RESUMO
The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays an important role in viral replication and transcription and received great attention as a vital target for drug/peptide development. Therapeutic agents such as small-molecule drugs or peptides that interact with the Cys-His present in the catalytic site of Mpro are an efficient way to inhibit the protease. Although several emergency-approved vaccines showed good efficacy and drastically dropped the infection rate, evolving variants are still infecting and killing millions of people globally. While a small-molecule drug (Paxlovid) received emergency approval, small-molecule drugs have low target specificity and higher toxicity. Besides small-molecule drugs, peptide therapeutics are thus gaining increasing popularity as they are easy to synthesize and highly selective and have limited side effects. In this study, we investigated the therapeutic value of 67 peptides targeting Mpro using molecular docking. Subsequently, molecular dynamics (MD) simulations were implemented on eight protein-peptide complexes to obtain molecular-level information on the interaction between these peptides and the Mpro active site, which revealed that temporin L, indolicidin, and lymphocytic choriomeningitis virus (LCMV) GP1 are the best candidates in terms of stability, interaction, and structural compactness. These peptides were synthesized using the solid-phase peptide synthesis protocol, purified by reversed-phase high-performance liquid chromatography (RP-HPLC), and authenticated by mass spectrometry (MS). The in vitro fluorometric Mpro activity assay was used to validate the computational results, where temporin L and indolicidin were observed to be very active against SARS-CoV-2 Mpro with IC50 values of 38.80 and 87.23 µM, respectively. A liquid chromatography-MS (LC-MS) assay was developed, and the IC50 value of temporin L was measured at 23.8 µM. The solution-state nuclear magnetic resonance (NMR) structure of temporin L was determined in the absence of sodium dodecyl sulfate (SDS) micelles and was compared to previous temporin structures. This combined investigation provides critical insights and assists us to further develop peptide inhibitors of SARS-CoV-2 Mpro through structural guided investigation.
Assuntos
COVID-19 , Peptídeo Hidrolases , Humanos , SARS-CoV-2 , Simulação de Acoplamento Molecular , Antivirais/farmacologia , Inibidores de Proteases/farmacologia , Simulação de Dinâmica MolecularRESUMO
Acute lymphoblastic leukaemia is currently treated with bacterial L-asparaginase; however, its side effects raise the need for the development of improved and efficient novel enzymes. Previously, we obtained low anti-asparaginase antibody production and high serum enzyme half-life in mice treated with the P40S/S206C mutant; however, its specific activity was significantly reduced. Thus, our aim was to test single mutants, S206C and P40S, through in vitro and in vivo assays. Our results showed that the drop in specific activity was caused by P40S substitution. In addition, our single mutants were highly stable in biological environment simulation, unlike the double-mutant P40S/S206C. The in vitro cell viability assay demonstrated that mutant enzymes have a higher cytotoxic effect than WT on T-cell-derived ALL and on some solid cancer cell lines. The in vivo assays were performed in mice to identify toxicological effects, to evoke immunological responses and to study the enzymes' pharmacokinetics. From these tests, none of the enzymes was toxic; however, S206C elicited lower physiological changes and immune/allergenic responses. In relation to the pharmacokinetic profile, S206C exhibited twofold higher activity than WT and P40S two hours after injection. In conclusion, we present bioengineered E. coli asparaginases with high specific enzyme activity and fewer side effects.
