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1.
Molecules ; 26(21)2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34771067

RESUMO

Gastrointestinal tract infection caused by Helicobacter pylori is a common virulent disease found worldwide, and the infection rate is much higher in developing countries than in developed ones. In the pathogenesis of H. pylori in the gastrointestinal tract, the secretion of the urease enzyme plays a major role. Therefore, inhibition of urease is a better approach against H. pylori infection. In the present study, a series of syn and anti isomers of N-substituted indole-3-carbaldehyde oxime derivatives was synthesized via Schiff base reaction of appropriate carbaldehyde derivatives with hydroxylamine hydrochloride. The in vitro urease inhibitory activities of those derivatives were evaluated against that of Macrotyloma uniflorum urease using the modified Berthelot reaction. Out of the tested compounds, compound 8 (IC50 = 0.0516 ± 0.0035 mM) and compound 9 (IC50 = 0.0345 ± 0.0008 mM) were identified as the derivatives with potent urease inhibitory activity with compared to thiourea (IC50 = 0.2387 ± 0.0048 mM). Additionally, in silico studies for all oxime compounds were performed to investigate the binding interactions with the active site of the urease enzyme compared to thiourea. Furthermore, the drug-likeness of the synthesized oxime compounds was also predicted.


Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Helicobacter pylori/efeitos dos fármacos , Indóis/farmacologia , Oximas/farmacologia , Urease/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Helicobacter pylori/enzimologia , Indóis/síntese química , Indóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oximas/síntese química , Oximas/química , Estereoisomerismo , Urease/metabolismo
2.
Molecules ; 26(21)2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34770855

RESUMO

In the last two years, nucleosides analogues, a class of well-established bioactive compounds, have been the subject of renewed interest from the scientific community thanks to their antiviral activity. The COVID-19 global pandemic, indeed, spread light on the antiviral drug Remdesivir, an adenine C-nucleoside analogue. This new attention of the medical community on Remdesivir prompts the medicinal chemists to investigate once again C-nucleosides. One of the essential building blocks to synthetize these compounds is the D-(+)-ribono-1,4-lactone, but some mechanistic aspects linked to the use of different carbohydrate protecting groups remain unclear. Here, we present our investigations on the use of benzylidene as a ribonolactone protecting group useful in the synthesis of C-purine nucleosides analogues. A detailed 1D and 2D NMR structural study of the obtained compounds under different reaction conditions is presented. In addition, a molecular modeling study at the B3LYP/6-31G* level of theory with the SM8 solvation model for CHCl3 and DMSO to support the obtained results is used. This study allows for clarifying mechanistic aspects as the side reactions and structural rearrangements liked to the use of the benzylidene protecting group.


Assuntos
Compostos de Benzilideno/química , Lactonas/química , Nucleosídeos/síntese química , Ribose/análogos & derivados , Adenina/análogos & derivados , Antivirais/química , COVID-19/tratamento farmacológico , COVID-19/prevenção & controle , Humanos , Lactonas/síntese química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Nucleosídeos/metabolismo , Nucleosídeos de Purina , Ribose/síntese química , Ribose/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Estereoisomerismo
3.
Molecules ; 26(19)2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34641289

RESUMO

The dihydropyranoindole structures were previously identified as promising scaffolds for improving the anti-cancer activity of histone deacetylase inhibitors. This work describes the synthesis of related furoindoles and their ability to synergize with suberoylanilide hydroxamic acid (SAHA) against neuroblastoma and breast cancer cells. The nucleophilic substitution of hydroxyindole methyl esters with α-haloketones yielded the corresponding arylether ketones, which were subsequently cyclized to tricyclic and tetracyclic furoindoles. The furoindoles showed promising individual cytotoxic efficiency against breast cancer cells, as well as decent SAHA enhancement against cancer cells in select cases. Interestingly, the best IC50 value was obtained with the non-cyclized intermediate.


