIs are considered to modulate neurodegenerative conditions through regulating cAMP and cGMP in the brain. In this sense, several synthetic or natural molecules inhibiting various PDE subtypes such as rolipram and roflumilast (PDE4 inhibitors), vinpocetine (PDE1 inhibitor), cilostazol and milrinone (PDE3 inhibitors), sildenafil and tadalafil (PDE5 inhibitors), etc have been reported showing encouraging results for the treatment of AD. In this review, PDE superfamily will be scrutinized from the view point of structural features, isoforms, functions and pharmacology particularly attributed to PDEs as target for AD therapy.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores de Fosfodiesterase/farmacologia , Animais , Humanos , Inibidores de Fosfodiesterase/uso terapêutico
11.
Bioorg Chem ; 92: 103304, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31561108

RESUMO

In the current study, forty-four new [3-(2/3/4-methoxyphenyl)-6-oxopyridazin-1(6H)-yl]methyl carbamate derivatives were synthesized and evaluated for their ability to inhibit electric eel acetylcholinesterase (EeAChE) and equine butyrylcholinesterase (eqBuChE) enzymes. According to the inhibitory activity results, [3-(2-methoxyphenyl)-6-oxopyridazin-1(6H)-yl]methyl heptylcarbamate (16c, eqBuChE, IC50 = 12.8 µM; EeAChE, no inhibition at 100 µM) was the most potent eqBuChE inhibitor among the synthesized compounds and was found to be a moderate inhibitor compared to donepezil (eqBuChE, IC50 = 3.25 µM; EeAChE, IC50 = 0.11 µM). Kinetic and molecular docking studies indicated that compounds 16c and 14c (hexylcarbamate derivative, eqBuChE, IC50 = 35 µM; EeAChE, no inhibition at 100 µM) were mixed-type inhibitors which accommodated within the catalytic active site (CAS) and peripheral anionic site (PAS) of hBuChE through stable hydrogen bonding and π-π stacking. Furthermore, it was determined that [3-(2-methoxyphenyl)-6-oxopyridazin-1(6H)-yl]methyl (4-methylphenyl)carbamate 7c (eqBuChE, IC50 = 34.5 µM; EeAChE, 38.9% inhibition at 100 µM) was the most active derivative against EeAChE and a competitive inhibitor binding to the CAS of hBuChE. As a result, 6-(2-methoxyphenyl)pyridazin-3(2H)-one scaffold is important for the inhibitory activity and compounds 7c, 14c and 16c might be considered as promising lead candidates for the design and development of selective BuChE inhibitors for Alzheimer's disease treatment.

12.
Chem Biodivers ; 16(9): e1900333, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31365785

RESUMO

In the current study, the ethanol extracts of flower, stem, and root parts of two endemic Turkish species, e. g., Haplophyllum sahinii O. Tugay & D. Ulukus and H. vulcanicum Boiss. & Heldr., were screened against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) associated with Alzheimer's disease as well as tyrosinase (TYR) linked to Parkinson's disease using ELISA microplate assay at 200 µg/mL. Among the extracts, the highest inhibition was caused by the stem extract of H. sahinii against BChE (IC50 =64.93±1.38 µg/mL). Consistently, all of the extracts were found to exert a selective inhibition towards BChE to some extent. It was only the root extract of H. vulcanicum that could inhibit AChE at low level (IC50 =203.18±5.33 µg/mL). None of the extracts displayed an inhibition over 50 % against TYR. Metabolite profiling of the extracts was achieved by a highly hyphenated liquid chromatographic mass spectrometric technique (HPLC-DAD-ESI-Q-TOF-MS/MS), which revealed the presence of furoquinoline (ß-fagarine, γ-fagarine) and amide (tubasenicine, tubacetine) alkaloids; furano- (rutamarin), pyrano- (xanthyletine), and geranyloxy coumarins; phenylpropanoid (secoisolariciresinol), arylnaphthalene (mono-O-acetyldiphyllin apioside), and dibenzylbutyrolactone (kusunokinin, haplomyrfolin) lignans. Several important differences were observed between the extracts analyzed. ß-Fagarine was the major alkaloid in H. vulcanicum, whereas γ-fagarine was present only in the roots of both Haplophyllum species; moreover, secoisolariciresinol and secoisolariciresinol dimethyl ether were the main lignans in the stems and flowers. This is the first study identifying ChE and TYR inhibitory effect and metabolic profiles of H. vulcanicum and H. sahinii.