Assuntos
Asparaginase , Escherichia coli , Animais , Asparaginase/genética , Asparaginase/metabolismo , Escherichia coli/genética , Camundongos , Humanos , Mutação , Linhagem Celular Tumoral , Feminino , Sobrevivência Celular/efeitos dos fármacos , Inflamação/genéticaRESUMO
Glycosmis cyanocarpa (Blume) Spreng is a plant in the Rutaceae family and a species in the Glycosmis genus that has received little attention. Therefore, this research aimed to report the chemical and biological analysis of Glycosmis cyanocarpa (Blume) Spreng. The chemical analysis involved the isolation and characterization of secondary metabolites through an extensive chromatographic study, and the structures of these metabolites were elucidated on the basis of a detailed analysis of NMR and HRESIMS spectroscopic data and by comparison with those of related compounds reported in the literature. Different partitions of the crude ethyl acetate (EtOAc) extract were evaluated for antioxidant, cytotoxic, and thrombolytic potentials. In chemical analysis, one new phenyl acetate derivative, namely 3,7,11,15-tetramethylhexadec-2-en-1-yl 2-phenylacetate (1), along with four known compounds N-methyl-3-(methylthio)-N-(2-phenylacetyl) acrylamide (2), penangin (3), ß-Caryophyllene oxide (4), and acyclic diterpene-phytol (5) were isolated for the first time from the stem and leaf of the plant. The ethyl acetate fraction showed significant free radical scavenging activity with an IC50 value of 11.536 µg/mL compared to standard ascorbic acid (4.816 µg/mL). In the thrombolytic assay, the dichloromethane fraction showed the maximum thrombolytic activity of 16.42% but was still insignificant compared to the standard streptokinase (65.98%). Finally, in a brine shrimp lethality bioassay, the LC50 values of dichloromethane, ethyl acetate, and aqueous fractions were found to be 0.687 µg/mL, 0.805 µg/mL, and 0.982 µg/mL which are significant compared to the standard vincristine sulfate of 0.272 µg/mL.
Assuntos
Extratos Vegetais , Rutaceae , Extratos Vegetais/química , Rutaceae/química , Cloreto de Metileno , Antioxidantes/química , Fibrinolíticos/químicaRESUMO
A new dimeric prenylated quinolone alkaloid, named 2,11-didemethoxy-vepridimerine A, was isolated from the root bark of Zanthoxylum rhetsa, together with twelve known compounds. The structure of the new compound was elucidated on the basis of spectroscopic investigations (NMR and Mass). The interaction of the isolated compounds with the main protease of SARS-CoV-2 (Mpro) was evaluated using molecular docking followed by MD simulations. The result suggests that 2,11-didemethoxy-vepridimerine A, the new compound, has the highest negative binding affinity against the Mpro with a free energy of binding of -8.5 Kcal/mol, indicating interaction with the Mpro. This interaction was further validated by 100 ns MD simulation. This implies that the isolated new compound, which can be employed as a lead compound for an Mpro-targeting drug discovery program, may be able to block the action of Mpro.
Assuntos
Alcaloides , Antineoplásicos , COVID-19 , Quinolonas , Zanthoxylum , SARS-CoV-2 , Simulação de Acoplamento Molecular , Alcaloides/farmacologia , Polímeros , Inibidores de Proteases , Simulação de Dinâmica MolecularRESUMO
Antimicrobial resistance and lack of new antibiotics to treat multidrug-resistant (MDR) bacteria is a significant public health problem. There is a discovery void and the pipeline of new classes of antibiotics in clinical development is almost empty. Therefore, it is important to understand the structure activity relationships (SAR) of current chemical classes as that can help the drug discovery community in their efforts to develop new antibiotics by modifying existing antibiotic classes. We studied the SAR of the C5-acylaminomethyl moiety of the linezolid, an oxazolidinone antibiotic, by synthesizing 25 compounds containing various aromatic, heteroaromatic and aliphatic substitutions. Our findings suggest that this position is highly important for the function of this antibiotic class, since only smaller non-polar fragments are tolerated at this position while larger and polar ones lead to a decrease in activity compared to linezolid. Our findings have led us to construct a structure activity relationship, around the C5-acylaminomethyl moiety of linezolid, that provides valuable insight into the function of the oxazolidinone class of antibiotics.
Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Linezolida/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Linezolida/síntese química , Linezolida/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Antibody-drug conjugates (ADCs) are a family of targeted therapeutic agents for the treatment of cancer. ADC development is a rapidly expanding field of research, with over 80 ADCs currently in clinical development and eleven ADCs (nine containing small-molecule payloads and two with biological toxins) approved for use by the FDA. Compared to traditional small-molecule approaches, ADCs offer enhanced targeting of cancer cells along with reduced toxic side effects, making them an attractive prospect in the field of oncology. To this end, this tutorial review aims to serve as a reference material for ADCs and give readers a comprehensive understanding of ADCs; it explores and explains each ADC component (monoclonal antibody, linker moiety and cytotoxic payload) individually, highlights several EMA- and FDA-approved ADCs by way of case studies and offers a brief future perspective on the field of ADC research.
