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1.
Mar Biotechnol (NY) ; 26(2): 404-420, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38558367

RESUMO

Optimization of antioxidants and angiotensin-converting enzyme (ACE) inhibitory potential gelatin hydrolysate production from Labeo rohita (rohu) swim bladder (SBGH) by alcalase using central composite design (CCD) of response surface methodology (RSM) was investigated. The maximum degree of hydrolysis (DH), 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS), total antioxidants (TAO), and ACE inhibitory activity were achieved at 0.1:1.0 (w/w) enzyme to substrate ratio, 61 °C hydrolysis temperature, and 94-min hydrolysis time. The resulting SBGH obtained at 19.92% DH exhibited the DPPH (24.28 µM TE/mg protein), ABTS (34.47 µM TE/mg protein), TAO (12.01 µg AAE/mg protein), and ACE inhibitory (4.91 µg/mg protein) activity. Furthermore, SBGH at 100 µg/ml displayed osteogenic property without any toxic effects on MC3T3-E1 cells. Besides, the protein content of rohu swim bladder gelatin (SBG) and SBGH was 93.68% and 94.98%, respectively. Both SBG and SBGH were rich in glycine, proline, glutamic acid, alanine, arginine, and hydroxyproline amino acids. Therefore, SBGH could be an effective nutraceutical in functional food development.


Assuntos
Sacos Aéreos , Inibidores da Enzima Conversora de Angiotensina , Antioxidantes , Gelatina , Animais , Gelatina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Antioxidantes/farmacologia , Antioxidantes/química , Sacos Aéreos/química , Sacos Aéreos/metabolismo , Camundongos , Hidrolisados de Proteína/química , Hidrolisados de Proteína/farmacologia , Osteogênese/efeitos dos fármacos , Cyprinidae/metabolismo , Hidrólise , Subtilisinas/metabolismo , Compostos de Bifenilo/química , Proteínas de Peixes/metabolismo , Picratos
2.
Sci Rep ; 14(1): 9195, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38649707

RESUMO

The development of novel antioxidant compounds with high efficacy and low toxicity is of utmost importance in the medicine and food industries. Moreover, with increasing concerns about the safety of synthetic components, scientists are beginning to search for natural sources of antioxidants, especially essential oils (EOs). The combination of EOs may produce a higher scavenging profile than a single oil due to better chemical diversity in the mixture. Therefore, this exploratory study aims to assess the antioxidant activity of three EOs extracted from Cymbopogon flexuosus, Carum carvi, and Acorus calamus in individual and combined forms using the augmented-simplex design methodology. The in vitro antioxidant assays were performed using DPPH and ABTS radical scavenging approaches. The results of the Chromatography Gas-Mass spectrometry (CG-MS) characterization showed that citral (29.62%) and niral (27.32%) are the main components for C. flexuosus, while D-carvone (62.09%) and D-limonene (29.58%) are the most dominant substances in C. carvi. By contrast, ß-asarone (69.11%) was identified as the principal component of A. calamus (30.2%). The individual EO exhibits variable scavenging activities against ABTS and DPPH radicals. These effects were enhanced through the mixture of the three EOs. The optimal antioxidant formulation consisted of 20% C. flexuosus, 53% C. carvi, and 27% A. calamus for DPPHIC50. Whereas 17% C. flexuosus, 43% C. carvi, and 40% A. calamus is the best combination leading to the highest scavenging activity against ABTS radical. These findings suggest a new research avenue for EOs combinations to be developed as novel natural formulations useful in food and biopharmaceutical products.


Assuntos
Acorus , Antioxidantes , Carum , Cymbopogon , Óleos Voláteis , Extratos Vegetais , Cymbopogon/química , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Antioxidantes/farmacologia , Antioxidantes/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Acorus/química , Carum/química , Cromatografia Gasosa-Espectrometria de Massas , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/química , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia
3.
Molecules ; 29(3)2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38338333