Assuntos
Neoplasias da Mama/enzimologia , Inibidores de Histona Desacetilases/farmacologia , Cetonas/síntese química , Neuroblastoma/enzimologia , Vorinostat/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Cetonas/química , Cetonas/farmacologia , Células MCF-7 , Neuroblastoma/tratamento farmacológico
4.
Molecules ; 26(19)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34641525

RESUMO

2,5-diketopiperazines (DKPs) are cyclic dipeptides ubiquitously found in nature. In particular, cyclo(Phe-Pro), cyclo(Leu-Pro), and cyclo(Val-Pro) are frequently detected in many microbial cultures. Each of these DKPs has four possible stereoisomers due to the presence of two chirality centers. However, absolute configurations of natural DKPs are often ambiguous due to the lack of a simple, sensitive, and reproducible method for stereochemical assignment. This is an important problem because stereochemistry is a key determinant of biological activity. Here, we report a synthetic DKP library containing all stereoisomers of cyclo(Phe-Pro), cyclo(Leu-Pro), and cyclo(Val-Pro). The library was subjected to spectroscopic characterization using mass spectrometry, NMR, and electronic circular dichroism (ECD). It turned out that ECD can clearly differentiate DKP stereoisomers. Thus, our ECD dataset can serve as a reference for unambiguous stereochemical assignment of cyclo(Phe-Pro), cyclo(Leu-Pro), and cyclo(Val-Pro) samples from natural sources. The DKP library was also subjected to a biological screening using assays for E. coli growth and biofilm formation, which revealed distinct biological effects of cyclo(D-Phe-L-Pro).


Assuntos
Dipeptídeos/química , Peptídeos Cíclicos/química , Dicroísmo Circular , Dicetopiperazinas/química , Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Escherichia coli/efeitos dos fármacos , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
5.
Molecules ; 26(19)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34641526

RESUMO

A new series of benzotriazole moiety bearing substituted imidazol-2-thiones at N1 has been designed, synthesized and evaluated for in vitro anticancer activity against the different cancer cell lines MCF-7(breast cancer), HL-60 (Human promyelocytic leukemia), and HCT-116 (colon cancer). Most of the benzotriazole analogues exhibited promising antiproliferative activity against tested cancer cell lines. Among all the synthesized compounds, BI9 showed potent activity against the cancer cell lines such as MCF-7, HL-60 and HCT-116 with IC50 3.57, 0.40 and 2.63 µM, respectively. Compound BI9 was taken up for elaborate biological studies and the HL-60 cells in the cell cycle were arrested in G2/M phase. Compound BI9 showed remarkable inhibition of tubulin polymerization with the colchicine binding site of tubulin. In addition, compound BI9 promoted apoptosis by regulating the expression of pro-apoptotic protein BAX and anti-apoptotic proteins Bcl-2. These results provide guidance for further rational development of potent tubulin polymerization inhibitors for the treatment of cancer.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Tionas/química , Triazóis/química , Triazóis/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Colchicina/metabolismo , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células HL-60 , Células Endoteliais da Veia Umbilical Humana , Humanos , Células MCF-7 , Triazóis/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
6.
Molecules ; 26(19)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34641533

RESUMO

Photodynamic therapy (PDT) represents an effective treatment to cure cancer. The targeting ability of the photosensitizer is of utmost importance. Photosensitizers that discriminate cancer cells can avoid the killing of normal cells and improve PDT efficacy. However, the design and synthesis of photosensitizers conjugated with a recognition unit of cancer cell markers is complex and may not effectively target cancer. Considering that the total RNA content in cancer cells is commonly higher than in normal cells, this study has developed the photosensitizer QICY with RNA-targeting abilities for the discrimination of cancer cells. QICY was specifically located in cancer cells rather than normal cells due to their stronger electrostatic interactions with RNA, thereby further improving the PDT effects on the cancer cells. After intravenous injection into mice bearing a xenograft tumor, QICY accumulated into the tumor location through the enhanced permeability and retention effect, automatically targeted cancer cells under the control of RNA, and inhibited tumor growth under 630 nm laser irradiation without obvious side effects. This intelligent photosensitizer with RNA-targeting ability not only simplifies the design and synthesis of cancer-cell-targeting photosensitizers but also paves the way for the further development of highly efficient PDTs.


