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1.
Eur J Med Chem ; 186: 111855, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31740051

RESUMO

There is an increasing interest in the field of cancer therapy for small compounds targeting pyrimidine biosynthesis, and in particular dihydroorotate dehydrogenase (DHODH), the fourth enzyme of this metabolic pathway. Three available DHODH structures, featuring three different known inhibitors, were used as templates to screen in silico an original chemical library from Erevan University. This process led to the identification of P1788, a compound chemically related to the alkaloid cerpegin, as a new class of pyrimidine biosynthesis inhibitors. In line with previous reports, we investigated the effect of P1788 on the cellular innate immune response. Here we show that pyrimidine depletion by P1788 amplifies cellular response to both type-I and type II interferons, but also induces DNA damage as assessed by γH2AX staining. Moreover, the addition of inhibitors of the DNA damage response led to the suppression of the P1788 stimulatory effects on the interferon pathway. This demonstrates that components of the DNA damage response are bridging the inhibition of pyrimidine biosynthesis by P1788 to the interferon signaling pathway. Altogether, these results provide new insights on the mode of action of novel pyrimidine biosynthesis inhibitors and their development for cancer therapies.


Assuntos
Furanos/farmacologia , Piridinas/farmacologia , Piridonas/farmacologia , Pirimidinas/antagonistas & inibidores , Células Cultivadas , Dano ao DNA , Relação Dose-Resposta a Droga , Furanos/síntese química , Furanos/química , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Piridonas/química , Pirimidinas/biossíntese , Relação Estrutura-Atividade
2.
Biosci Biotechnol Biochem ; 84(1): 25-30, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31516064

RESUMO

The Japanese orange fly, Bactrocera tsuneonis, infests various citrus crops. While male pheromone components accumulated in the rectal glands are well characterized for Bactrocera, but information regarding the chemical factors involved in the life cycles of B. tsuneonis remains scarce. Herein, several volatile chemicals including a γ-decalactone, (3R,4R)-3-hydroxy-4-decanolide [(3R,4R)-HD], were identified as major components, along with acetamide and spiroketals as minor components in the rectal gland complexes of male B. tsuneonis flies. The lactone (3R,4R)-HD was also identified in female rectal gland complexes. The amount of this compound in mature males was significantly higher than those observed in females and immature males. The lactone (3R,4R)-HD was detected in flies fed with sucrose only, indicating that this lactone is not derived from dietary sources during adulthood, but biosynthesized in vivo. The predominant accumulation of (3R,4R)-HD in mature males also suggests a possible role in reproductive behavior.


Assuntos
Lactonas/química , Glândula de Sal/química , Tephritidae/fisiologia , Acetamidas/síntese química , Acetamidas/química , Animais , Cromatografia Gasosa , Citrus , Dieta , Feminino , Furanos/síntese química , Furanos/química , Japão , Lactonas/síntese química , Masculino , Espectrometria de Massas , Reprodução/fisiologia , Atrativos Sexuais/química , Comportamento Sexual Animal/fisiologia , Compostos de Espiro/síntese química , Compostos de Espiro/química , Sacarose
3.
ChemSusChem ; 12(21): 4764-4768, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31490638

RESUMO

Furancarboxylic acids are promising biobased building blocks in pharmaceutical and polymer industries. In this work, dual-enzyme cascade systems composed of galactose oxidase (GOase) and alcohol dehydrogenases (ADHs) are constructed for controlled synthesis of 5-formyl-2-furancarboxylic acid (FFCA) and 2,5-furandicarboxylic acid (FDCA) from 5-hydroxymethylfurfural (HMF), based on the catalytic promiscuity of ADHs. The byproduct H2 O2 , which is produced in GOase-catalyzed oxidation of HMF to 2,5-diformylfuran (DFF), is used for horseradish peroxidase (HRP)-mediated regeneration of the oxidized nicotinamide cofactors for subsequent oxidation of DFF promoted by an ADH, thus implementing H2 O2 internal recycling. The desired products FFCA and FDCA are obtained with yields of more than 95 %.