RESUMO

Bacterial infections pose a significant risk to human health. Magnolol, derived from Magnolia officinalis, exhibits potent antibacterial properties. Synthetic biology offers a promising approach to manufacture such natural compounds. However, the plant-based biosynthesis of magnolol remains obscure, and the lack of identification of critical genes hampers its synthetic production. In this study, we have proposed a one-step conversion of magnolol from chavicol using laccase. After leveraging 20 transcriptomes from diverse parts of M. officinalis, transcripts were assembled, enriching genome annotation. Upon integrating this dataset with current genomic information, we could identify 30 laccase enzymes. From two potential gene clusters associated with magnolol production, highly expressed genes were subjected to functional analysis. In vitro experiments confirmed MoLAC14 as a pivotal enzyme in magnolol synthesis. Improvements in the thermal stability of MoLAC14 were achieved through selective mutations, where E345P, G377P, H347F, E346C, and E346F notably enhanced stability. By conducting alanine scanning, the essential residues in MoLAC14 were identified, and the L532A mutation further boosted magnolol production to an unprecedented level of 148.83 mg/L. Our findings not only elucidated the key enzymes for chavicol to magnolol conversion, but also laid the groundwork for synthetic biology-driven magnolol production, thereby providing valuable insights into M. officinalis biology and comparative plant science.


Assuntos
Compostos Alílicos , Lignanas , Magnolia , Fenóis , Humanos , Magnolia/genética , Magnolia/química , Lacase , Lignanas/química , Compostos de Bifenilo/química
4.
J Med Chem ; 67(5): 3668-3678, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38308631

RESUMO

FmlH, a bacterial adhesin of uropathogenic Escherichia coli (UPEC), has been shown to provide a fitness advantage in colonizing the bladder during chronic urinary tract infections (UTIs). Previously reported ortho-biphenyl glycosides based on ßGal and ßGalNAc have excellent binding affinity to FmlH and potently block binding to its natural carbohydrate receptor, but they lack oral bioavailability. In this paper, we outline studies where we have optimized compounds for improved pharmacokinetics, leading to the discovery of novel analogues with good oral bioavailability. We synthesized galactosides with the anomeric O-linker replaced with more stable S- and C-linked linkers. We also investigated modifications to the GalNAc sugar and modifications to the biphenyl aglycone. We identified GalNAc 69 with an IC50 of 0.19 µM against FmlH and 53% oral bioavailability in mice. We also obtained a FimlH-bound X-ray structure of lead compound 69 (AM4085) which has potential as a new antivirulence therapeutic for UTIs.


Assuntos
Infecções por Escherichia coli , Infecções Urinárias , Escherichia coli Uropatogênica , Camundongos , Animais , Lectinas , Adesinas de Escherichia coli/química , Infecções Urinárias/tratamento farmacológico , Compostos de Bifenilo/química , Escherichia coli Uropatogênica/metabolismo , Infecções por Escherichia coli/tratamento farmacológico
5.
Food Chem ; 444: 138654, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38335685

RESUMO

The effect of tannic acid (TA) binding on the thermal degradation of boscalid was studied in this work. The results revealed that TA binding has a significant impact on boscalid degradation. The degradation rate constant of bound boscalid was reduced, and its corresponding half-life was significantly prolonged compared to the free state. Four identical degradation products were detected in both states through UHPLC-Q-TOF-MS, indicating that degradation products were not affected by TA binding. Based on DFT and MS analysis, the degradation pathways of boscalid included hydroxyl substitution of chlorine atoms and cleavage of CN and CC bonds. The toxicity of B2 and B3 exceeded that of boscalid. In summary, the binding of TA and boscalid significantly affected the thermal degradation rate of boscalid while preserving the types of degradation products. This study contributed to a fundamental understanding of the degradation process of bound pesticide residues in complex food matrices.


Assuntos
Compostos de Bifenilo , Niacinamida , Niacinamida/análogos & derivados , Polifenóis , Compostos de Bifenilo/química , Niacinamida/química
6.
Front Cell Infect Microbiol ; 13: 1325347, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38152121

