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1.
Molecules ; 24(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505754

RESUMO

Novel derivatives of some non steroidal anti-inflammatory drugs, as well as of the antioxidants α-lipoic acid, trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid with lorazepam were synthesised by a straightforward method at satisfactory to high yields (40%-93%). All the tested derivatives strongly decreased lipidemic indices in rat plasma after Triton induced hyperlipidaemia. They also reduced acute inflammation and a number of them demonstrated lipoxygenase inhibitory activity. Those compounds acquiring antioxidant moiety were inhibitors of lipid peroxidation and radical scavengers. Therefore, the synthesised compounds may add to the current knowledge about multifunctional agents acting against various disorders implicating inflammation, dyslipidaemia and oxidative stress.


Assuntos
Hiperlipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico , Lorazepam/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Acrilatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Carragenina/química , Carragenina/farmacologia , Cromanos/química , Cromanos/farmacologia , Humanos , Hiperlipidemias/patologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Inibidores de Lipoxigenase/farmacologia , Lorazepam/análogos & derivados , Ratos , Ácido Tióctico/análogos & derivados , Ácido Tióctico/farmacologia
2.
Biochim Biophys Acta Biomembr ; 1861(8): 1489-1501, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247162

RESUMO

Free radical scavengers like α-phenyl-N-tert-butylnitrone (PBN) and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) have been widely used as protective agents in various biomimetic and biological models. A series of three amphiphilic Trolox and PBN derivatives have been designed by adding to those molecules a perfluorinated chain as well as a sugar group in order to render them amphiphilic. In this work, we have studied the interactions between these derivatives and lipid membranes to understand how they influence their ability to prevent membrane lipid oxidation. We showed the derivatives better inhibited the AAPH-induced oxidation of 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLiPC) small unilamellar vesicles (SUVs) than the parent compounds. One of the derivatives, bearing both PBN and Trolox moieties on the same fluorinated carrier, exhibited a synergistic antioxidant effect by delaying the oxidation process. We next investigated the ability of the derivatives to interact with DLiPC membranes in order to better understand the differences observed regarding the antioxidant properties. Surface tension and fluorescence spectroscopy experiments revealed the derivatives exhibited the ability to form monolayers at the air/water interface and spontaneously penetrated lipid membranes, underlying pronounced hydrophobic properties in comparison to the parent compounds. We observed a correlation between the hydrophobic properties, the depth of penetration and the antioxidant properties and showed that the location of these derivatives in the membrane is a key parameter to rationalize their antioxidant efficiency. Molecular dynamics (MD) simulations supported the understanding of the mechanism of action, highlighting various key physical-chemical descriptors.


Assuntos
Antioxidantes/farmacologia , Cromanos/química , Lipídeos de Membrana/química , Óxidos de Nitrogênio/química , Sinergismo Farmacológico , Flúor/química , Peroxidação de Lipídeos , Membranas Artificiais , Oxirredução
3.
Int J Mol Sci ; 20(11)2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31181693

RESUMO

Retinoids are present in human tissues exposed to light and under increased risk of oxidative stress, such as the retina and skin. Retinoid cation radicals can be formed as a result of the interaction between retinoids and other radicals or photoexcitation with light. It has been shown that such semi-oxidized retinoids can oxidize certain amino acids and proteins, and that α-tocopherol can scavenge the cation radicals of retinol and retinoic acid. The aim of this study was to determine (i) whether ß-, γ-, and δ-tocopherols can also scavenge these radicals, and (ii) whether tocopherols can scavenge the cation radicals of another form of vitamin A-retinal. The retinoid cation radicals were generated by the pulse radiolysis of benzene or aqueous solution in the presence of a selected retinoid under oxidizing conditions, and the kinetics of retinoid cation radical decays were measured in the absence and presence of different tocopherols, Trolox or urate. The bimolecular rate constants are the highest for the scavenging of cation radicals of retinal, (7 to 8) × 109 M-1·s-1, followed by retinoic acid, (0.03 to 5.6) × 109 M-1·s-1, and retinol, (0.08 to 1.6) × 108 M-1·s-1. Delta-tocopherol is the least effective scavenger of semi-oxidized retinol and retinoic acid. The hydrophilic analogue of α-tocopherol, Trolox, is substantially less efficient at scavenging retinoid cation radicals than α-tocopherol and urate, but it is more efficient at scavenging the cation radicals of retinoic acid and retinol than δ-tocopherol. The scavenging rate constants indicate that tocopherols can effectively compete with amino acids and proteins for retinoid cation radicals, thereby protecting these important biomolecules from oxidation. Our results provide another mechanism by which tocopherols can diminish the oxidative damage to the skin and retina and thereby protect from skin photosensitivity and the development and/or progression of changes in blinding retinal diseases such as Stargardt's disease and age-related macular degeneration (AMD).