Assuntos
Antineoplásicos/uso terapêutico , Imunoconjugados/uso terapêutico , Neoplasias/tratamento farmacológico , Antineoplásicos/química , Ensaios Clínicos como Assunto , Aprovação de Drogas , Humanos , Imunoconjugados/químicaRESUMO
To date very few promising leads from natural products (NP) secondary metabolites with antiviral and immunomodulatory properties have been identified for promising/potential intervention for COVID-19. Using in-silico docking studies and genome based various molecular targets, and their in vitro anti-SARS CoV-2 activities against whole cell and/or selected protein targets, we select a few compounds of interest, which can be used as potential leads to counteract effects of uncontrolled innate immune responses, in particular those related to the cytokine storm. A critical factor for prevention and treatment of SARS-CoV-2 infection relates to factors independent of viral infection or host response. They include population-related variables such as concurrent comorbidities and genetic factors critically relevant to COVID-19 health disparities. We discuss population risk factors related to SARS-CoV-2. In addition, we focus on virulence related to glucose-6-phosphate dehydrogenase deficiency (G6PDd), the most common human enzymopathy. Review of data on the response of individuals and communities with high prevalence of G6PDd to NP, prompts us to propose the rationale for a population-specific management approach to rationalize design of therapeutic interventions of SARS-CoV-2 infection, based on use of NP. This strategy may lead to personalized approaches and improve disease-related outcomes.
Assuntos
Produtos Biológicos , Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Antivirais/química , Antivirais/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/uso terapêutico , COVID-19/epidemiologia , Deficiência de Glucosefosfato Desidrogenase/tratamento farmacológico , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , HumanosRESUMO
Gram-negative bacteria possess numerous defenses against antibiotics, due to the intrinsic permeability barrier of their outer membrane (OM), explaining the recalcitrance of some common and life-threatening infections. We report the formulation of a new drug, PPA148, which shows promising activity against all Gram-negative bacteria included in the ESKAPEE pathogens. PPA148 was solubilized by inclusion complexation with cyclodextrin followed by encapsulation in liposomes. The complex and liposomal formulation presented increased activity against E. coli compared to the pure drug when assessed with the Kirby Bauer assay. The novel formulation containing 1 µg PPA148 reached similar efficacy levels equivalent to those of 30 µg of pure rifampicin. A range of biophysical techniques was used to explore the mechanism of drug uptake. Langmuir trough (LT) and neutron reflectivity (NR) techniques were employed to monitor the interactions between the drug and the formulation with model membranes. We found evidence for liposome fusion with the model Gram-negative outer membrane and for cyclodextrins acting as inner membrane (IM) permeation enhancers without presenting intrinsic antimicrobial activity. An antibiotic-in-cyclodextrin-in-liposomes (ACL) formulation was developed, which targets both the bacterial OM and IM, and offers promise as a means to breach the Gram-negative cell envelope.
Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Membrana Externa Bacteriana/metabolismo , Benzodiazepinas/administração & dosagem , Benzodiazepinas/farmacocinética , Ciclodextrinas/química , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Escherichia coli/metabolismo , Pirróis/administração & dosagem , Pirróis/farmacocinética , Antibacterianos/química , Membrana Externa Bacteriana/efeitos dos fármacos , Benzodiazepinas/química , Permeabilidade da Membrana Celular/efeitos dos fármacos , Farmacorresistência Bacteriana , Escherichia coli/efeitos dos fármacos , Bicamadas Lipídicas/metabolismo , Lipossomos , Fusão de Membrana , Modelos Biológicos , Pirróis/química , Rifampina/farmacologia , SolubilidadeRESUMO
A series of Sulfonamide-based Schiff bases (E)-4-(benzylideneamino)-N-(6-methoxypyridazin-3-yl) benzenesulfonamide (3a-r) targeting Urease Inhibition was synthesized from sulphamethoxy pyridazine and substituted aldehydes. The prepared compounds were characterized by various spectroscopic techniques including FTIR, 1HNMR, 13CNMR, and spectrometric HRMS analysis. The most active agent (3g) bearing halogens and OH groups gave IC50 value of 2.20 µM for urease inhibition against the standard Thiourea (IC50 = 20.03 ± 2.06) and the overall trend within the series was 3g > 3n > 3p > 3j > 3q > 3h, 3o > 3l, 3r > 3k, 3m > 3a > 3d > 3e > 3f. Structure-activity relationship study established that the nature as well as the position of varying groups attached to aryl group had crucial roles in defining the urease inhibition activity. Additionally, in silico investigation was carried out which demonstrated that the compounds exhibit polar and apolar contacts with the crucial residues in the binding site of urease. The ADME analysis suggested all the synthesized compounds to be non-toxic, and likely to undergo passive gastrointestinal absorption. Taken together, the study suggests that the synthesized Sulfonamide-based Schiff bases derivatives may serve as potential hits as urease inhibitors.
Assuntos
Simulação de Acoplamento Molecular/métodos , Bases de Schiff/química , Urease/antagonistas & inibidores , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Two new epimeric bibenzylated monoterpenes machaerifurogerol (1a) and 5-epi-machaerifurogerol (1b), and four known isoflavonoids (+)-vestitol (2), 7-O-methylvestitol (3), (+)-medicarpin (4), and 3,8-dihydroxy-9-methoxypterocarpan (5) were isolated from Machaerium Pers. This plant was previously assigned as Machaerium multiflorum Spruce, from which machaeriols A-D (6-9) and machaeridiols A-C (10-12) were reported, and all were then re-isolated, except the minor compound 9, for a comprehensive antimicrobial activity evaluation. Structures of the isolated compounds were determined by full NMR and mass spectroscopic data. Among the isolated compounds, the mixture 10 + 11 was the most active with an MIC value of 1.25 µg/mL against methicillin-resistant Staphylococcus aureus (MRSA) strains BAA 1696, -1708, -1717, -33591, and vancomycin-resistant Enterococcus faecium (VRE 700221) and E. faecalis (VRE 51299) and vancomycin-sensitive E. faecalis (VSE 29212). Compounds 6-8 and 10-12 were found to be more potent against MRSA 1708, and 6, 11, and 12 against VRE 700221, than the drug control ciprofloxacin and vancomycin. A combination study using an in vitro Checkerboard method was carried out for machaeriols (7 or 8) and machaeridiols (11 or 12), which exhibited a strong synergistic activity of 12 + 8 (MIC 0.156 and 0.625 µg/mL), with >32- and >8-fold reduction of MIC's, compared to 12, against MRSA 1708 and -1717, respectively. In the presence of sub-inhibitory concentrations on polymyxin B nonapeptide (PMBN), compounds 10 + 11, 11, 12, and 8 showed activity in the range of 0.5-8 µg/mL for two strains of Acinetobacter baumannii, 2-16 µg/mL against Pseudomonas aeruginosa PAO1, and 2 µg/mL against Escherichia coli NCTC 12923, but were inactive (MIC > 64 µg/mL) against the two isolates of Klebsiella pneumoniae.
