RESUMEN
A series of novel sulfonyl hydrazide based ß-carboline derivatives (SX1-SX32) were designed and synthesized, and their structures were characterized on NMR and HRMS. Their α-glucosidase inhibitory screening results found that compounds (SX1-SX32) presented potential α-glucosidase inhibitory: IC50 values being 2.12 ± 0.33-19.37 ± 1.49 µM. Compound SX29 with a para-phenyl (IC50: 2.12 ± 0.33 µM) presented the strongest activity and was confirmed as a noncompetitive inhibitor. Fluorescence spectra, CD spectra and molecular docking were conducted to describe the inhibition mechanism of SX29 against α-glucosidase. Cells cytotoxicity indicated SX29 (0-32 µM) had no cytotoxicity on 293T cells. In particular, in vivo experiments revealed that oral administration of SX29 could regulate hyperglycemia and glucose tolerance of diabetic mice. These achieved findings indicated that sulfonyl hydrazide based ß-carboline derivatives bore promising potential for discovering new α-glucosidase inhibitors with hypoglycemic activity.
RESUMEN
Indole-based bis-acylhydrazone compounds can inhibit the activity of α-glucosidase and control the concentration of blood glucose. In this paper, the characteristics of three indole-based bis-acylhydrazone compounds with different inhibitory activities of α-glucosidase as well as the interaction with α-glucosidase were studied by experiments and computational simulation techniques. Enzyme kinetic and spectral experiments showed that the indole-based bis-acylhydrazone compounds were able to inhibit enzyme activity through mixed inhibition dominated by competitive inhibition, and during the binding reaction, indole-based bis-acylhydrazone compounds can quench the intrinsic fluorescence of α-glucosidase through static quenching and an aggregation of the indole-based bis-acylhydrazone with α-glucosidase produces a stable complex with a molar ratio of 1:1, and the combination of indole-based bis-acylhydrazone compounds could lead to slight change in the conformation of α-glucosidase. The theoretical simulation demonstrated that the stability of the complex systems was positively correlated with the inhibitory activity of indole-based bis-acylhydrazone compounds, and the indole-based bis-acylhydrazone compounds occupied the active site in the multi-ligand system, resulting in a significant decrease in the binding ability of starch to active amino acids. These results suggested that indole-based bis-acylhydrazone compound was expected to be a new type of α-glucosidase inhibitor.
Asunto(s)
Inhibidores de Glicósido Hidrolasas , Hidrazonas , Indoles , alfa-Glucosidasas , alfa-Glucosidasas/metabolismo , alfa-Glucosidasas/química , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/farmacología , Indoles/química , Indoles/farmacología , Hidrazonas/química , Hidrazonas/farmacología , Cinética , Simulación del Acoplamiento Molecular , Análisis EspectralRESUMEN
In the quest for potent α-glucosidase inhibitors to combat diabetes, a series of novel thiosemicarbazide-based ß-carboline derivatives (CTL1â¼36) were synthesized and evaluated. CTL1â¼36 exhibited remarkable inhibitory effects against α-glucosidase, with IC50 values ranging from 2.81 to 12.40 µM, significantly surpassing the positive control acarbose (IC50 = 564.28 µM). Notably, CTL26 demonstrated the most potent inhibition (IC50 = 2.81 µM) and was characterized as a non-competitive inhibitor. Through a combination assay with fluorescence quenching, 3D fluorescence spectra, CD spectra, and molecular docking, we elucidated that CTL26 formed a complex with α-glucosidase via hydrogen bondings and hydrophobic interactions, leading to α-glucosidase conformation changes that impaired enzymatic activity. In vivo studies revealed that oral administration of CTL26 (25 and 50 mg/kg/d) reduced fasting blood glucose levels, enhanced glucose tolerance, and ameliorated lipid abnormalities in diabetic mice. These findings positioned CTL26 as a promising candidate for the development of α-glucosidase inhibitors with anti-diabetic potential.