Assuntos
Cromanos/química , Depuradores de Radicais Livres/química , Retinoides/química , Tocoferóis/química , Ácido Úrico/química , Cátions/química
4.
Immunopharmacol Immunotoxicol ; 41(2): 337-348, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31056974

RESUMO

Objective: The isochroman-type fungal metabolite 3,7-dimethyl-1,8-hydroxy-6-methoxyisochroman (DMHM) was isolated from the extracts of a marine-derived fungal strain of Penicillium sp. SF-6013. In this study, we investigated the effect of DMHM on inflammatory response. Materials and methods: Anti-inflammatory effects of DMHM were examined in lipopolysaccharide (LPS)-stimulated RAW264.7 and BV2 cells. We observed their anti-inflammatory effects by ELISA, qRT-PCR, and western blot analysis. Results: DMHM revealed that it suppressed the production of prostaglandin E2 (PGE2), nitric oxide (NO), cyclooxygenase-2 (COX-2), and inducible NO synthase (iNOS) in LPS-stimulated RAW264.7 and BV2 cells. Furthermore, DMHM decreased the mRNA expression of pro-inflammatory cytokines including interleukin (IL)-1ß and IL-6. Therefore, DMHM was further investigated to elucidate the mechanisms of its anti-inflammatory properties; the results indicated that its effect was mediated by the suppression of the nuclear factor (NF)-κB and c-Jun N-terminal kinase (JNK) MAPK pathways. Furthermore, the anti-inflammatory activity of DMHM correlated with its induction of heme oxygenase-1 (HO)-1 expression via activation of the nuclear factor erythroid 2-like 2 (Nrf2) pathway. Discussion and conclusions: Collectively, the results of this study suggest that DMHM inhibited several inflammatory pathways including the NF-κB and MAPK pathways, and induced Nrf2-mediated HO-1 expression, demonstrating its potential usefulness for treating inflammatory and neuroinflammatory diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Cromanos/farmacologia , Heme Oxigenase-1/imunologia , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Membrana/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Animais , Anti-Inflamatórios/química , Cromanos/química , Ciclo-Oxigenase 2/imunologia , Dinoprostona/imunologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Óxido Nítrico/imunologia , Penicillium/química , Células RAW 264.7
5.
Mol Med Rep ; 19(6): 5007-5014, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942406

RESUMO

Myocardial infarction (MI) is associated with a high risk of mortality and is a major global health concern. The present study aimed to investigate the protective effects of (3R)­5,6,7­trihydroxy­3­isopropyl­3­methylisochroman­1­one (TIM) against MI induced by isoproterenol (ISO) in a rat model and the underlying mechanisms. Wistar rats were assigned to 4 groups (n=10): The control group received saline treatment; the ISO group received an intraperitoneal injection of ISO (100 mg/kg); and the TIM (low) and TIM (high) groups received an intraperitoneal injection of ISO, plus a 1 and 2 mg/kg dose of TIM orally, respectively. TIM rats were treated with TIM daily for 12 days and received ISO injections on the final 2 days to induce MI. Cardiac function, apoptosis index and protein expression were subsequently determined. The levels of oxidative stress markers were determined by ELISAs, whereas DNA damage was detected using a Cell Death Detection ELISA kit. Gene and protein expression were determined via reverse transcription­quantitative polymerase chain reaction and western blot analyses, respectively. Following treatment with ISO, the maximum left ventricular contraction/relaxation velocity and left ventricular systolic pressure were significantly decreased, whereas the left ventricular end­diastolic pressure was increased; however, treatment with TIM significantly ameliorated ISO­induced cardiac dysfunction. Additionally, TIM treatment significantly decreased oxidative stress and inhibited the apoptosis of cardiomyocytes, as determined by a decrease in caspase activities, increased expression of B­cell lymphoma 2 (Bcl­2) and reduced expression of cleaved caspase­3, cleaved caspase­9 and Bcl­2­associated X. Furthermore, treatment with TIM upregulated the levels of apelin in the plasma and myocardium of ISO­treated rats. The results indicated that TIM protected cardiomyocytes against ISO­induced MI, potentially via the apelin/apelin receptor signaling pathway. The results of the present study suggested that TIM may be a potential novel therapy for the treatment of MI.