Assuntos
Álcool Desidrogenase/metabolismo , Furaldeído/análogos & derivados , Furanos/síntese química , Biocatálise , Ácidos Dicarboxílicos/síntese química , Furaldeído/química , Furanos/química , Galactose Oxidase , Peróxido de Hidrogênio , Oxirredução
4.
Eur J Med Chem ; 181: 111562, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31377592

RESUMO

The interaction between G-Protein coupled receptor CXCR4 and its natural ligand CXCL12 has been linked to inflammation experienced by patients with Irritable Bowel Disease (IBD). Blocking this interaction could potentially reduce inflammatory symptoms in IBD patients. In this work, several thiophene-based and furan-based compounds modeled after AMD3100 and WZ811-two known antagonists that interrupt the CXCR4-CXCL12 interaction-were synthesized and analyzed. Fifteen hit compounds were identified; these compounds exhibited effective concentrations (EC) lower than 1000 nM (AMD3100) and inhibited invasion of metastatic cells by at least 45%. Selected compounds (2d, 2j, 8a) that inhibited metastatic invasion at a higher rate than WZ811 (62%) were submitted for a carrageenan inflammation test, where both 8a and 2j reduced inflammation in the same range as WZ811 (40%) but did not reduce inflammation more than 40%. Select compounds were also modeled in silico to show key residue interactions. These preliminary results with furan-based and thiophene-based analogues contribute to the new class on heterocyclic aromatic-based CXCR4 antagonists.


Assuntos
Furanos/farmacologia , Compostos Heterocíclicos/farmacologia , Inflamação/tratamento farmacológico , Receptores CXCR4/antagonistas & inibidores , Tiofenos/farmacologia , Animais , Carragenina/administração & dosagem , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Furanos/síntese química , Furanos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Membro Posterior/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptores CXCR4/metabolismo , Relação Estrutura-Atividade , Tiofenos/química
5.
Chem Pharm Bull (Tokyo) ; 67(8): 888-895, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366838

RESUMO

New sugar hydrazones incorporating furan and/or 1,3,4-thiadiazole ring systems were synthesized by reaction of the corresponding hydrazide with different aldose sugars. Heterocyclization of the formed hydrazones afforded the derived acyclic nucleoside analogues possessing the 1,3,4-oxadiazoline as modified nucleobase via acetylation followed by the heterocyclization process. The anticancer activity of the synthesized compounds was studied against human liver carcinoma cell (HepG-2) and at human normal retina pigmented epithelium cells (RPE-1). High activities were revealed by compounds 3, 12 and 14 with IC50 values near to that of the reference drug doxorubicin.


Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Furanos/farmacologia , Oxidiazóis/farmacologia , Açúcares/farmacologia , Tiadiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Furanos/química , Células Hep G2 , Humanos , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Relação Estrutura-Atividade , Açúcares/síntese química , Açúcares/química , Tiadiazóis/síntese química , Tiadiazóis/química
6.
Talanta ; 205: 120166, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31450476

RESUMO

Collecting sweat sample for onsite testing is a sophisticated process as the analysis process must be completed in a real-time with a highly absorptive and sensitive device in order to gain a useful assessment of its content. Thus, we developed a chemical probe incorporated into microfibrillated cellulose to introduce a novel, simple, robust and flexible aerogel. This chromogenic sponge-like aerogel assay demonstrated a color change from yellow to orange, red and blue depending on the sweat biochemical changes. Novel pH sensitive tricyanofuran hydrazone probe was prepared, characterized and encapsulated in-situ within microfibrillated cellulose to follow up sweat pH changes. The solvatochromic performance in several solvents of different polarities and the reversible pH correlated color change of this tricyanofuran hydrazone probe in an acetonitrile solution was explored by UV-Vis absorption spectra. The microporous and microfibrillated sponge-like cellulose substrate was fabricated by activation of wood pulp using phosphoric acid followed by freeze-drying process. Morphological characterization, thermal stability and fiber crystallinity of the prepared aerogel were explored using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) and thermogravimetric analysis (TGA). The visual color change was explored by studying the CIE LAB color space coordinates and color strength values. The cytotoxicity of the sponge-like aerogel sensor was also evaluated.


Assuntos
Celulose/química , Colorimetria/métodos , Suor/química , Linhagem Celular , Furanos/síntese química , Furanos/química , Géis , Humanos , Concentração de Íons de Hidrogênio , Nitrilos/síntese química , Nitrilos/química , Solventes/química , Temperatura Ambiente , Fatores de Tempo
7.
Molecules ; 24(14)2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31336669

RESUMO

A new and direct approach to the construction of the core framework of the herbicidal natural products cornexistin and hydroxycornexistin has been developed. Formation of the nine-membered carbocycle found in the natural products has been accomplished by an intramolecular Nozaki-Hiyama-Kishi reaction between a vinylic iodide and an aldehyde. Good yields of carbocyclic products were obtained from the reaction, but diastereomeric mixtures of allylic alcohols were produced. The cyclisation reaction was successful irrespective of the relative configuration of the stereogenic centres in the cyclisation precursor.