Assuntos
Neoplasias/patologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , RNA/química , Animais , Células COS , Linhagem Celular Tumoral , Chlorocebus aethiops , Feminino , Humanos , Injeções Intravenosas , Terapia com Luz de Baixa Intensidade , Células MCF-7 , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/síntese química , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Chem Pharm Bull (Tokyo) ; 69(10): 1017-1028, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34602570

RESUMO

Celecoxib, a nonsteroidal anti-inflammatory drug, has been reported to have antitumor and antimetastatic activities, and it has potential for application in cancer treatments. The expression of matrix metalloproteinase (MMP)-2/9 is strongly correlated with cancer malignancy, and inhibition of these MMPs is believed to be effective in improving the antitumor and antimetastatic effects of drugs. We have previously revealed that UTX-121, which converted the sulfonamide of celecoxib to methyl ester, has more potent MMP-2/9 inhibitory activity than celecoxib. Based on these findings, we identified compounds with improved MMP inhibitory activity through a structure-activity relationship (SAR) study, using UTX-121 as a lead compound. Among them, compounds 9c and 10c, in which the methyl group of the p-tolyl group was substituted for Cl or F, showed significantly higher antitumor activity than UTX-121, and suppressed the expression of MMP-2/9 and activation of pro MMP-2. Our findings suggest that compounds 9c and 10c may be potent lead compounds for the development of more effective antitumor drugs targeting MMP.


Assuntos
Antineoplásicos/farmacologia , Desenvolvimento de Medicamentos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Inibidores de Metaloproteinases de Matriz/síntese química , Inibidores de Metaloproteinases de Matriz/química , Estrutura Molecular , Relação Estrutura-Atividade
9.
Chem Pharm Bull (Tokyo) ; 69(10): 1029-1033, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34602571

RESUMO

In a previous study, we found that the thiophene carboxamide solamin analog, which is a mono-tetrahydrofuran annonaceous acetogenin, showed potent antitumor activity through the inhibition of mitochondrial complex I. In this study, we synthesized analogs with short alkyl chains instead of the n-dodecyl group in the tail part. We evaluated their growth inhibitory activities against human cancer cell lines. We found that the alkyl chain in the tail part plays an essential role in their activity.


Assuntos
Acetogeninas/farmacologia , Antineoplásicos/farmacologia , Acetogeninas/síntese química , Acetogeninas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Conformação Molecular , Relação Estrutura-Atividade
10.
Molecules ; 26(20)2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34684709

RESUMO

We performed an in silico, in vitro, and in vivo assessment of a potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (compound 1) as a potential prodrug for cognitive function improvement in ischemic brain injury. Using in silico methods, we predicted the pharmacological efficacy and possible safety in rat models. In addition, in silico data showed neuroprotective features of compound 1, which were further supported by in vitro experiments in a glutamate excitotoxicity-induced model in newborn rat cortical neuron cultures. Next, we checked whether compound 1 is capable of crossing the blood-brain barrier in intact and ischemic animals. Compound 1 improved animal behavior both in intact and ischemic rats and, even though the concentration in intact brains was low, we still observed a significant anxiety reduction and activity escalation. We used molecular docking and molecular dynamics to support our hypothesis that compound 1 could affect the AMPA receptor function. In a rat model of acute focal cerebral ischemia, we studied the effects of compound 1 on the behavior and neurological deficit. An in vivo experiment demonstrated that compound 1 significantly reduced the neurological deficit and improved neurological symptom regression, exploratory behavior, and anxiety. Thus, here, for the first time, we show that compound 1 can be considered as an agent for restoring cognitive functions.