Assuntos
Receptores de Apelina/metabolismo , Apelina/metabolismo , Cromanos/farmacologia , Coração/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Cromanos/química , Cromanos/uso terapêutico , Isoproterenol/toxicidade , Masculino , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
6.
Eur J Med Chem ; 170: 16-27, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30878829

RESUMO

A series of Flexible Heteroarotinoid (Flex-Het) analogs was synthesized and their biological activities were evaluated against the A2780 ovarian cancer cell line. The objective of this study was to establish structure-activity relationships (SARs) for new Flex-Het derivatives, which were previously inaccessible due to the limited availability of aryl isothiocyanate precursors. The current work developed a synthesis of isothiocyanate 13 and used it to prepare 14 diverse thiourea analogs of the lead compound SHetA2 (1, NSC-721689) from a range of commercial amines. Additionally, five new ureas were prepared along with nine N-benzylthioureas, five derivatives incorporating hydrazine or hydrazide linkers and four desmethyl compounds. Potencies and efficacies were determined for each derivative. Some of the new Flex-Hets displayed high activity with IC50 values ranging from 1.86 to 4.70 µM and 85.6-95.9% efficacies, which are comparable to or better than the lead compound (IC50 3.17 µM, 84.3% efficacy). Although SHetA2 is scheduled to enter clinical trials in the near future, alternative backup drug candidates have been identified in this work. The new agents possess similar pharmacological properties and retain selective activity against A2780 ovarian cancer cells. Although a mixed SAR was obtained for these analogs, diversified, highly potent molecules were identified for further investigation. In particular, agents 2c-d and 3e-f, which incorporated CF3 and OCF3 groups in place of NO2 on the pendent aryl ring, displayed high activity and excellent differentiation between normal and cancerous cells.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cromanos/química , Cromanos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Tionas/química , Tionas/farmacologia , Tioureia/análogos & derivados , Tioureia/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromanos/síntese química , Feminino , Humanos , Neoplasias Ovarianas/patologia , Relação Estrutura-Atividade , Tionas/síntese química , Tioureia/síntese química
7.
J Pharm Biomed Anal ; 170: 124-131, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30921646

RESUMO

SHetA2 is a flexible heteroarotinoid that has the potential to prevent and treat lung, ovarian and cervical cancer without significant toxicity. A simple and reliable high performance liquid chromatographic (HPLC) method was developed to determine SHetA2 concentrations in the lungs, reproductive organs and plasma of mice. SHetA2 was extracted from these biological matrices by solid phase and liquid-liquid extraction in the presence of 4% H3PO4 and acetonitrile followed by filtration through a Captiva® filtration plate. Drug concentrations in the filtrates were quantified by a Waters HPLC Alliance system coupled with XBridge® C18 column, guard column and UV detection at 361 nm. The mobile phase consisted of methanol and 0.25 N sodium acetate buffer (80:20, v/v) at pH: 3. SHetA2 was eluted after 5.35 and 6.14 min for tissues and plasma, respectively. Recovery of SHetA2 from biological samples was more than 95% of the spiked amount in tissues and more than 80% of the spiked amount in plasma. The limit of detection (LOD) was 0.005 µg/mL and the limit of quantitation (LOQ) was 0.025 µg/mL, which were 280 and 56 times lower than the predicted therapeutic concentration of SHetA2, respectively. The method was suitable to quantify SHetA2 concentrations in biological matrices from animal studies administering the drug by the vaginal, pulmonary and oral routes that had the purpose of determining the pharmacokinetic parameters of drug disposition. The HPLC method developed meets the ICH Harmonized Tripartite Guideline of a reliable, sensitive, reproducible and accurate method to be used in the determination of drug concentrations in biological samples.