RESUMO

The unreasonable use of antibiotics is one of the important causes of antimicrobial resistance (AMR) that poses a huge public health threat. Magnolol is a traditional Chinese medicine exhibiting antibacterial-, antifungal-, anti-inflammatory-, and antioxidant activities. However, it is unclear whether magnolol has an inhibitory effect on mycoplasma. This study found that magnolol showed excellent inhibitory activity against various mycoplasmas. Magnolol showed dose-dependent inhibition of Mycoplasma synoviae growth and biofilm formation in vitro. Magnolol caused severely sunken and wrinkled M. synoviae cell membranes at the minimum inhibitory concentration, and an enlarged cell diameter. The chicken embryo infection model showed that magnolol significantly reduced M. synoviae pathogenicity in vivo. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the citrate cycle, glycolysis/gluconeogenesis, and pyruvate metabolism were significantly disturbed at the minimum inhibitory concentration of magnolol. Interestingly, 41% of differential metabolites were in the categories of lipids and lipid-like molecules. Protegenin A was up-regulated 58752-fold after magnolol treatment. It belongs to fatty acyls, and destroys cell membrane integrity and cell activity. Ghosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, and phosphatidylserine related to membrane maintenance and stress response were widely down-regulated. Collectively, our results illustrate the feasibility of magnolol as a phytochemical compound to treat mycoplasma infection.


Assuntos
Lignanas , Mycoplasma synoviae , Animais , Embrião de Galinha , Lignanas/farmacologia , Lignanas/química , Antibacterianos/farmacologia , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/química , Mycoplasma synoviae/genética
7.
Anal Chem ; 95(48): 17603-17612, 2023 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-37973790

RESUMO

Despite the rapid advances in process analytical technology, the assessment of protein refolding efficiency has largely relied on off-line protein-specific assays and/or chromatographic procedures such as reversed-phase high-performance liquid chromatography and size exclusion chromatography. Due to the inherent time gap pertaining to traditional methods, exploring optimum refolding conditions for many recombinant proteins, often expressed as insoluble inclusion bodies, has proven challenging. The present study describes a novel protein refolding sensor that utilizes liquid crystals (LCs) to discriminate varying protein structures during unfolding and refolding. An LC layer containing 4-cyano-4'-pentylbiphenyl (5CB) intercalated with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) is used as a sensing platform, and its proof-of-concept performance is demonstrated using lysozyme as a model protein. As proteins unfold or refold, a local charge fluctuation at their surfaces modulates their interaction with zwitterionic phospholipid DOPE. This alters the alignment of DOPE molecules at the aqueous/LC interface, affecting the orientational ordering of bulk LC (i.e., homeotropic to planar for refolding and planar to homeotropic for unfolding). Differential polarized optical microscope images of the LC layer are subsequently generated, whose brightness directly linked to conformational changes of lysozyme molecules is quantified by gray scale analysis. Importantly, our LC-based refolding sensor is compatible with diverse refolding milieus for real-time analysis of lysozyme refolding and thus likely to facilitate the refolding studies of many proteins, especially those lacking a method to determine structure-dependent biological activity.


Assuntos
Cristais Líquidos , Muramidase , Cristais Líquidos/química , Fosfolipídeos/química , Compostos de Bifenilo/química
8.
Artigo em Inglês | MEDLINE | ID: mdl-37844406

RESUMO

Magnolol and honokiol have been reported to exhibit anti-cancer activity. However, few studies are in relation to the interaction of magnolol/honokiol with vascular endothelial growth factor 2 (VEGFR2). In this study, a membrane chromatography method based on VEGFR2 was established for the interaction characteristic analysis between drug and receptor. The selectivity, repeatability and stability of the chromatographic model were evaluated using drugs acting on different receptors. The affinity between VEGFR2 and magnolol/honokiol was verified by cell membrane chromatography. The binding sites of magnolol/honokiol and VEGFR2 were analyzed by zonal elution. Especially, the dissociation equilibrium constants (Kd) of magnolol/honokiol and VEGFR2 were measured by zonal elution and stepwise frontal analysis respectively. In addition, the actions of magnolol/honokiol on VEGFR2 were analyzed by stepwise frontal analysis at different temperatures. The results showed that the binding sites of magnolol and honokiol on VEGFR2 were different from sorafenib, indicating that magnolol and honokiol could be used as competitive agents for self-competitive displacement experiment. The Kd values (order of magnitude) of magnolol/honokiol with VEGFR2 measured by stepwise frontal analysis were consistent with the zonal elution results. Honokiol binds VEGFR2 with higher affinity than magnolol. The main forces that stabilize the interactions of honokiol with VEGFR2 are hydrogen bonds and van der Waal's forces, and the main force of magnolol is electrostatic forces. These discoveries could assist in the prediction of drug activity and understanding for the underlying mechanism.