Assuntos
AVC Isquêmico/tratamento farmacológico , Pirrolidinas/química , Pirrolidinas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Isquemia Encefálica , Cognição/efeitos dos fármacos , Cognição/fisiologia , Modelos Animais de Doenças , Ácido Glutâmico/farmacologia , Infarto da Artéria Cerebral Média , AVC Isquêmico/fisiopatologia , Masculino , Simulação de Acoplamento Molecular , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Cultura Primária de Células , Pirrolidinas/síntese química , Ratos , Ratos Wistar , Acidente Vascular Cerebral
11.
Molecules ; 26(19)2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34641628

RESUMO

This work aims to assess the recently established anti-inflammatory and antioxidant potential of melatonin of plant origin extracted from the plant matrix as a phytomelatonin complex (PHT-MLT), and compare its activity with synthetic melatonin (SNT-MLT) when used on its own or with vitamin C. For this purpose, a COX-2 enzyme inhibitory activity test, an antiradical activity in vitro and on cell lines assays, was performed on both PHT-MLT and SNT-MLT products. COX-2 inhibitory activity of PHT-MLT was found to be ca. 6.5 times stronger than that of SNT-MLT (43.3% and 6.7% enzyme inhibition, equivalent to the activity of acetylsalicylic acid in conc. 30.3 ± 0.2 and 12.0 ± 0.3 mg/mL, respectively). Higher antiradical potential and COX-2 inhibitory properties of PHT-MLT could be explained by the presence of additional naturally occurring constituents in alfalfa, chlorella, and rice, which were clearly visible on the HPLC-ESI-QTOF-MS fingerprint. The antiradical properties of PHT-MLT determined in the DPPH test (IC50 of 21.6 ± 1 mg of powder/mL) were found to originate from the presence of other metabolites in the 50% EtOH extract while SNT-MLT was found to be inactive under the applied testing conditions. However, the antioxidant studies on HaCaT keratinocytes stimulated with H2O2 revealed a noticeable activity in all samples. The presence of PHT-MLT (12.5, 25 and 50 µg/mL) and vitamin C (12.5, 25 and 50 µg/mL) in the H2O2-pretreated HaCaT keratinocytes protected the cells from generating reactive oxygen species. This observation confirms that MLT-containing samples affect the intracellular production of enzymes and neutralize the free radicals. Presented results indicated that MLT-containing products in combination with Vitamin C dosage are worth to be considered as a preventive alternative in the therapy of various diseases in the etiopathogenesis, of which radical and inflammatory mechanisms play an important role.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Ciclo-Oxigenase 2/metabolismo , Queratinócitos/citologia , Melatonina/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Antioxidantes/síntese química , Antioxidantes/química , Ácido Ascórbico/farmacologia , Linhagem Celular , Regulação para Baixo , Sinergismo Farmacológico , Radicais Livres/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/efeitos adversos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Melatonina/síntese química , Melatonina/química , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia
12.
Molecules ; 26(19)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34641508

RESUMO

A concise and efficient synthesis of the proposed structure of aaptoline A, a 7,8-dihydroxyquinoline derived from a marine sponge, was accomplished in seven steps with a 52% overall yield. A key feature of the synthesis is the high-yielding Ag(I)-catalyzed cycloisomerization of the N-propargylaniline precursor to afford the quinoline carboxylate skeleton from acid-labile methyl aminobenzoate. However, the spectral data of the synthesized aaptoline A were not consistent with those of previous studies. The structure of the synthesized aaptoline A was confirmed by combined 2D NMR analysis. Additional studies on the bioactivity of the synthesized aaptoline A revealed that it has the ability to protect dopaminergic neurons against MPP+-induced neurotoxicity in C. elegans. In addition, impaired food-sensing ability and travel distance capability in C. elegans were significantly ameliorated by aaptoline A treatment, suggesting that aaptoline A can protect dopaminergic neurons both morphologically and functionally.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Hidroxiquinolinas/química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , 1-Metil-4-fenilpiridínio/toxicidade , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Neurônios Dopaminérgicos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/síntese química , Poríferos/química
13.
Molecules ; 26(19)2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34641548