Assuntos
Antineoplásicos/química , Cromanos/química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/métodos , Tionas/química , Acetonitrilos/química , Administração Oral , Animais , Feminino , Limite de Detecção , Extração Líquido-Líquido/métodos , Masculino , Camundongos , Reprodutibilidade dos Testes
8.
Bioorg Med Chem ; 27(7): 1382-1390, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30819619

RESUMO

ROCK1 and ROCK2 are highly homologous isoforms. Accumulated studies indicate that they have distinct different functions, and the development of isoform selective ROCK inhibitors will pave new roads for the treatment of various diseases. In this work, a series of amide-chroman derivatives were synthesized and biologically evaluated in order to develop potent and isoform selective ROCK2 inhibitors. Remarkably, (S)-6-methoxy-chroman-3-carboxylic acid (4-pyridin-4-yl-phenyl)-amide ((S)-7c) possessed ROCK2 inhibitory activity with an IC50 value of 3 nM and 22.7-fold isoform selectivity (vs. ROCK1). Molecular docking indicated that hydrophobic interactions were the key element for the high potency and isoform selectivity of (S)-7c. The binding free energies predicted by MM/GBSA were in good agreement with the experimental bioactivities, and the analysis of individual energy terms suggested that residue Lys105 in ROCK1 or Lys121 in ROCK2 was the key residue for the isoform selectivity of (S)-7c.


Assuntos
Cromanos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Cromanos/síntese química , Cromanos/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismo
9.
Oxid Med Cell Longev ; 2019: 2069250, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906500

RESUMO

The newly synthesized coumarin derivative with dopamine, 3-(1-((3,4-dihydroxyphenethyl)amino)ethylidene)-chroman-2,4-dione, was completely structurally characterized by X-ray crystallography. It was shown that several types of hydrogen bonds are present, which additionally stabilize the structure. The compound was tested in vitro against different cell lines, healthy human keratinocyte HaCaT, cervical squamous cell carcinoma SiHa, breast carcinoma MCF7, and hepatocellular carcinoma HepG2. Compared to control, the new derivate showed a stronger effect on both healthy and carcinoma cell lines, with the most prominent effect on the breast carcinoma MCF7 cell line. The molecular docking study, obtained for ten different conformations of the new compound, showed its inhibitory nature against CDKS protein. Lower inhibition constant, relative to one of 4-OH-coumarine, proved stronger and more numerous interactions with CDKS protein. These interactions were carefully examined for both parent molecule and derivative and explained from a structural point of view.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Cromanos/síntese química , Cromanos/farmacologia , Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Cromanos/química , Cristalografia por Raios X , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular
10.
Talanta ; 195: 850-856, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30625627

RESUMO

Hydrogen sulfide or H2S is known as an important gasotransmitter involved in regulation of many physiological and pathological processes. Since a small amount of H2S is produced by endogenous cells in the body and microorganisms in the gastrointestinal tract (GI tract), the current detection probes are limited for their use in measurement of unpretentious change of H2S level both in vitro and in vivo. Therefore, development of a highly sensitive and responsive fluorescent probe for measurement of H2S in vivo is of great significance for investigation of H2S function and toxicity. Here, we designed a novel fluorescent probe AC-N3 through introducing azide in 6-position of chroman dye based on the hypothesis that 6-position (para-position) of chromone may be a potential trigger of fluorescent properties. The probe AC-N3 exhibits a better selectivity without interference from analytes, high sensitivity and little cytotoxicity. In addition, we confirmed that the conversion of electron-donating group in 6-position of chromone can trigger the change of fluorescence, which can be applied to design of other fluorescent probes.


Assuntos
Azidas/química , Cromanos/química , Corantes Fluorescentes/química , Sulfeto de Hidrogênio/análise , Células HeLa , Humanos , Sulfeto de Hidrogênio/química , Microscopia de Fluorescência , Imagem Óptica
11.
Chem Biodivers ; 16(3): e1800581, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30600902

RESUMO

Fourteen chromane derivatives of seven pairs of enantiomers (1-14) have been obtained from the ethanolic extract of the flower buds of Tussilago farfara L. Their structures with absolute configurations have been elucidated by detailed spectroscopic analyses, chemical methods, and particularly comparison of experimental ECD spectra with theoretically computed ones. Biological evaluations revealed that they did not show cytoprotective, antimicrobial, and α-glucosidase inhibitory activities.