Assuntos
Inibidores da Colinesterase/farmacologia , Cumarínicos/farmacologia , Lignanas/farmacologia , Extratos Vegetais/farmacologia , Quinolinas/farmacologia , Rutaceae/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Cromatografia Líquida de Alta Pressão , Cumarínicos/química , Cumarínicos/metabolismo , Humanos , Lignanas/química , Lignanas/metabolismo , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Quinolinas/química , Quinolinas/metabolismo , Rutaceae/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Turquia
13.
Chem Biodivers ; 16(5): e1900017, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30891904

RESUMO

Cholinergic therapy based on cholinesterase (ChE) inhibitory drugs is the mainstay for the treatment of Alzheimer's disease. Therefore, an extensive research has been continuing for the discovery of drug candidates as inhibitors of acetyl- and butyrylcholinesterase. In this study, two natural molecules, e. g. hyperforin and hyuganin C were tested in vitro for their AChE and BChE inhibitory activity. Both of the compounds were ineffective against AChE, whereas hyperforin (IC50 =141.60±3.39 µm) and hyuganin C (IC50 =38.86±1.69 µm) were found to be the highly active inhibitors of BChE as compared to galantamine (IC50 =46.58±0.91 µm) which was used as the reference. Then, these molecules were further proceeded to molecular docking experiments in order to establish their interactions at the active site of BChE. The molecular docking results indicated that both of them are able to block the access to key residues in the catalytic triad of the enzyme, while they complement some of the hydrophobic residues of the cavity, what is consistent with our in vitro data. While both compounds were predicted as mutagenic, only hyuganin C showed hepatotoxicity in in silico analysis. According to whole outcomes that we obtained, particularly hyuganin C besides hyperforin are the promising BChE inhibitors, which can be the promising compounds for AD therapy.


Assuntos
Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Cumarínicos/química , Floroglucinol/análogos & derivados , Terpenos/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Apiaceae/química , Sítios de Ligação , Butirilcolinesterase/química , Domínio Catalítico , Cumarínicos/isolamento & purificação , Simulação de Acoplamento Molecular , Floroglucinol/química , Extratos Vegetais/química , Relação Quantitativa Estrutura-Atividade , Termodinâmica
14.
Biomed Pharmacother ; 112: 108612, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30798142

RESUMO

Many food-derived phytochemicals and their derivatives represent a cornucopia of new anti-cancer compounds. Luteolin (3,4,5,7-tetrahydroxy flavone) is a flavonoid found in different plants such as vegetables, medicinal herbs, and fruits. It acts as an anticancer agent against various types of human malignancies such as lung, breast, glioblastoma, prostate, colon, and pancreatic cancers. It also blocks cancer development in vitro and in vivo by inhibition of proliferation of tumor cells, protection from carcinogenic stimuli, and activation of cell cycle arrest, and by inducing apoptosis through different signaling pathways. Luteolin can additionally reverse epithelial-mesenchymal transition (EMT) through a mechanism that involves cytoskeleton shrinkage, induction of the epithelial biomarker E-cadherin expression, and by down-regulation of the mesenchymal biomarkers N-cadherin, snail, and vimentin. Furthermore, luteolin increases levels of intracellular reactive oxygen species (ROS) by activation of lethal endoplasmic reticulum stress response and mitochondrial dysfunction in glioblastoma cells, and by activation of ER stress-associated proteins expressions, including phosphorylation of eIF2α, PERK, CHOP, ATF4, and cleaved-caspase 12. Accordingly, the present review article summarizes the progress of recent research on luteolin against several human cancers.


Assuntos
Antineoplásicos/uso terapêutico , Flavonoides/uso terapêutico , Luteolina/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Flavonoides/química , Humanos , Luteolina/química , Neoplasias/metabolismo , Neoplasias/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
15.
Phytomedicine ; 54: 259-264, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30668376