RESUMO

A small series of nitro group-bearing enamides was designed, synthesized (NEA1-NEA5), and evaluated for their inhibitory profiles of monoamine oxidases (MAOs) and ß-site amyloid precursor protein cleaving enzyme 1 (ß-secretase, BACE1). Compounds NEA3 and NEA1 exhibited a more potent MAO-B inhibition (IC50 value = 0.0092 and 0.016 µM, respectively) than the standards (IC50 value = 0.11 and 0.14 µM, respectively, for lazabemide and pargyline). Moreover, NEA3 and NEA1 showed greater selectivity index (SI) values toward MAO-B over MAO-A (SI of >1652.2 and >2500.0, respectively). The inhibition and kinetics studies suggested that NEA3 and NEA1 are reversible and competitive inhibitors with Ki values of 0.013 ± 0.005 and 0.0049 ± 0.0002 µM, respectively, for MAO-B. In addition, both NEA3 and NEA1 showed efficient BACE1 inhibitions with IC50 values of 8.02 ± 0.13 and 8.21 ± 0.03 µM better than the standard quercetin value (13.40 ± 0.04 µM). The parallel artificial membrane permeability assay (PAMPA) method demonstrated that all the synthesized derivatives can cross the blood-brain barrier (BBB) successfully. Docking analyses were performed by employing an induced-fit docking approach in the GLIDE module of Schrodinger, and the results were in agreement with their in vitro inhibitory activities. The present study resulted in the discovery of potent dual inhibitors toward MAO-B and BACE1, and these lead compounds can be fruitfully explored for the generation of newer, clinically active agents for the treatment of neurodegenerative disorders.


Assuntos
Amidas/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores da Monoaminoxidase/química , Monoaminoxidase/química , Inibidores de Proteases/química , Amidas/síntese química , Amidas/metabolismo , Barreira Hematoencefálica/metabolismo , Membranas Artificiais , Estrutura Molecular , Inibidores da Monoaminoxidase/metabolismo , Inibidores de Proteases/metabolismo
14.
Molecules ; 26(19)2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34641551

RESUMO

Tomatidine has recently generated a lot of interest amongst the pharmacology, medicine, and biology fields of study, especially for its newfound activity as an antibiotic agent capable of targeting multiple strains of bacteria. In the light of its low natural abundance and high cost, an efficient and scalable multi-gram synthesis of tomatidine has been developed. This synthesis uses a Suzuki-Miyaura-type coupling reaction as a key step to graft an enantiopure F-ring side chain to the steroidal scaffold of the natural product, which was accessible from low-cost and commercially available diosgenin. A Lewis acid-mediated spiroketal opening followed by an azide substitution and reduction sequence is employed to generate the spiroaminoketal motif of the natural product. Overall, this synthesis produced 5.2 g in a single pass in 15 total steps and 15.2% yield using a methodology that is atom economical, scalable, and requires no flash chromatography purifications.


Assuntos
Antibacterianos/síntese química , Produtos Biológicos/síntese química , Tomatina/análogos & derivados , Antibacterianos/química , Produtos Biológicos/química , Estrutura Molecular , Tomatina/síntese química , Tomatina/química
15.
Nat Chem Biol ; 17(11): 1168-1177, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34675420

RESUMO

The pace of progress in biomedical research directly depends on techniques that enable the quantitative interrogation of interactions between proteins and other biopolymers, or with their small-molecule ligands. Time-resolved Förster resonance energy transfer (TR-FRET) assay platforms offer high sensitivity and specificity. However, the paucity of accessible and biocompatible luminescent lanthanide complexes, which are essential reagents for TR-FRET-based approaches, and their poor cellular permeability have limited broader adaptation of TR-FRET beyond homogeneous and extracellular assay applications. Here, we report the development of CoraFluors, a new class of macrotricyclic terbium complexes, which are synthetically readily accessible, stable in biological media and exhibit photophysical and physicochemical properties that are desirable for biological studies. We validate the performance of CoraFluors in cell-free systems, identify cell-permeable analogs and demonstrate their utility in the quantitative domain-selective characterization of Keap1 ligands, as well as in isoform-selective target engagement profiling of HDAC1 inhibitors in live cells.