Assuntos
Antibacterianos/farmacologia , Benzopiranos/farmacologia , Fabaceae/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Enterococos Resistentes à Vancomicina/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/isolamento & purificação , Benzopiranos/química , Benzopiranos/isolamento & purificação , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
Fourier transform infrared spectroscopy (FTIR) has been shown to be a promising tool for identifying the mode of action of drugs. However, most previous studies have focused on the analysis of fixed or dried cells. The measurement of living cells has the advantage of obtaining time series data, and the in situ approach eliminates the need for fixing or drying the cells. In this study, the potential of live-cell FTIR method for the identification of the mode of action of drugs was demonstrated. Four different drugs were tested, with two of the drugs having the same mode of action (tamoxifen and toremifene) and the other two having different modes of action (imatinib and doxorubicin). Live cells were treated in the four drugs at and below the IC50 level (i.e. the concentration of drug required to inhibit the growth of cells by 50%), and the changes to their spectra after the addition of drugs were monitored over a 24-hour period. Principal component analysis (PCA) of the spectral data shows that drugs with different modes of action are well-separated, while the drugs with the same mode of action are grouped together. The results also show that at IC50, the separation appears to be the clearest at 2 hours for imatinib and tamoxifen/toremifene and 6 hours for doxorubicin. However, at 50% of the IC50 drug concentration, the separation appears to be the best at longer incubation time, i.e. 24 hours, for all four drugs. In conclusion, live-cell FTIR has shown to be able to distinguish and group spectral signatures of cells treated with drugs of known modes of action after a relatively short time of exposure. Further collection of live-cell data would enable an algorithm to be developed for the prediction of the modes of action of novel drugs, which can help in the preclinical drug screening process.
Assuntos
Antineoplásicos/classificação , Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Mesilato de Imatinib/farmacologia , Tamoxifeno/farmacologia , Toremifeno/farmacologia , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Análise de Componente Principal , Espectroscopia de Infravermelho com Transformada de Fourier/métodosRESUMO
Efflux pumps are widely implicated in antibiotic resistance because they can extrude the majority of clinically relevant antibiotics from within cells to the extracellular environment. However, there is increasing evidence from many studies to suggest that the pumps also play a role in biofilm formation. These studies have involved investigating the effects of efflux pump gene mutagenesis and efflux pump inhibitors on biofilm formation, and measuring the levels of efflux pump gene expression in biofilms. In particular, several key pathogenic species associated with increasing multidrug resistance, such as Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus, have been investigated, whilst other studies have focused on Salmonella enterica serovar Typhimurium as a model organism and problematic pathogen. Studies have shown that efflux pumps, including AcrAB-TolC of E. coli, MexAB-OprM of P. aeruginosa, AdeFGH of A. baumannii and AcrD of S. enterica, play important roles in biofilm formation. The substrates for such pumps, and whether changes in their efflux activity affect biofilm formation directly or indirectly, remain to be determined. By understanding the roles that efflux pumps play in biofilm formation, novel therapeutic strategies can be developed to inhibit their function, to help disrupt biofilms and improve the treatment of infections. This review will discuss and evaluate the evidence for the roles of efflux pumps in biofilm formation and the potential approaches to overcome the increasing problem of biofilm-based infections.
Assuntos
Bactérias/crescimento & desenvolvimento , Proteínas de Bactérias/fisiologia , Biofilmes/crescimento & desenvolvimento , Farmacorresistência Bacteriana Múltipla , Proteínas de Membrana Transportadoras/fisiologia , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Moduladores de Transporte de Membrana/farmacologia , Percepção de QuorumRESUMO
Two new cis-clerodane-type furanoditerpenes, crispenes F and G (1 and 2), together with seven known compounds, were isolated from the stems of Tinospora crispa. Crispenes F and G (1 and 2) inhibited STAT3 dimerization in a cell-free fluorescent polarization assay and were found to have significant cytotoxicity against a STAT3-dependent MDA-MB 231 breast cancer cell line, while being inactive in a STAT3-null A4 cell line. These two compounds share structural similarities with a previously reported STAT3 inhibitor, crispene E, isolated from the same plant. Molecular docking studies suggested that the molecules inhibit STAT3 by interacting with its SH2 domain.
Assuntos
Diterpenos Clerodânicos/química , Diterpenos Clerodânicos/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Terpenos/química , Terpenos/farmacologia , Tinospora/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Dimerização , Humanos , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologiaRESUMO
As a part of our ongoing research on endophytic fungi, we have isolated a sesterterpene mycotoxin, fusaproliferin (FUS), from a Fusarium solani strain, which is associated with the plant Aglaonema hookerianum Schott. FUS showed rapid and sub-micromolar IC50 against pancreatic cancer cell lines. Time-dependent survival analysis and microscopy imaging showed rapid morphological changes in cancer cell lines 4 h after incubation with FUS. This provides a new chemical scaffold that can be further developed to obtain more potent synthetic agents against pancreatic cancer.