Assuntos
Lignanas , Fator A de Crescimento do Endotélio Vascular , Compostos de Bifenilo/química , Cromatografia , Membrana Celular
9.
J Antibiot (Tokyo) ; 76(12): 731-734, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37845350

RESUMO

A new formanilide dimer, fraxinin (1), and three known formanilides (2‒4) were isolated from the culture broth of Perenniporia fraxinea using silica gel and Sephadex LH-20 column chromatographies, medium-pressure liquid chromatography (MPLC), and preparative HPLC. The structures of these compounds were determined by spectroscopic methods, such as NMR and mass analysis, and by comparison of the spectra with previously reported data. The free radical scavenging activities of the isolated compounds were assessed using 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals. Compounds 1‒3 exhibited ABTS radical scavenging activity with IC50 values in the range of 57.2-250.2 µM. Compounds 2 and 4 marginally reduced disease incidence of powdery mildew with a control value of 42% at 1.0 mg ml-1 in cucumber leaf disk assay.


Assuntos
Antioxidantes , Sequestradores de Radicais Livres , Sequestradores de Radicais Livres/farmacologia , Sequestradores de Radicais Livres/química , Antioxidantes/farmacologia , Antioxidantes/química , Compostos de Bifenilo/química , Picratos/química
10.
Chem Biol Interact ; 386: 110747, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37816447

RESUMO

Lignans are plant-derived polyphenolic compounds with a plethora of biological applications. Also, regarded as phytoestrogens, the lignans offer a variety of health benefits of which the anti-cancer effects are the most attractive. Honokiol is a lignan isolated from various parts of trees belonging to the genus Magnolia. The bioactivity of honokiol is attributed to its characteristic physical properties, which include small size and the presence of two phenolic groups that may interact with proteins in cell membranes via hydrophobic interactions, aromatic pi orbital co-valency, and hydrogen bonding. The hydrophobicity of honokiol enables its rapid dissolution in lipids and the crossing of physiological barriers, including the blood-brain barrier and cerebrospinal fluid. These factors contribute towards the high bioavailability of honokiol which further support its candidature in medicinal research. Therefore, the anticancer properties of honokiol are of particular interest as many of the contemporary anticancer drugs suffer from bioavailability drawbacks, which necessitates the identification and development of novel candidate molecules directed as anticancer chemotherapeutics. The antioncogenic profile of honokiol also arises from the regulation of various signalling pathways associated with oncogenesis, arresting of the cell cycle by regulation of cyclic proteins, upregulation of epithelial markers and downregulation of mesenchymal markers leading to the inhibition of epithelial-mesenchymal transition, and preventing the metastasis by restricting cell migration and invasion due to the downregulation of matrix-metalloproteinases. In this review, we discuss the anticancer properties of honokiol.


Assuntos
Lignanas , Neoplasias , Humanos , Lignanas/farmacologia , Lignanas/química , Fenóis , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/química , Relação Estrutura-Atividade , Linhagem Celular Tumoral
11.
Chem Biodivers ; 20(8): e202300754, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37401658

RESUMO

Magnolol and Honokiol are the primary active components that have been identified and extracted from Magnolia officinalis, and several investigations have demonstrated that they have significant pharmacological effects. Despite their therapeutic benefits for a wide range of illnesses, research on and the implementation of these compounds have been hindered by their poor water solubility and low bioavailability. Researchers are continually using chemical methods to alter their structures to make them more effective in treating and preventing diseases. Researchers are also continuously developing derivative drugs with high efficacy and few adverse effects. This article summarizes and analyzes derivatives with significant biological activities reported in recent research obtained by structural modification. The modification sites have mainly focused on the phenolic hydroxy groups, benzene rings, and diene bonds. Changes to the allyl bisphenol structure will result in unexpected benefits, including high activity, low toxicity, and good bioavailability. Furthermore, alongside earlier experimental research in our laboratory, the structure-activity relationships of magnolol and honokiol were preliminarily summarized, providing experimental evidence for improving their development and utilization.