Assuntos
Técnicas de Química Sintética , Furanos/síntese química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Furanos/química , Furanos/farmacologia , Herbicidas/síntese química , Herbicidas/química , Estrutura Molecular , Acoplamento Oxidativo
8.
Chemistry ; 25(46): 10954-10964, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31215691

RESUMO

Epicocconone 1 is a natural chromophore isolated from the fungus Epicoccum nigrum that has shown applications in proteomics and fluorescent microscopy thanks to its unique pro-fluorescence properties. The modification of the skeleton of the natural product by replacing the triene side chain by a fluorenyl scaffold can noticeably increase the fluorophore's absorption coefficient. The synthesis of the analogues of the natural product has been made possible by the use of a palladium-catalyzed carbonylation reaction, allowing the construction of the ß-keto-dioxinone key intermediate. Two-photon absorption cross-section measurements of the fluorenyl epicocconone analogues show a structure dependency with values ranging from 60 to 280 GM and live cell imaging show intense staining of intracellular vesicle-like structures around the nucleus.


Assuntos
Benzopiranos/química , Fluorenos/química , Corantes Fluorescentes/química , Furanos/química , Cetonas/química , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Animais , Benzopiranos/síntese química , Catálise , Fluorenos/síntese química , Corantes Fluorescentes/síntese química , Furanos/síntese química , Cetonas/síntese química , Imagem Óptica/métodos , Células PC12 , Paládio/química , Ratos
9.
Int J Mol Sci ; 20(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052594

RESUMO

Biopolymers are gaining increasing importance as substitutes for plastics derived from fossil fuels, especially for packaging applications. In particular, furanoate-based polyesters appear as the most credible alternative due to their intriguing physic/mechanical and gas barrier properties. In this study, block copolyesters containing 2,5-furan and trans-1,4-cyclohexane moieties were synthesized by reactive blending, starting from the two parent homopolymers: poly(propylene furanoate) (PPF) and poly(propylene cyclohexanedicarboxylate) (PPCE). The whole range of molecular architectures, from long block to random copolymer with a fixed molar composition (1:1 of the two repeating units) was considered. Molecular, thermal, tensile, and gas barrier properties of the prepared materials were investigated and correlated to the copolymer structure. A strict dependence of the functional properties on the copolymers' block length was found. In particular, short block copolymers, thanks to the introduction of more flexible cyclohexane-containing co-units, displayed high elongation at break and low elastic modulus, thus overcoming PPF's intrinsic rigidity. Furthermore, the exceptionally low gas permeabilities of PPF were further improved due to the concomitant action of the two rings, both capable of acting as mesogenic groups in the presence of flexible aliphatic units, and thus responsible for the formation of 1D/2D ordered domains, which in turn impart outstanding barrier properties.


Assuntos
Cicloexanos/química , Furanos/química , Gases/química , Poliésteres/química , Cicloexanos/síntese química , Módulo de Elasticidade , Embalagem de Alimentos , Furanos/síntese química , Permeabilidade , Poliésteres/síntese química , Temperatura Ambiente
10.
Mar Drugs ; 17(4)2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027184

RESUMO

Here, we describe a general stereoselective synthesis of the marine furanosesquiterpenes structurally related to pallescensins 1-2. The stereoisomeric forms of the pallescensin 1, pallescensin 2, and dihydropallescensin 2 were obtained in high chemical and isomeric purity, whereas isomicrocionin-3 was synthesized for the first time. The sesquiterpene framework was built up by means of the coupling of the C10 cyclogeranyl moiety with the C5 3-(methylene)furan moiety. The key steps of our synthetic procedure are the stereoselective synthesis of four cyclogeraniol isomers, their conversion into the corresponding cyclogeranylsulfonylbenzene derivatives, their alkylation with 3-(chloromethyl)furan, and the final reductive cleavage of the phenylsulfonyl functional group to afford the whole sesquiterpene framework. The enantioselective synthesis of the α-, 3,4-dehydro-γ- and γ-cyclogeraniol isomers was performed using both a lipase-mediated resolution procedure and different regioselective chemical transformations.