Assuntos
Cromanos/química , Flores/química , Extratos Vegetais/química , Raízes de Plantas/química , Tussilago/química , Cromanos/isolamento & purificação , Teoria da Densidade Funcional , Humanos , Conformação Molecular , Extratos Vegetais/isolamento & purificação , Estereoisomerismo , Células Tumorais Cultivadas
12.
Food Chem ; 279: 288-293, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30611492

RESUMO

A protocol for determining the location of antioxidants (AOs) in a micro-heterogeneous medium was applied to three series of AOs with increasing hydrophobicities: chromancarboxylic acid ("Trolox") esters, caffeic acid and its esters, and gallic acid and its esters. The observed paradoxical behaviour of these and other commonly encountered antioxidants was rationalized with the aid of a pictorial simile, the "diving-swan" analogy, that explains the orientation and location of an amphiphobic AO when it reacts with a radical probe in the micellar interface.


Assuntos
Antioxidantes/química , Ácidos Cafeicos/química , Cromanos/química , Ácido Gálico/química , Micelas , Antioxidantes/análise , Ésteres/química , Interações Hidrofóbicas e Hidrofílicas
13.
Nat Prod Res ; 33(13): 1870-1875, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29792356

RESUMO

Four previously undescribed isochromanes were isolated from the fermentation broth of an endophytic fungus Aspergillus fumigatus, which was obtained from the fruiting body of Cordyceps sinensis. Their structures were elucidated through extensive spectroscopic analyses. One racemic isochromane was further purified by chiral HPLC to yield a pair of enantiomers and their absolute configurations were determined by quantum chemical ECD calculations. These isolated compounds were evaluated for cytotoxicity against two cell lines (MV4-11 and MDA-ME-231) and the result showed that compounds 1a and 2 exhibited moderate growth inhibition against MV4-11 cell line.


Assuntos
Aspergillus fumigatus/química , Cromanos/isolamento & purificação , Cordyceps , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cromanos/química , Cromanos/farmacologia , Citotoxinas/isolamento & purificação , Inibidores do Crescimento/isolamento & purificação , Humanos , Estrutura Molecular , Análise Espectral , Estereoisomerismo
14.
Chem Biol Drug Des ; 93(3): 254-261, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30264436

RESUMO

Sulfone/sulfoxide-containing carbohydrate derived thiochromans were found to be highly active antiplasmodial agents. However, the inability of the sulfone/sulfoxide functional groups for further derivatization and manipulation limited the potential for further exploration. In this study, based on the interesting and important physicochemical properties, as well as amenability of sulfoximines (isosters of sulfones) for further derivatization, a series of novel sulfoximine-type carbohydrate-derived thiochroman derivatives have been successfully synthesized, characterized, and evaluated for their antiplasmodial activity. Although the replacement of the sulfone functional group with a sulfoximine unit improved the antiplasmodial activity of the scaffolds, the activity was highly dependent on the configuration of the stereogenic centre at the sulfur atom. Moreover, analysis of the crystal structures of the sulfoximine analogues revealed that the bond between the sulfur and nitrogen atoms of the sulfoximine functional group is not a true double bond but rather a polarized single bond.


Assuntos
Antimaláricos/síntese química , Cromanos/química , Desenho de Drogas , Safrol/análogos & derivados , Sulfonas/química , Alquilação , Antimaláricos/química , Antimaláricos/farmacologia , Carboidratos/química , Sobrevivência Celular/efeitos dos fármacos , Cromanos/síntese química , Cromanos/farmacologia , Células HeLa , Humanos , Plasmodium falciparum/efeitos dos fármacos , Safrol/síntese química , Safrol/química , Safrol/farmacologia , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacologia
15.
J Ind Microbiol Biotechnol ; 46(3-4): 375-383, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30284140

RESUMO

Natural product discovery in the microbial world has historically been biased toward aerobes. Recent in silico analysis demonstrates that genomes of anaerobes encode unexpected biosynthetic potential for natural products, however, chemical data on natural products from the anaerobic world are extremely limited. Here, we review the current body of work on natural products isolated from strictly anaerobic microbes, including recent genome mining efforts to discover polyketides and non-ribosomal peptides from anaerobes. These known natural products of anaerobes have demonstrated interesting molecular scaffolds, biosynthetic logic, and/or biological activities, making anaerobes a promising reservoir for future natural product discovery.