Assuntos
Lignanas , Magnolia , Lignanas/farmacologia , Lignanas/química , Compostos de Bifenilo/química , Relação Estrutura-Atividade , Magnolia/química
12.
Zhongguo Zhong Yao Za Zhi ; 48(14): 3806-3814, 2023 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-37475072

RESUMO

The weight coefficients of appearance traits, extract yield of standard decoction, and total content of honokiol and magnolol were determined by analytic hierarchy process(AHP), criteria importance though intercrieria correlation(CRITIC), and AHP-CRITIC weighting method, and the comprehensive scores were calculated. The effects of ginger juice dosage, moistening time, proces-sing temperature, and processing time on the quality of Magnoliae Officinalis Cortex(MOC) were investigated, and Box-Behnken design was employed to optimize the process parameters. To reveal the processing mechanism, MOC, ginger juice-processed Magnoliae Officinalis Cortex(GMOC), and water-processed Magnoliae Officinalis Cortex(WMOC) were compared. The results showed that the weight coefficients of the appearance traits, extract yield of standard decoction, and total content of honokiol and magnolol determined by AHP-CRITIC weighting method were 0.134, 0.287, and 0.579, respectively. The optimal processing parameters of GMOC were ginger juice dosage of 8%, moistening time of 120 min, and processing at 100 ℃ for 7 min. The content of syringoside and magnolflorine in MOC decreased after processing, and the content of honokiol and magnolol followed the trend of GMOC>MOC>WMOC, which suggested that the change in clinical efficacy of MOC after processing was associated with the changes of chemical composition. The optimized processing technology is stable and feasible and provides references for the modern production and processing of MOC.


Assuntos
Medicamentos de Ervas Chinesas , Lignanas , Magnolia , Magnolia/química , Medicamentos de Ervas Chinesas/química , Compostos de Bifenilo/química , Lignanas/química
13.
Spectrochim Acta A Mol Biomol Spectrosc ; 300: 122898, 2023 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-37247554

RESUMO

Raman spectroscopy is an important tool to understand the structural and molecular behaviour of the liquid crystals when they undergo through different temperatures. It also helps to understand the different phase changes of the liquid crystal material as temperature changes. In this work, the structural properties of two nematic liquid crystals having relatively high clearing temperature namely 4 butylcyclohexyl-3, 5-difluoro-4- isothiocyanato biphenyl and 4-pentylcyclohexyl-3, 5-difluoro-4-isothiocyanato biphenyl are studied. The study is done using temperature dependent Raman spectroscopy. From the studies of the two compounds it has been found that the experimental values are agree well with the various functional groups and different bond assignments recorded in literature. This agreement validates the presence of different functional groups and different stretching bonds in the two studied liquid crystal compounds. Deformations of some of the peak positions of the two liquid crystal compounds have been observed with the change in phase at different temperature. Also to understand the behaviour of the Raman peak near the clearing temperatures of the liquid crystal compounds the linewidth of the different peak values at different temperature have also been studied. From the line width study, the various phase transition temperatures of the two liquid crystalline compounds can be confirmed.


Assuntos
Cristais Líquidos , Temperatura , Cristais Líquidos/química , Análise Espectral Raman/métodos , Compostos de Bifenilo/química
14.
Bioorg Med Chem Lett ; 90: 129349, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37236375

RESUMO

Molecular design, synthesis, in vitro and in vivo studies of novel derivatives of indole-3-carboxylic acid new series of angiotensin II receptor 1 antagonists is presented. Radioligand binding studies using [125I]-angiotensin II displayed that new derivatives of indole-3-carboxylic acid have a high nanomolar affinity for the angiotensin II receptor (AT1 subtype) on a par with the known pharmaceuticals such as losartan. Biological studies of synthesized compounds in spontaneously hypertensive rats have demonstrated that compounds can lower blood pressure when administered orally. Maximum the decrease in blood pressure was 48 mm Hg with oral administration of 10 mg/kg and antihypertensive effect was observed for 24 h, which is superior to losartan.