Assuntos
Técnicas de Química Sintética/métodos , Furanos/química , Furanos/síntese química , Sesquiterpenos/química , Sesquiterpenos/síntese química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Isomerismo , Estereoisomerismo
11.
Phytochemistry ; 163: 187-194, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31014820

RESUMO

Smoke derived karrikinolide and trimethylbutenolide exerted neuroprotective effects against monoamine oxidase and acetylcholinesterase. Synthesis of potent analogs was achieved. Sulphur substitution in the bicyclic ring structure of KAR1 displayed the most encouraging activity returning IC50 values of 13.75 ±â€¯0.001 µM and 0.03 ±â€¯0.02 µM for monoamine oxidase A and B and 0.08 ±â€¯0.006 µM for acetylcholinesterase. Neuroprotective butenolides may be particularly useful in the treatment of depressive disorders, Alzheimer's and Parkinson's diseases.


Assuntos
4-Butirolactona/análogos & derivados , Transtorno Depressivo/tratamento farmacológico , Furanos/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Piranos/farmacologia , 4-Butirolactona/síntese química , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Acetilcolinesterase/metabolismo , Relação Dose-Resposta a Droga , Furanos/síntese química , Furanos/química , Humanos , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Piranos/síntese química , Piranos/química , Relação Estrutura-Atividade
12.
J Sci Food Agric ; 99(11): 4993-4999, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30977142

RESUMO

BACKGROUND: Furan is a potential carcinogen that can be formed in various heat-treated foods, including milk beverages. Studies on the formation and mitigation of furan in milk beverages are rare. In the present study, the effects of ingredients on furan formation and the reduction of furan by sugar alcohols and antioxidants of bamboo leaves (AOB) were investigated in a milk beverage model system. RESULTS: The results obtained demonstrated that the Maillard reaction is the major pathway for furan formation in a milk beverage model system, and the type of sugar has a great influence on furan formation. High fructose corn syrup (HFCS 55) was more favorable for furan formation than sucrose. Thermal oxidation of ascorbic acid and lipids significantly enhanced furan generation. Xylitol, sorbitol and mannitol inhibited furan formation in model systems by replacing sucrose or HFCS. The maximum inhibition percentage of furan formation was observed when sucrose/HFCS was substituted completely by xylitol and the inhibition rate was 78.28% and 88.64% separately for the sucrose/HFCS-containing system. AOB significantly inhibited furan formation and the inhibition rate reached 32.13% and 28.52% separately for the sucrose/HFCS-containing system. CONCLUSION: The present study demonstrates that the use of sugar alcohols and AOB could be a feasible way of reducing furan formation in thermally processed milk beverages. © 2019 Society of Chemical Industry.


Assuntos
Antioxidantes/farmacologia , Carcinógenos/síntese química , Furanos/síntese química , Folhas de Planta/química , Sasa , Álcoois Açúcares/farmacologia , Animais , Antioxidantes/química , Bebidas/análise , Furanos/antagonistas & inibidores , Temperatura Alta , Humanos , Lipídeos/farmacologia , Reação de Maillard , Leite/química , Álcoois Açúcares/química
13.
Molecules ; 24(6)2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30875923

RESUMO

A one pot-two step procedure for the synthesis of diethyl furan-2,5-dicarboxylate (DEFDC) starting from mucic acid without isolation of the intermediate furan dicarboxylic acid (FDCA) was studied. Then, the production of three different kinds of furan-based polyesters- polyethylene-2,5-furan dicarboxylate (PEF), polyhydropropyl-2,5-furan dicarboxylate(PHPF) and polydiglycerol-2,5-furandicarboxylate (PDGF)-was realized through a Co(Ac)2·4H2O catalyzed polytransesterification performed at 160 °C between DEFDC and a defined diol furan-based prepolymer or pure diglycerol. In parallel to polymerization process, an unattended regioselective 1-OH acylation of glycerol by direct microwave-heated FDCA diester transesterification led to the formation of a symmetric prepolymer ready for further polymerization and clearly identified by 2D NMR sequences. Furthermore, the synthesis of a more soluble and hydrophilic diglycerol-based furanic polyester was also achieved. The resulting biobased polymers were characterized by NMR, FT-IR spectroscopy, DSC, TGA and XRD. The morphologies of the resulted polymers were observed by FE-SEM and the purity of the material by EDX.