Asunto(s)
Carbolinas , Diabetes Mellitus Experimental , Inhibidores de Glicósido Hidrolasas , Semicarbacidas , alfa-Glucosidasas , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/química , Animales , alfa-Glucosidasas/metabolismo , Carbolinas/farmacología , Carbolinas/química , Carbolinas/síntesis química , Semicarbacidas/farmacología , Semicarbacidas/química , Semicarbacidas/síntesis química , Ratones , Relación Estructura-Actividad , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Estructura Molecular , Simulación del Acoplamiento Molecular , Relación Dosis-Respuesta a Droga , Masculino , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Glucemia/análisis , HumanosRESUMEN
Axially chiral carboxylic acids are important motifs in chiral catalysts and ligands. We herein reported the synthesis of axially chiral carboxylic acids via Pd(II)-catalyzed atroposelective C-H olefination using carboxylic acid as the native directing group. A broad range of axial chiral biaryl-2-carboxylic acids were synthesized in good yields with high enantioselectivities (up to 84% yield with 99% ee). Gram-scale reaction and further transformation reactions also provide a platform for synthetic applications of this method.
RESUMEN
Forty-one 1,3,4-thiadiazolyl-containing thiazolidine-2,4-dione derivatives (MY1-41) were designed and synthesized as protein tyrosine phosphatase 1B (PTP1B) inhibitors with activity against diabetes mellitus (DM). All synthesized compounds (MY1-41) presented potential PTP1B inhibitory activities, with half-maximal inhibitory concentration (IC50) values ranging from 0.41 ± 0.05 to 4.68 ± 0.61 µM, compared with that of the positive control lithocholic acid (IC50 = 9.62 ± 0.14 µM). The most potent compound, MY17 (IC50 = 0.41 ± 0.05 µM), was a reversible, noncompetitive inhibitor of PTP1B. Circular dichroism spectroscopy and molecular docking were employed to analyze the binding interaction between MY17 and PTP1B. In HepG2 cells, MY17 treatment could alleviate palmitic acid (PA)-induced insulin resistance by upregulating the expression of phosphorylated insulin receptor substrate and protein kinase B. In vivo, oral administration of MY17 could reduce the fasting blood glucose level and improve glucose tolerance and dyslipidemia in mice suffering from DM.
Asunto(s)
Diabetes Mellitus Experimental , Hipoglucemiantes , Simulación del Acoplamiento Molecular , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Tiazolidinedionas , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Animales , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/síntesis química , Hipoglucemiantes/uso terapéutico , Células Hep G2 , Ratones , Tiazolidinedionas/farmacología , Tiazolidinedionas/química , Tiazolidinedionas/síntesis química , Diabetes Mellitus Experimental/tratamiento farmacológico , Relación Estructura-Actividad , Masculino , Tiadiazoles/farmacología , Tiadiazoles/química , Tiadiazoles/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Resistencia a la Insulina , Glucemia/efectos de los fármacos , Glucemia/análisis , Glucemia/metabolismoRESUMEN
In order to find effective α-glucosidase inhibitors, a series of thiazolidine-2,4-dione derivatives (C1 â¼ 36) were synthesized and evaluated for α-glucosidase inhibitory activity. Compared to positive control acarbose (IC50 = 654.35 ± 65.81 µM), all compounds (C1 â¼ 36) showed stronger α-glucosidase inhibitory activity with IC50 values of 0.52 ± 0.06 â¼ 9.31 ± 0.96 µM. Among them, C23 with the best anti-α-glucosidase activity was a reversible mixed-type inhibitor. Fluorescence quenching suggested the binding process of C23 with α-glucosidase in a static process. Fluorescence quenching, CD spectra, and 3D fluorescence spectra results also implied that the binding of C23 with α-glucosidase caused the conformational change of α-glucosidase to inhibit the activity. Molecular docking displayed the binding interaction of C23 with α-glucosidase. Compound C23 (8 â¼ 64 µM) showed no cytotoxicity against LO2 and 293 cells. Moreover, oral administration of C23 (50 mg/kg) could reduce blood glucose and improve glucose tolerance in mice.