Assuntos
Antineoplásicos/farmacologia , Fusarium/química , Neoplasias Pancreáticas/tratamento farmacológico , Terpenos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Endófitos/química , Feminino , Humanos , Estrutura Molecular , Micotoxinas/farmacologia , Neoplasias Pancreáticas/patologia , Terpenos/químicaRESUMO
The aim of the study was to use in silico and in vitro techniques to evaluate whether a triple formulation of antiretroviral drugs (tenofovir, darunavir, and dapivirine) interacted with P-glycoprotein (P-gp) or exhibited any other permeability-altering drug-drug interactions in the colorectal mucosa. Potential drug interactions with P-gp were screened initially using molecular docking, followed by molecular dynamics simulations to analyze the identified drug-transporter interaction more mechanistically. The transport of tenofovir, darunavir, and dapivirine was investigated in the Caco-2 cell models and colorectal tissue, and their apparent permeability coefficient (Papp), efflux ratio (ER), and the effect of transporter inhibitors were evaluated. In silico, dapivirine and darunavir showed strong affinity for P-gp with similar free energy of binding; dapivirine exhibiting a ΔGPB value -38.24 kcal/mol, darunavir a ΔGPB value -36.84 kcal/mol. The rank order of permeability of the compounds in vitro was tenofovir < darunavir < dapivirine. The Papp for tenofovir in Caco-2 cell monolayers was 0.10 ± 0.02 × 10-6 cm/s, ER = 1. For dapivirine, Papp was 32.2 ± 3.7 × 10-6 cm/s, but the ER = 1.3 was lower than anticipated based on the in silico findings. Neither tenofovir nor dapivirine transport was influenced by P-gp inhibitors. The absorptive permeability of darunavir (Papp = 6.4 ± 0.9 × 10-6 cm/s) was concentration dependent with ER = 6.3, which was reduced by verapamil to 1.2. Administration of the drugs in combination did not alter their permeability compared to administration as single agents. In conclusion, in silico modeling, cell culture, and tissue-based assays showed that tenofovir does not interact with P-gp and is poorly permeable, consistent with a paracellular transport mechanism. In silico modeling predicted that darunavir and dapivirine were P-gp substrates, but only darunavir showed P-gp-dependent permeability in the biological models, illustrating that in silico modeling requires experimental validation. When administered in combination, the disposition of the proposed triple-therapy antiretroviral drugs in the colorectal mucosa will depend on their distinctly different permeability, but was not interdependent.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Darunavir/química , Pirimidinas/química , Tenofovir/química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/uso terapêutico , Células CACO-2 , Doenças do Colo/prevenção & controle , Doenças do Colo/virologia , Darunavir/uso terapêutico , Infecções por HIV/prevenção & controle , Humanos , Simulação de Acoplamento Molecular , Pirimidinas/uso terapêutico , Tenofovir/uso terapêuticoRESUMO
Bioactivity-guided fractionation of the ethyl acetate extract obtained from the culture of the endophytic fungus Fusarium solani resulted in the isolation of one new naphthoquinone, 9-desmethylherbarine (1), and two azaanthraquinone derivatives, 7-desmethylscorpinone (2) and 7-desmethyl-6-methylbostrycoidin (3), along with four known compounds. Their structures were elucidated by spectral analysis, as well as a direct comparison of spectral data with those of known compounds. Azaanthraquinones 2 and 3 showed cytotoxic activity against four human tumor cell lines, MDA MB 231, MIA PaCa2, HeLa, and NCI H1975. A molecular docking study suggested DNA interactions as the mode of action of these naphthoquinones and azaanthraquinones.
Assuntos
Antraquinonas/isolamento & purificação , Antraquinonas/farmacologia , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Compostos Aza/isolamento & purificação , Compostos Aza/farmacologia , Fusarium/química , Naftoquinonas/isolamento & purificação , Naftoquinonas/farmacologia , Acetatos , Antraquinonas/química , Antineoplásicos/química , Compostos Aza/química , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftoquinonas/química , Ressonância Magnética Nuclear BiomolecularRESUMO
Gemma Nixon, Khondaker Miraz Rahman and John Spencer introduce the RSC Chemical Biology themed collection on 'Medicinal Chemistry Small Molecule Probes'.