RESUMO

BACKGROUND: Medicinal plants are a proven source of drug-like small molecules with activity towards targets relevant for diseases of the central nervous system (CNS). Plant species of the Apiaceae family have to date yielded a number of neuroactive metabolites, such as coumarin derivatives with acetylcholinesterase inhibitory activity or anti-seizure activity. PURPOSE: To accelerate the discovery of neuroactive phytochemicals with potential as CNS drug leads, we sought to rapidly isolate furanocoumarins, primary constituents of the dichloromethane (DCM) extract of the fruits of Peucedanum alsaticum L. (Apiaceae), using high-performance counter-current chromatography (HPCCC) and to evaluate their neuroactivity using both in vitro and in vivo microscale bioassays based on cholinesterase ELISAs and zebrafish epilepsy models. RESEARCH METHODS AND PROCEDURE: In this study the DCM extract was subjected to HPCCC for the efficient separation (60 min) and isolation of furanocoumarins. Isolated compounds were identified with TOF-ESI-MS and NMR techniques and examined as inhibitors of AChE and BChE using ELISA microtiter assays. Anti-seizure properties of the extract and of the isolated compounds were evaluated using a zebrafish epilepsy model based on the GABAA antagonist pentylenetetrazol (PTZ), which induces increased locomotor activity and seizure-like behavior. RESULTS: The solvent system, composed of n-heptane, ethyl acetate, methanol and water (3:1:3:1, v/v/v/v), enabled the isolation of 2.63 mg lucidafuranocoumarin A (purity 98%) and 8.82 mg bergamottin (purity 96%) from 1.6 g crude DCM extract. The crude extract, at a concentration of 100 µg/ml, exhibited a weak inhibitory activity against acetylcholinesterase (AChE) (9.63 ±â€¯1.59%) and a moderate inhibitory activity against butyrylcholinestrase (BChE) (49.41 ±â€¯2.19%). Lucidafuranocoumarin A (100 µg/ml) was inactive against AChE but showed moderate inhibition towards BChE (40.66 ±â€¯1.25%). The DCM extract of P. alsaticum fruits (0.62-1.75 µg/ml) and bergamottin (2-10 µm) exhibited weak anti-seizure activity, while lucidafuranocoumarin A (10-16 µm) was found to significantly inhibit PTZ-induced seizures. The percentage of seizure inhibition for the isolated compounds, at their most bioactive concentration, was 26% for bergamottin and 69% for lucidafuranocoumarin A. CONCLUSION: Our findings underscore the utility of HPCCC for the rapid isolation of rare coumarin derivatives, and the potential of microscale in vivo bioassays based on zebrafish disease models for the rapid assessment of neuroactivity of these drug-like natural products.


Assuntos
Apiaceae/química , Cumarínicos/isolamento & purificação , Distribuição Contracorrente/métodos , Furocumarinas/isolamento & purificação , Animais , Anticonvulsivantes/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Cumarínicos/química , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Epilepsia/tratamento farmacológico , Furocumarinas/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Plantas Medicinais/química , Peixe-Zebra
16.
Curr Med Chem ; 26(18): 3260-3278, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30678614

RESUMO

Benzimidazole scaffold has been efficiently used for the design of various pharmacologically active molecules. Indeed, there are various benzimidazole drugs, available today, employed for the treatment of different diseases. Although there is no benzimidazole moiety containing a drug used in clinic today for the treatment of Alzheimer's Disease (AD), there have been many benzimidazole derivative compounds designed and synthesized to act on some of the validated and non-validated targets of AD. This paper aims to review the literature to describe these benzimidazole containing molecules designed to target some of the biochemical cascades shown to be involved in the development of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzimidazóis/química , Inibidores da Colinesterase , Aminoaciltransferases/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Descoberta de Drogas , Histamina/metabolismo , Antagonistas dos Receptores Histamínicos/química , Humanos
17.
Pharmacol Res ; 141: 466-480, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30639373

RESUMO

The Hedgehog pathway is essential for embryonic development but also for tissue and organ homeostasis in adult organisms. Activation of this pathway leads to the expression of target genes involved in proliferation, angiogenesis and stem cell self-renewal. Moreover, abnormal persistence of Hedgehog signaling is directly involved in a wide range of human cancers. Development of novel strategies targeting the Hedgehog pathway has become a subject of increased interest in anticancer therapy. These data are sustained by pre-clinical studies demonstrating that Hedgehog pathway inhibitors could represent an effective strategy against a heterogeneous panel of malignancies. Limited activity in other tumor types could be explained by the existence of crosstalk between the Hedgehog pathway and other signaling pathways that can compensate for its function. This review describes the Hedgehog pathway in detail, with its physiological roles during embryogenesis and adult tissues, and summarizing the preclinical evidence on its inhibition, the crosstalk between Hedgehog and other cancer-related pathways and finally the potential therapeutic effects of emerging compounds.


Assuntos
Antineoplásicos/farmacologia , Proteínas Hedgehog/metabolismo , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Receptores Notch/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo
18.
Mini Rev Med Chem ; 19(8): 688-705, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30387392

RESUMO

BACKGROUND: Since deficit of acetylcholine has been evidenced in the Alzheimer's disease (AD) patients, cholinesterase inhibitors are currently the most specified drug category for the remediation of AD. METHOD: In the present study, 16 compounds (1-16) with dicarbonyl skeletons have been synthesized and tested for their inhibitory potential in vitro against AChE and BChE using ELISA microtiter plate assays at 100 µg/mL. Since metal accumulation is related to AD, the compounds were also tested for their metal-chelation capacity. RESULTS AND CONCLUSION: All the investigated dicarbonyl compounds exerted none or lower than 30% inhibition against both cholinesterases, whereas compounds 2, 8 and 11 showed 37, 42, 41% of inhibition towards BChE, being the most active. The highest metal-chelation capacity was observed with compound 8 (53.58 ± 2.06%). POM and DFT analyses are in good harmonization with experimental data.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/química , Inibidores da Colinesterase/uso terapêutico , Desenho de Fármacos , Acetilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/efeitos dos fármacos , Teoria da Densidade Funcional , Ensaio de Imunoadsorção Enzimática , Humanos , Modelos Moleculares
19.
Bioorg Chem ; 84: 355-362, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30530106