Assuntos
Bactérias Anaeróbias/genética , Bactérias Anaeróbias/metabolismo , Produtos Biológicos/metabolismo , Vias Biossintéticas/genética , Cromanos/química , Família Multigênica , Naftóis/química , Peptídeos/química , Fenazinas/química , Hidrocarbonetos Policíclicos Aromáticos/química , Policetídeos/química , Tioamidas/química
16.
Cancer Lett ; 443: 157-166, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30503556

RESUMO

SL-1-39 [1-(4-chloro-3-methylphenyl)-3-(4-nitrophenyl)thiourea] is a new flexible heteroarotinoid (Flex-Het) analog derived from the parental compound, SHetA2, previously shown to inhibit cell growth across multiple cancer types. The current study aims to determine growth inhibitory effects of SL-1-39 across the different subtypes of breast cancer cells and delineate its molecular mechanism. Our results demonstrate that while SL-1-39 blocks cell proliferation of all breast cancer subtypes tested, it has the highest efficacy against HER2+ breast cancer cells. Molecular analyses suggest that SL-1-39 prevents S phase progression of HER2+ breast cancer cells (SKBR3 and MDA-MB-453), which is consistent with reduced expression of key cell-cycle regulators at both the protein and transcriptional levels. SL-1-39 treatment also decreases the protein levels of HER2 and pHER2 as well as its downstream effectors, pMAPK and pAKT. Reduction of HER2 and pHER2 at the protein level is attributed to increased lysosomal degradation of total HER2 levels. This is the first study to show that a flexible heteroarotinoid analog modulates the HER2 signaling pathway through lysosomal degradation, and thus further warrants the development of SL-1-39 as a therapeutic option for HER2+ breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Cromanos/síntese química , Lisossomos/metabolismo , Receptor ErbB-2/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Catecóis/química , Catecóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromanos/química , Cromanos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Proteólise , Receptor ErbB-2/genética , Tionas/química
17.
Food Chem ; 278: 469-475, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-30583398

RESUMO

Chlorogenic acid (5CQA) is a dietary polyphenol known for its high biological activity. Antioxidative behavior of 5CQA relative to trolox (Tx) toward the HO and CH3OO radicals in aqueous solution at pH = 7.4 was simulated using density functional theory. This is the first study where behavior of monoanion and dianion of 5CQA at physiological conditions is described. Both anionic forms undergo only hydrogen atom transfer (HAT) mechanism with CH3OO. With HO, anionic forms of 5CQA conform to the HAT, radical adduct formation, sequential proton loss electron transfer, and single electron transfer - proton transfer mechanisms. Contribution of dianion to scavenging HO is comparable to that of more abundant monoanion. The calculated rate constant for overall reaction of 5CQA with HO is in perfect agreement with the corresponding experimental value. In comparison to Tx, 5CQA is more reactive toward HO, but less reactive toward CH3OO.


Assuntos
Antioxidantes/química , Ácido Clorogênico/química , Cromanos/química , Teoria da Densidade Funcional , Transporte de Elétrons , Concentração de Íons de Hidrogênio , Hidróxidos/química , Prótons , Água/química
18.
Molecules ; 23(12)2018 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-30551624