RESUMO
Since the introduction of quinolone and fluoroquinolone antibiotics to treat bacterial infections in the 1960s, there has been a pronounced increase in the number of bacterial species that have developed resistance to fluoroquinolone treatment. In 2017, the World Health Organization established a priority list of the most critical Gram-negative resistant pathogens. These included Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli. In the last three decades, investigations into the mechanisms of fluoroquinolone resistance have revealed that mutations in the target enzymes of fluoroquinolones, DNA gyrase or topoisomerase IV, are the most prevalent mechanism conferring high levels of resistance. Alterations to porins and efflux pumps that facilitate fluoroquinolone permeation and extrusion across the bacterial cell membrane also contribute to the development of resistance. However, there is a growing observation of novel mutants with newer generations of fluoroquinolones, highlighting the need for novel treatments. Currently, steady progress has been made in the development of novel antimicrobial agents that target DNA gyrase or topoisomerase IV through different avenues than current fluoroquinolones to prevent target-mediated resistance. Therefore, an updated review of the current understanding of fluoroquinolone resistance within the literature is imperative to aid in future investigations.
RESUMO
Platelets are necessary for maintaining haemostasis. Separately, platelets are important for the propagation of inflammation during the host immune response against infection. The activation of platelets also causes inappropriate inflammation in various disease pathologies, often in the absence of changes to haemostasis. The separate functions of platelets during inflammation compared with haemostasis are therefore varied and this will be reflected in distinct pathways of activation. The activation of platelets by the nucleotide adenosine diphosphate (ADP) acting on P2Y1 and P2Y12 receptors is important for the development of platelet thrombi during haemostasis. However, P2Y1 stimulation of platelets is also important during the inflammatory response and paradoxically in scenarios where no changes to haemostasis and platelet aggregation occur. In these events, Rho-GTPase signalling, rather than the canonical phospholipase Cß (PLCß) signalling pathway, is necessary. We describe our current understanding of these differences, reflecting on recent advances in knowledge of P2Y1 structure, and the possibility of biased agonism occurring from activation via other endogenous nucleotides compared with ADP. Knowledge arising from these different pathways of P2Y1 stimulation of platelets during inflammation compared with haemostasis may help therapeutic control of platelet function during inflammation or infection, while preserving essential haemostasis. LINKED ARTICLES: This article is part of a themed issue on Platelet purinergic receptor and non-thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc.
Assuntos
Plaquetas , Agregação Plaquetária , Humanos , Difosfato de Adenosina/metabolismo , Plaquetas/fisiologia , Transdução de Sinais , Inflamação/metabolismo , Receptores Purinérgicos P2Y1/metabolismo , Receptores Purinérgicos P2Y12/metabolismo , Ativação PlaquetáriaRESUMO
A new 2-quinolone alkaloid, iso-oligophyline (1), and two very unusual C34 terpenoids, proposed names ravespanol (2) and ravespanone (3), along with two known compounds, ß-sitosterol (4), and methyl linoleate (5), were isolated from the leaf extract of Ravenia spectabilis engl. Methyl linoleate constitutes the first report of isolation from this species. We have already reported the isolation of atanine (6), oligophyline (7), ravenoline (8), and arborinine (9) from the plant. Based on nuclear magnetic resonance (NMR) spectroscopy and mass spectrometric analysis, the structure of the isolated chemicals was determined. The crude fractions and four compounds (6,7,8 and 9) were evaluated for a cytotoxicity study on a panel of six human stomach cancer cell lines (SCL, SCL-6, SCL-37'6, SCL-9, K-3, N21) by MTT assay. Among the plant extracts and isolated compounds, petroleum ether fraction and compound 7 exhibited the highest cytotoxic activity against SCL and SCL-6 cells, where the IC50 values were 17.9 and 16.56 µM, respectively.