Assuntos
Complexos de Coordenação/química , Transferência Ressonante de Energia de Fluorescência , Corantes Fluorescentes/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Células HEK293 , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/antagonistas & inibidores , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Estrutura Molecular
16.
Molecules ; 26(19)2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34641566

RESUMO

Antimicrobial resistance was one of the top priorities for global public health before the start of the 2019 coronavirus pandemic (COVID-19). Moreover, in this changing medical landscape due to COVID-19, finding new organic structures with antimicrobial and antiviral properties is a priority in current research. The Biginelli synthesis that mediates the production of pyrimidine compounds has been intensively studied in recent decades, especially due to the therapeutic properties of the resulting compounds, such as calcium channel blockers, anticancer, antiviral, antimicrobial, anti-inflammatory or antioxidant compounds. In this review we aim to review the Biginelli syntheses reported recently in the literature that mediates the synthesis of antimicrobial compounds, the spectrum of their medicinal properties, and the structure-activity relationship in the studied compounds.


Assuntos
Anti-Infecciosos/síntese química , Pirimidinas/síntese química , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Técnicas de Química Sintética/métodos , Descoberta de Drogas , Resistência Microbiana a Medicamentos , Humanos , Modelos Moleculares , Pirimidinas/química , Pirimidinas/farmacologia , SARS-CoV-2/efeitos dos fármacos
17.
Nat Commun ; 12(1): 5808, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34608152

RESUMO

The nucleotides diadenosine triphosphate (Ap3A) and diadenosine tetraphosphate (Ap4A) are formed in prokaryotic and eukaryotic cells. Since their concentrations increase significantly upon cellular stress, they are considered to be alarmones triggering stress adaptive processes. However, their cellular roles remain elusive. To elucidate the proteome-wide interactome of Ap3A and Ap4A and thereby gain insights into their cellular roles, we herein report the development of photoaffinity-labeling probes and their employment in chemical proteomics. We demonstrate that the identified ApnA interactors are involved in many fundamental cellular processes including carboxylic acid and nucleotide metabolism, gene expression, various regulatory processes and cellular response mechanisms and only around half of them are known nucleotide interactors. Our results highlight common functions of these ApnAs across the domains of life, but also identify those that are different for Ap3A or Ap4A. This study provides a rich source for further functional studies of these nucleotides and depicts useful tools for characterization of their regulatory mechanisms in cells.


Assuntos
Fosfatos de Dinucleosídeos/metabolismo , Proteômica , Trifosfato de Adenosina/metabolismo , Fosfatos de Dinucleosídeos/química , Endorribonucleases/metabolismo , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Células HEK293 , Humanos , L-Lactato Desidrogenase/metabolismo , Fosfoglicerato Quinase/metabolismo , Marcadores de Fotoafinidade/síntese química , Marcadores de Fotoafinidade/química , Marcadores de Fotoafinidade/metabolismo , Ligação Proteica , Enzimas Ativadoras de Ubiquitina/metabolismo
18.
Chem Biol Interact ; 349: 109678, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34600868

RESUMO

The present study describes the synthesis of pyridinium derivatives of betulin, including new 4-methyl- and 3,5-methyl-pyridinium analogs, their effect on artificial membrane systems (liposomes), cytotoxicity in models of prokaryotic (E. coli K-12 MG1655) and eukaryotic cells (rat thymocytes), as well as their effect on the functioning of membrane systems of rat liver mitochondria. We have shown that the presence of methyl groups in the pyridine ring of compounds determines the ability of the derivatives to effectively permeabilize the artificial membrane of lecithin liposomes for the fluorescent probe sulforhodamine B. The 4-methyl- and 3,5-methyl-pyridinium analogs inhibit the growth of E. coli K-12 MG1655 and, at the same time, did not have a cytotoxic effect on rat thymocytes. However, in the latter case, we noted a decrease in the mitochondrial potential of cells. The studied compounds reduced the functional activity of mitochondria, suppressing the activity of complexes of the respiratory chain and reducing the membrane potential. In addition, compounds containing methyl groups in the p- and m-positions of the pyridine ring were also able to permeabilize the inner membrane of mitochondria, causing them to swell. In this case, the most lipophilic compound containing two methyl substituents at the m-position of the pyridine fragment was most effective and had a protonophore effect on mitochondria. The paper discusses the dependence of the membranotropic and biological actions of the quaternized pyridine derivatives of betulin on their structure and lipophilicity.