RESUMO

Tyrosinase is a key enzyme in melanin synthesis, catalyzing the initial rate-limiting steps of melanin synthesis. Abnormal and excessive melanin synthesis is the primary cause of serious skin disorders including melasma, senile lentigo, freckles, and age spots. In attempts to find potent and safe tyrosinase inhibitors, we designed and synthesized a novel compound, (Z)-3-(3-bromo-4-hydroxybenzylidene)thiochroman-4-one (MHY1498), and evaluated its tyrosinase inhibitory activity in vitro and in silico. The chemical structures of (Z)-3-benzylidenethiochroman-4-one analogues, including the novel compound MHY1498, were rationally designed and synthesized as hybrid structures of reported potent tyrosinase inhibitors, which were confirmed both in vitro and in vivo: (Z)-5-(substituted benzylidene)thiazolidine-2,4-diones (Compound A) and 2-(substituted phenyl)benzo[d]thiazoles (Compound B). During screening, MHY1498 showed a strong dose-dependent inhibitory effect on mushroom tyrosinase. The IC50 value of MHY1498 (4.1 ± 0.6 µM) was significantly lower than that of the positive control, kojic acid (22.0 ± 4.7 µM). In silico molecular multi-docking simulation and inhibition mechanism studies indicated that MHY1498 interacts competitively with the tyrosinase enzyme, with greater affinity for the active site of tyrosinase than the positive control. Furthermore, in B16F10 melanoma cells treated with α-melanocyte-stimulating hormone, MHY1498 suppressed both melanin production and tyrosinase activity. In conclusion, our data demonstrate that MHY1498, a synthesized novel compound, effectively inhibits tyrosinase activity and has potential for treating hyperpigmentation and related disorders.


Assuntos
Cromanos/farmacologia , Simulação por Computador , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Agaricales/enzimologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Cromanos/síntese química , Cromanos/química , Desenho de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Concentração Inibidora 50 , Cinética , Melaninas/biossíntese , Melanoma Experimental/patologia , Camundongos , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase/metabolismo , Pironas/farmacologia
19.
Bioorg Med Chem ; 26(20): 5443-5461, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30270002

RESUMO

The non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and inhibitor of nuclear factor kappa-B kinase ε (IKKε) play a key role in insulin-independent pathways that promote energy storage and block adaptive energy expenditure during obesity. Utilizing docking calculations and the x-ray structure of TBK1 bound to amlexanox, an inhibitor of these kinases with modest potency, a series of analogues was synthesized to develop a structure activity relationship (SAR) around the A- and C-rings of the core scaffold. A strategy was developed wherein R7 and R8 A-ring substituents were incorporated late in the synthetic sequence by utilizing palladium-catalyzed cross-coupling reactions on appropriate bromo precursors. Analogues display IC50 values as low as 210 nM and reveal A-ring substituents that enhance selectivity toward either kinase. In cell assays, selected analogues display enhanced phosphorylation of p38 or TBK1 and elicited IL-6 secretion in 3T3-L1 adipocytes better than amlexanox. An analogue bearing a R7 cyclohexyl modification demonstrated robust IL-6 production in 3T3-L1 cells as well as a phosphorylation marker of efficacy and was tested in obese mice where it promoted serum IL-6 response, weight loss, and insulin sensitizing effects comparable to amlexanox. These studies provide impetus to expand the SAR around the amlexanox core toward uncovering analogues with development potential.


Assuntos
Quinase I-kappa B/antagonistas & inibidores , Obesidade/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Células 3T3-L1 , Aminação , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Cromanos/síntese química , Cromanos/química , Cromanos/farmacologia , Cromanos/uso terapêutico , Cristalografia por Raios X , Desenho de Drogas , Humanos , Quinase I-kappa B/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Obesidade/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/metabolismo , Piridinas/síntese química , Piridinas/uso terapêutico
20.
Eur J Med Chem ; 160: 171-182, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30340140

RESUMO

We describe the design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors with carboxamide derivatives as the P2 ligands. We have specifically designed aminothiochromane and aminotetrahydronaphthalene-based carboxamide ligands to promote hydrogen bonding and van der Waals interactions in the active site of HIV-1 protease. Inhibitors 4e and 4j have shown potent enzyme inhibitory and antiviral activity. High resolution X-ray crystal structures of 4d- and 4k-bound HIV-1 protease revealed molecular insights into the ligand-binding site interactions.


Assuntos
Antivirais/farmacologia , Cromanos/farmacologia , Desenho de Drogas , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Naftalenos/farmacologia , Antivirais/síntese química , Antivirais/química , Cromanos/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , HIV/efeitos dos fármacos , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , Ligantes , Modelos Moleculares , Estrutura Molecular , Naftalenos/química , Relação Estrutura-Atividade
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