RESUMO

Coumarins of synthetic or natural origins are an important chemical class exerting diverse pharmacological activities. In the present study, 26 novel O-alkylcoumarin derivatives were synthesized and have been tested at 100 µM for their in vitro inhibitory potential against acetylcholinesterase (AChE) and butyrlcholinesterase (BChE) targets which are the key enzymes playing role in the pathogenesis of Alzheimer's disease. Among the tested coumarins, none of them could inhibit AChE, whereas 12 of them exerted a marked and selective inhibition against BChE as compared to the reference (galanthamine, IC50 = 46.58 ±â€¯0.91 µM). In fact, 10 of the active coumarins showed higher inhibition (IC50 = 7.01 ±â€¯0.28 µM - 43.31 ±â€¯3.63 µM) than that of galanthamine. The most active ones were revealed to be 7-styryloxycoumarin (IC50 = 7.01 ±â€¯0.28 µM) and 7-isopentenyloxy-4-methylcoumarin (IC50 = 8.18 ±â€¯0.74 µM). In addition to the in vitro tests, MetaCore/MetaDrug binary QSAR models and docking simulations were applied to evaluate the active compounds by ligand-based and target-driven approaches. The predicted pharmacokinetic profiles of the compounds suggested that the compounds reveal lipophilic character and permeate blood brain barrier (BBB) and the ADME models predict higher human serum protein binding percentages (>50%) for the compounds. The calculated docking scores indicated that the coumarins showing remarkable BChE inhibition possessed favorable free binding energies in interacting with the ligand-binding domain of the target. Therefore, our results disclose that O-alkylcoumarins are promising selective inhibitors of cholinesterase enzymes, particularly BChE in our case, which definitely deserve further studies.


Assuntos
Acetilcolinesterase/química , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Cumarínicos/química , Acetilcolinesterase/metabolismo , Sítios de Ligação , Barreira Hematoencefálica , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/metabolismo , Cumarínicos/metabolismo , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade
20.
Phytomedicine ; 42: 25-33, 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29655693

RESUMO

BACKGROUND: Many natural products, particularly phenolic compounds, have been reported to have a strong inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the key enzymes in the pathology of Alzheimer's disease (AD). HYPOTHESIS: Therefore, we hypothesized that some xanthahumol, naringenin, and acyl phloroglucinol derivatives (1-14) isolated from Humulus lupulus L. (hops) may have an inhibitory potential against AChE and BChE. METHODS: Inhibitory potential of compounds 1-14 were tested against AChE and BChE using ELISA microtiter assay. Different molecular docking simulations, including IFD and GOLD protocols, were implemented to verify the interactions between the ligands and the active site amino acids and also their binding energies inside the catalytic crevices of AChE and BChE. ADME/Tox analysis were used to determine pharmacological activities of the compounds. RESULTS: Among them, 3­hydroxy­xanthohumol (IC50 = 51.25 ±â€¯0.88 µM) and xanthohumol (IC50 = 71.34 ±â€¯2.09 µM), displayed a moderate AChE inhibition in comparison to that of the reference (galanthamine, IC50 = 2.52 ±â€¯0.15 µM). In addition to 3­hydroxy­xanthohumol (IC50 = 63.07 ±â€¯3.76 µM) and xanthohumol (IC50 = 32.67 ±â€¯2.82 µM), 8-prenylnaringenin (IC50 = 86.58 ±â€¯3.74 µM) also showed micromolar-range inhibition against BChE (galanthamine, IC50 = 46.58 ±â€¯0.91 µM). Rest of the compounds were found to be either inactive or having inhibition below 50%. Prediction of pharmacokinetic studies suggested that all the ligands revealed acceptable drug-like profiles. Docking simulations demonstrate not only the prediction of ligand binding energies of the compounds inside the catalytic domains of the targets, but also highlight the critical amino acids contributing to stabilizations of the ligands. CONCLUSION: Our findings revealed that xanthohumol in particular could be considered as lead molecule to explore new cholinesterase inhibitors for AD.


Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Flavanonas/farmacologia , Flavonoides/farmacologia , Humulus/química , Propiofenonas/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Flavanonas/química , Flavonoides/química , Humanos , Simulação de Acoplamento Molecular , Floroglucinol/química , Propiofenonas/química , Relação Estrutura-Atividade
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