Assuntos
Lipossomos , Mitocôndrias Hepáticas/metabolismo , Piridinas/química , Triterpenos/química , Análise Espectral/métodos , Triterpenos/síntese química
19.
Int J Mol Sci ; 22(19)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34638791

RESUMO

Ruthenium complexes are developed as substitutes for platinum complexes to be used in the chemotherapy of hematological and gynecological malignancies, such as ovarian cancer. We synthesized and screened 14 ruthenium half-sandwich complexes with bidentate monosaccharide ligands in ovarian cancer cell models. Four complexes were cytostatic, but not cytotoxic on A2780 and ID8 cells. The IC50 values were in the low micromolar range (the best being 0.87 µM) and were similar to or lower than those of the clinically available platinum complexes. The active complexes were cytostatic in cell models of glioblastoma, breast cancer, and pancreatic adenocarcinoma, while they were not cytostatic on non-transformed human skin fibroblasts. The bioactive ruthenium complexes showed cooperative binding to yet unidentified cellular target(s), and their activity was dependent on reactive oxygen species production. Large hydrophobic protective groups on the hydroxyl groups of the sugar moiety were needed for biological activity. The cytostatic activity of the ruthenium complexes was dependent on reactive species production. Rucaparib, a PARP inhibitor, potentiated the effects of ruthenium complexes.


Assuntos
Neoplasias/tratamento farmacológico , Compostos de Rutênio/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Complexos de Coordenação , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Espécies Reativas de Oxigênio , Compostos de Rutênio/síntese química , Compostos de Rutênio/química , Compostos de Rutênio/uso terapêutico
20.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638990

RESUMO

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with glucose intolerance and insulin resistance, often culminating in Type 2 Diabetes (T2D). Importantly, our team has recently shown that the TNF superfamily (TNFSF) member protein, TNFSF14, has been reported to protect against high fat diet induced obesity and pre-diabetes. We hypothesized that mimics of TNFSF14 may therefore be valuable as anti-diabetic agents. In this study, we use in silico approaches to identify key regions of TNFSF14 responsible for binding to the Herpes virus entry mediator and Lymphotoxin ß receptor. In vitro evaluation of a selection of optimised peptides identified six potentially therapeutic TNFSF14 peptides. We report that these peptides increased insulin and fatty acid oxidation signalling in skeletal muscle cells. We then selected one of these promising peptides to determine the efficacy to promote metabolic benefits in vivo. Importantly, the TNFSF14 peptide 7 reduced high fat diet-induced glucose intolerance, insulin resistance and hyperinsulinemia in a mouse model of obesity. In addition, we highlight that the TNFSF14 peptide 7 resulted in a marked reduction in liver steatosis and a concomitant increase in phospho-AMPK signalling. We conclude that TNFSF14-derived molecules positively regulate glucose homeostasis and lipid metabolism and may therefore open a completely novel therapeutic pathway for treating obesity and T2D.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Obesidade/complicações , Obesidade/tratamento farmacológico , Peptídeos/administração & dosagem , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/administração & dosagem , Animais , Sítios de Ligação , Glicemia/metabolismo , Simulação por Computador , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Intolerância à Glucose/tratamento farmacológico , Intolerância à Glucose/metabolismo , Homeostase/efeitos dos fármacos , Hiperinsulinismo/tratamento farmacológico , Hiperinsulinismo/metabolismo , Hipoglicemiantes/síntese química , Resistência à Insulina , Receptor beta de Linfotoxina/química , Receptor beta de Linfotoxina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/metabolismo , Peptídeos/síntese química , Membro 14 de Receptores do Fator de Necrose Tumoral/química , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/química , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo
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