Assuntos
Anti-Hipertensivos , Hipertensão , Ratos , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Losartan/farmacologia , Hipertensão/tratamento farmacológico , Antagonistas de Receptores de Angiotensina/química , Antagonistas de Receptores de Angiotensina/farmacologia , Pressão Sanguínea , Ratos Endogâmicos SHR , Receptores de Angiotensina/metabolismo , Angiotensina II/farmacologia , Tetrazóis/química , Compostos de Bifenilo/química
15.
Bioorg Chem ; 134: 106455, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36913880

RESUMO

Obesity is a complex disease defined as an excessive amount of body fat. It is considered a risk factor for several pathologies; therefore, there is an increasing interest in its treatment. Pancreatic lipase (PL) plays a key role in fat digestion, and its inhibition is a preliminary step in the search for anti-obesity agents. For this reason, many natural compounds and their derivatives are studied as new PL inhibitors. This study reports the synthesis of a library of new compounds inspired by two natural neolignans, honokiol (1) and magnolol (2) and bearing amino or nitro groups linked to a biphenyl core. The synthesis of unsymmetrically substituted biphenyls was achieved through an optimisation of the Suzuki-Miyaura cross-coupling reaction followed by the insertion of allyl chains, thus furnishing the O- and/or N-allyl derivatives, and finally, a sigmatropic rearrangement yielding in some cases, the C-allyl analogues. Magnolol, honokiol and the twenty-one synthesised biphenyls were evaluated for their in vitro inhibitory activity toward PL. Three compounds (15b, 16 and 17b) were more effective inhibitors than the natural neolignans (magnolol IC50 = 158.7 µM and honokiol IC50 = 115.5 µM) with IC50 of 41-44 µM. Detailed studies through kinetics suggested better inhibitory activity of the synthetic analogues compared with the natural 1 and 2. Magnolol (Ki = 614.3 µM; K'i of 140.9 µM) and the synthetic biphenyls 15b (Ki = 286.4 µM; K'i = 36.6 µM) and 16 (Ki = 176.2 µM; K'i = 6.4 µM) are mixed-type inhibitors, whereas honokiol (Ki = 674.8 µM) and 17b (Ki = 249 µM) are competitive inhibitors. Docking studies corroborated these findings, showing the best fitting for intermolecular interaction between biphenyl neolignans and PL. The above outcomes highlighted how the proposed structures could be considered interesting candidates for future studies for the development of more effective PL inhibitors.


Assuntos
Lignanas , Lignanas/química , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/química
16.
Science ; 380(6640): eadd6220, 2023 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-36862765

RESUMO

Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein-coupled receptors. Searching for receptors to sense beneficial omega-3 FAs of fish oil enabled the identification of GPR120, which is involved in a spectrum of metabolic diseases. Here, we report six cryo-electron microscopy structures of GPR120 in complex with FA hormones or TUG891 and Gi or Giq trimers. Aromatic residues inside the GPR120 ligand pocket were responsible for recognizing different double-bond positions of these FAs and connect ligand recognition to distinct effector coupling. We also investigated synthetic ligand selectivity and the structural basis of missense single-nucleotide polymorphisms. We reveal how GPR120 differentiates rigid double bonds and flexible single bonds. The knowledge gleaned here may facilitate rational drug design targeting to GPR120.


Assuntos
Desenho de Fármacos , Ácidos Graxos Ômega-3 , Receptores Acoplados a Proteínas G , Microscopia Crioeletrônica , Ligantes , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Ácidos Graxos Ômega-3/química , Ácidos Graxos Ômega-3/metabolismo , Humanos , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Conformação Proteica , Ácido Eicosapentaenoico/química , Ácido Eicosapentaenoico/metabolismo , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único
17.
Chem Biodivers ; 20(4): e202300010, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36876631

RESUMO

Aspergetherins A-D (1-4), four new chlorinated biphenyls, were isolated from the rice fermentation of a marine sponge symbiotic fungus Aspergillus terreus 164018, along with seven known biphenyl derivatives (5-11). The structures of four new compounds were determined by a comprehensive analysis of the spectroscopic data, including HR-ESI-MS and 2D NMR data. All 11 isolates were evaluated for their anti-bacterial activity against two strains of methicillin-resistant Staphylococcus aureus (MRSA). Among them, compounds 1, 3, 8 and 10 showed anti-MRSA activity with MIC values of 1.0-128 µg/mL. Preliminary structure-activity relationship analysis unveiled that both chlorinated substitution and esterification of 2-carboxylic acid could impact the antibacterial activity of biphenyls.