Assuntos
Ácidos Dicarboxílicos/síntese química , Furanos/síntese química , Açúcares Ácidos/química , Catálise , Ácidos Dicarboxílicos/química , Esterificação , Furanos/química , Espectroscopia de Ressonância Magnética , Polimerização , Solventes/química
14.
Bioorg Chem ; 85: 585-599, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30878891

RESUMO

A large number of natural products containing the propellane scaffold have been reported to exhibit cytotoxicity against several cancers; however, their mechanism of action is still unknown. Anticancer drugs targeting DNA are mainly composed of small planar molecule/s that can interact with the DNA helix, causing DNA malfunction and cell death. The aim of this study was to design and synthesize propellane derivatives that can act as DNA intercalators and/or groove binders. The unique structure of the propellane derivatives and their ability to display planar ligands with numerous possible geometries, renders them potential starting points to design new drugs targeting DNA in cancer cells. New substituted furo-imidazo[3.3.3]propellanes were synthesized via the reaction of substituted alkenylidene-hydrazinecarbothioamides with 2-(1,3-dioxo-2,3-dihydro-1H-2-ylidene)propanedinitrile in tetrahydrofuran at room temperature. The structures of the products were confirmed by a combination of elemental analysis, NMR, ESI-MS, IR and single crystal X-ray analysis. Interestingly, 5c, 5d and 5f showed an ability to interact with Calf Thymus DNA (CT-DNA). Their DNA-binding mode was investigated using a combination of absorption spectroscopy, DNA melting, viscosity, CD spectroscopy measurements, as well as competitive binding studies with several dyes. Their cytotoxicity was evaluated against the NCI-60 panel of cancer cell lines. 5c, 5d and 5f exhibited similar anti-proliferative activity against the A549 non-small cell lung cancer (NSCLC) cell line. Further mechanistic studies revealed their ability to induce DNA damage in the A549 cell line, as well as apoptosis, evidenced by elevated Annexin V expression, enhanced caspase 3/7 activation and PARP cleavage. In this study, we present the potential for designing novel propellanes to provoke cytotoxic activity, likely through DNA binding-induced DNA damage and apoptosis.


Assuntos
Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , DNA/metabolismo , Furanos/farmacologia , Imidazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Linhagem Celular Tumoral , DNA/química , Dano ao DNA/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Furanos/metabolismo , Humanos , Imidazóis/síntese química , Imidazóis/metabolismo , Conformação de Ácido Nucleico/efeitos dos fármacos , Temperatura de Transição , Viscosidade
15.
Nat Chem ; 11(4): 342-350, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30903037

RESUMO

The architecture and bioactivity of natural products frequently serve as embarkation points for the exploration of biologically relevant chemical space. Total synthesis followed by derivative synthesis has historically enabled a deeper understanding of structure-activity relationships. However, synthetic strategies towards a natural product are not always guided by hypotheses regarding the structural features required for bioactivity. Here, we report an approach to natural product total synthesis that we term 'pharmacophore-directed retrosynthesis'. A hypothesized, pharmacophore of a natural product is selected as an early synthetic target and this dictates the retrosynthetic analysis. In an ideal application, sequential increases in the structural complexity of this minimal structure enable development of a structure-activity relationship profile throughout the course of the total synthesis effort. This approach enables the identification of simpler congeners retaining bioactivity at a much earlier stage of a synthetic effort, as demonstrated here for the spongiane diterpenoid, gracilin A, leading to simplified derivatives with potent neuroprotective and immunosuppressive activity.


Assuntos
Acetatos/química , Diterpenos/química , Furanos/química , Imunossupressores/química , Fármacos Neuroprotetores/química , Acetatos/síntese química , Acetatos/farmacologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cristalografia por Raios X , Reação de Cicloadição , Diterpenos/síntese química , Diterpenos/farmacologia , Desenho de Drogas , Furanos/síntese química , Furanos/farmacologia , Humanos , Imunossupressores/síntese química , Imunossupressores/farmacologia , Membranas Mitocondriais/metabolismo , Conformação Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
16.
Molecules ; 24(5)2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30866442

RESUMO

Sporotrichosis is a neglected fungal infection caused by Sporothrix spp., which have a worldwide distribution. The standard antifungal itraconazole has been recommended as a first-line therapy. However, failure cases in human and feline treatment have been reported in recent years. This study aimed to synthesize several α- and ß-2,3-dihydrofuranaphthoquinones and evaluate them against Sporothrix schenckii and Sporothrix brasiliensis-the main etiological agents of sporotrichosis in Brazil. The stability of these compounds was also investigated under different storage conditions for 3 months. The samples were removed at 0, 60, and 90 days and assessed by ¹H-NMR, and their in vitro antifungal susceptibility was tested. Furthermore, we evaluated the superficial changes caused by the most effective and stable compounds using scanning electron microscopy and determined their effects when combined with itraconazole. Nine dihydrofuranaphthoquinones showed good antifungal activity and stability, with MIC values of 2⁻32 µM. Compounds 6 and 10 were the most active dihydrofuranaphthoquinones in vitro for both species; in fungi, these compounds induced yeast⁻hyphae conversion and alteration in the hyphae and conidia structures. Compound 10 also exhibited a synergistic activity with itraconazole against S. schenckii, with a ΣFIC index value of 0.3. Our results indicate that Compounds 6 and 10 are potential candidates for the development of new antifungal agents for the treatment of sporotrichosis.


Assuntos
Antifúngicos/síntese química , Furanos/síntese química , Itraconazol/farmacologia , Naftoquinonas/síntese química , Sporothrix/efeitos dos fármacos , Antifúngicos/química , Antifúngicos/farmacologia , Brasil , Estabilidade de Medicamentos , Sinergismo Farmacológico , Furanos/química , Furanos/farmacologia , Humanos , Hifas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Estrutura Molecular , Naftoquinonas/química , Naftoquinonas/farmacologia , Esporos Fúngicos/efeitos dos fármacos
17.
Int J Mol Sci ; 20(3)2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30736278

RESUMO

Staphylococcus aureus causes various infectious diseases, from skin impetigo to life-threatening bacteremia and sepsis, thus appearing an important target for antimicrobial therapeutics. In turn, the rapid development of antibiotic resistance and biofilm formation makes it extremely robust against treatment. Here, we unravel the molecular mechanism of the antimicrobial activity of the recently unveiled F105 consisting of three pharmacophores: chlorinated 2(5H)-furanone, sulfone, and l-menthol moieties. F105 demonstrates highly selective activity against Gram-positive bacteria and biofilm-embedded S. aureus and exhibits low risk of resistance development. We show explicitly that the fluorescent analogue of F105 rapidly penetrates into Gram-positive bacteria independently of their cell integrity and viability and accumulates there. By contrast, Gram-negative bacteria remain impermeable and, therefore, insusceptible to F105. Apparently, in bacterial cells, F105 induces reactive oxygen species (ROS) formation and nonspecifically interacts with a number of proteins, including ROS-utilizing ones. Using native and 2D PAGE, we confirm that F105 changes the charge of some proteins by either oxidation or direct interaction with them. Therefore, it seems justified to conclude that being simultaneously a ROS inducer and damaging proteins responsible for ROS utilization, F105 impairs the cellular anti-ROS defense representing a prospective ROS-inducing antibacterial agent.


Assuntos
Antibacterianos/farmacologia , Furanos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Descoberta de Drogas , Furanos/síntese química , Furanos/química , Humanos , Peróxido de Hidrogênio/farmacologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/metabolismo
18.
Magn Reson Chem ; 57(6): 285-293, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30632625

RESUMO

The quantitative structure-activity relationship models of 40 phenylhydrazine-substituted tetronic acid derivatives were established between the 1 H nuclear magnetic resonance (NMR) and 13 C NMR chemical shifts and the antifungal activity against Fusarium graminearum, Botrytis cinerea, Rhizoctonia cerealis, and Colletotrichum capsici. The models were validated by R, R2 , RA 2 , variance inflation factor, F, and P values testing and residual analysis. It was concluded from the models that the 13 C NMR chemical shifts of C8, C10, C7, and the 1 H NMR chemical shifts of Ha contributed positively to the activity against Fusarium graminearum, Botrytis cinerea, Colletotrichum capsici, and Rhizoctonia cerealis, respectively. The models indicated that decreasing the election cloud density of specific nucleuses in compounds, for example, by the substituting of electron withdrawing groups, would improve the antifungal activity. These models demonstrated the practical application meaning of chemical shifts in the quantitative structure-activity relationship study. Furthermore, a practical guide was provided for further structural optimization of the antifungal phenylhydrazine-substituted tetronic acid derivatives based on the 1 H NMR and 13 C NMR chemical shifts.