Assuntos
Antibacterianos , Aspergillus , Compostos de Bifenilo , Poríferos , Animais , Antibacterianos/química , Aspergillus/química , Staphylococcus aureus Resistente à Meticilina/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Poríferos/microbiologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia
18.
Molecules ; 28(2)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36677790

RESUMO

Honokiol is a natural bisphenol neolignan present in the bark of Magnolia officinalis, whose extracts have been employed in oriental medicine to treat several disorders, showing a variety of biological properties, including antitumor activity, potentially related to radical scavenging. Six bisphenol neolignans with structural motifs related to the natural bioactive honokiol were synthesized. Their chain-breaking antioxidant activity was evaluated in the presence of peroxyl (ROO•) and hydroperoxyl (HOO•) radicals by both experimental and computational methods. Depending on the number and position of the hydroxyl and alkyl groups present on the molecules, these derivatives are more or less effective than the reference natural compound. The rate constant of the reaction with ROO• radicals for compound 7 is two orders of magnitude greater than that of honokiol. Moreover, for compounds displaying quinonic oxidized forms, we demonstrate that the addition of 1,4 cyclohexadiene, able to generate HOO• radicals, restores their antioxidant activity, because of the reducing capability of the HOO• radicals. The antioxidant activity of the oxidized compounds in combination with 1,4-cyclohexadiene is, in some cases, greater than that found for the starting compounds towards the peroxyl radicals. This synergy can be applied to maximize the performances of these new bisphenol neolignans.


Assuntos
Antioxidantes , Lignanas , Antioxidantes/farmacologia , Antioxidantes/química , Lignanas/farmacologia , Lignanas/química , Fenóis/farmacologia , Compostos de Bifenilo/química , Sequestradores de Radicais Livres/farmacologia , Radicais Livres
19.
Mol Divers ; 27(2): 767-791, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35604512

RESUMO

A two-step reaction method was used to synthesize a series of rhodanine-based Schiff bases (2-33) that were characterized using spectroscopic techniques. All compounds were assessed for α-amylase inhibitory and radical scavenging (DPPH and ABTS) activities. In comparison to the standard acarbose (IC50 = 9.08 ± 0.07 µM), all compounds demonstrated good to moderate α-amylase inhibitory activity (IC50 = 10.91 ± 0.08-61.89 ± 0.102 µM). Compounds also demonstrated significantly higher DPPH (IC50 = 10.33 ± 0.02-96.65 ± 0.03 µM) and ABTS (IC50 = 12.01 ± 0.12-97.47 ± 0.13 µM) radical scavenging activities than ascorbic acid (DPPH, IC50 = 15.08 ± 0.03 µM; ABTS, IC50 = 16.09 ± 0.17 µM). The limited structure-activity relationship (SAR) suggests that the position and nature of the substituted groups on the phenyl ring have a vital role in varying inhibitory potential. Among the series, compounds with an electron-withdrawing group at the para position showed the highest potency. Kinetic studies revealed that the compounds followed a competitive mode of inhibition. Molecular docking results are found to agree with experimental findings, showing that compounds reside in the active pocket due to the main rhodanine moiety.


Assuntos
Rodanina , Rodanina/farmacologia , Simulação de Acoplamento Molecular , Bases de Schiff/química , Cinética , Compostos de Bifenilo/química , Relação Estrutura-Atividade , alfa-Amilases/química , Estrutura Molecular
20.
Int J Pharm ; 632: 122530, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36563798

RESUMO

Antibiotic is one of the most important discoveries in human and animal medicine. However, the inefficient use of antibiotics has caused widespread and persistent contamination of ecosystems, setting off microbial resistance storms. Magnolol is a botanical antibiotic, but poor physicochemical properties result in low bioavailability. Increasing solubility of magnolol can help to reduce the doses of medications to patients, minimize bothersome side effects. In this work, three novel multicomponent crystalline solids were synthesized from magnolol and isomeric coformers by mechanochemistry. It was found that the multicomponent crystalline solids achieved the customizable release profile of magnolol by manipulating the substituent positions of the isomers and complexation. Antibacterial activity test showed that bioactivity on two bacteria was considerably improved by designed MGN multicomponent crystals. In addition, the coformers controlled the dissolution behavior and further stabilized the improvement according to the variable statistical analysis. In conclusion, the properties of antibiotic multicomponent solids can be manipulated through the coformers. This provides an effective strategy for managing the release of drugs to meet individual biological differences and diverse therapeutic needs.


Assuntos
Ecossistema , Lignanas , Animais , Humanos , Solubilidade , Compostos de Bifenilo/química , Lignanas/química
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