Assuntos
Fungicidas Industriais/síntese química , Furanos/síntese química , Espectroscopia de Ressonância Magnética/métodos , Fenil-Hidrazinas/síntese química , Ascomicetos/efeitos dos fármacos , Botrytis/efeitos dos fármacos , Fungicidas Industriais/farmacologia , Furanos/farmacologia , Fusarium/efeitos dos fármacos , Estrutura Molecular , Fenil-Hidrazinas/farmacologia , Relação Quantitativa Estrutura-Atividade , Rhizoctonia/efeitos dos fármacos
19.
RNA ; 25(4): 423-430, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30609994

RESUMO

We have designed structure-based ligands for the guanidine-II riboswitch that bind with enhanced affinity, exploiting the twin binding sites created by loop-loop interaction. We synthesized diguanidine species, comprising two guanidino groups covalently connected by Cn linkers where n = 4 or 5. Calorimetric and fluorescent analysis shows that these ligands bind with a 10-fold higher affinity to the riboswitch compared to guanidine. We determined X-ray crystal structures of the riboswitch bound to the new ligands, showing that the guanidino groups are bound to both nucleobases and backbone within the binding pockets, analogously to guanidine binding. The connecting chain passes through side openings in the binding pocket and traverses the minor groove of the RNA. The combination of the riboswitch loop-loop interaction and our novel ligands has potential applications in chemical biology.


Assuntos
Furanos/química , Guanidina/análogos & derivados , Nucleotídeos/química , Riboswitch , Sítios de Ligação , Cristalografia por Raios X , Desenho de Drogas , Furanos/síntese química , Guanidina/síntese química , Guanidina/química , Ligações de Hidrogênio , Ligantes , Modelos Moleculares , Conformação de Ácido Nucleico
20.
Bioorg Chem ; 82: 290-305, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30396063

RESUMO

Approximately 60% of human cancers exhibit enhanced activity of ERK1 and ERK2, reflecting their multiple roles in tumor initiation and progression. Acquired drug resistance, especially mechanisms associated with the reactivation of the MAPK (RAF/MEK/ERK) pathway represent a major challenge to current treatments of melanoma and several other cancers. Recently, targeting ERK has evolved as a potentially attractive strategy to overcome this resistance. Herein, we report the design and synthesis of novel series of fused naphthofuro[3,2-c]quinoline-6,7,12-triones 3a-f and pyrano[3,2-c]quinoline-6,7,8,13-tetraones 5a,b and 6, as potential ERK inhibitors. New inhibitors were synthesized and identified by different spectroscopic techniques and X-ray crystallography. They were evaluated for their ability to inhibit ERK1/2 in an in vitro radioactive kinase assay. 3b and 6 inhibited ERK1 with IC50s of 0.5 and 0.19 µM, and inhibited ERK2 with IC50s of 0.6 and 0.16 µM respectively. Kinetic mechanism studies revealed that the inhibitors are ATP-competitive inhibitors where 6 inhibited ERK2 with a Ki of 0.09 µM. Six of the new inhibitors were tested for their in vitro anticancer activity against the NCI-60 panel of tumor cell lines. Compound 3b and 6 were the most potent against most of the human tumor cell lines tested. Moreover, 3b and 6 inhibited the proliferation of the BRAF mutant A375 melanoma cells with IC50s of 3.7 and 0.13 µM, respectively. In addition, they suppressed anchorage-dependent colony formation. Treatment of the A375 cell line with 3b and 6 inhibited the phosphorylation of ERK substrates p-90RSK and ELK-1 and induced apoptosis in a dose dependent manner. Finally, a molecular docking study showed the potential binding mode of 3b and 6 within the ATP catalytic binding site of ERK2.


Assuntos
Antineoplásicos/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Naftoquinonas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Domínio Catalítico , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Furanos/química , Furanos/farmacocinética , Furanos/farmacologia , GTP Fosfo-Hidrolases/genética , Humanos , Proteínas de Membrana/genética , Proteína Quinase 1 Ativada por Mitógeno/química , Estrutura Molecular , Mutação , Naftoquinonas/síntese química , Naftoquinonas/química , Naftoquinonas/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas B-raf/genética , Piranos/síntese química , Piranos/química , Piranos/farmacocinética , Piranos/farmacologia , Quinolonas/síntese química , Quinolonas/química , Quinolonas/farmacocinética , Relação Estrutura-Atividade
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