Asunto(s)
Inhibidores de Glicósido Hidrolasas , Hipoglucemiantes , Tiazolidinedionas , Ratones , Animales , Inhibidores de Glicósido Hidrolasas/química , Hipoglucemiantes/química , Estructura Molecular , Relación Estructura-Actividad , alfa-Glucosidasas/metabolismo , Simulación del Acoplamiento Molecular , TiazolidinasRESUMEN
Orthosiphon aristatus is a well-known folkloric medicine and herb for Guangdong soup for the treatment of rheumatism in China. Eight isopimarane-type and migrated pimarane-type diterpenoids (1-8), including a new one with a rarely occurring α,ß-unsaturated diketone C-ring, were isolated from O. aristatus. Their structures were determined by spectroscopic methods and quantum chemical calculations. Furthermore, the most abundant compound, orthosiphol K, was structurally modified by modern synthetic techniques to give seven new derivatives (9-15). The anti-rheumatoid arthritis activity of these diterpenoids were evaluated on a TNF-α induced MH7A human rheumatoid fibroblast-like synoviocyte model. Compound 10 showed the most potent activity among these compounds. Based on their inhibitory effects on the release levels of IL-1ß, the preliminary structure-activity relationships were concluded. Furthermore, western blot analysis revealed that 10 could increase the expression of IκBα and decrease the expression of NF-κB p65, and the expression levels of COX-2 and NLRP3 proteins were consequently down-regulated.
Asunto(s)
Artritis Reumatoide , Diterpenos , Orthosiphon , Humanos , Orthosiphon/química , Orthosiphon/metabolismo , Abietanos , Artritis Reumatoide/tratamiento farmacológico , Factor de Necrosis Tumoral alfa , Diterpenos/farmacología , Diterpenos/química , FN-kappa B/metabolismoRESUMEN
A series of chromone derivatives bearing thiazolidine-2,4-dione moiety (5 â¼ 37) were synthesized and evaluated for their PTP1B inhibitory activity, interaction analysis and effects on insulin pathway in palmitic acid (PA)-induced HepG2 cells. The results showed that all derivatives presented potential PTP1B inhibitory activity with IC50 values of 1.40 ± 0.04 â¼ 16.83 ± 0.54 µM comparing to that of positive control lithocholic acid (IC50: 9.62 ± 0.14 µM). Among them, compound 9 had the strongest PTP1B inhibitory activity with the IC50 value of 1.40 ± 0.04 µM. Inhibition kinetic study revealed that compound 9 was a reversible mixed-type inhibitor against PTP1B. CD spectra results confirmed that compound 9 changed the secondary structure of PTP1B by their interaction. Molecular docking explained the detailed binding between compound 9 and PTP1B. Compound 9 also showed 19-fold of selectivity for PTP1B over TCPTP. Moreover compound 9 could recovery PA-induced insulin resistance by increasing the phosphorylation of IRSI and AKT. CETSA results showed that compound 9 significantly increased the thermal stability of PTP1B.
Asunto(s)
Inhibidores Enzimáticos , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Tiazolidinedionas , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Tiazolidinas , Inhibidores Enzimáticos/química , Diseño de Fármacos , Ácido Palmítico/farmacologíaRESUMEN
Gemcitabine (GEM) is a standard chemotherapeutic agent for patients with pancreatic cancer; however, GEM-based chemotherapy has a high rate of toxicity. A combination of GEM and active constituents from natural products may enhance its therapeutic efficacy and reduce its toxicity. This study investigated the synergistic effects of the combination of liriopesides B (LirB) from Liriope spicata var. prolifera and GEM on human pancreatic cancer cells. The results of our study showed that the combination of LirB and GEM synergistically decreased the viability of pancreatic cancer cells. The combination also caused a strong increase in apoptosis and a strong decrease in cell migration and invasion. Furthermore, LirB combined with GEM had potent inhibitory effects on pancreatic cancer stem cells (CSCs). Studies on the mechanisms of action showed that the combination more potently inhibited protein kinase B (Akt) and nuclear factor kappa B (NF-κB), as well as the downstream antiapoptotic molecules B-cell lymphoma 2 (Bcl-2) and survivin than either agent used alone. The results of this study suggest that the combination of LirB with GEM may improve the efficacy of GEM for the treatment of pancreatic cancer.
Asunto(s)
Gemcitabina , Neoplasias Pancreáticas , Humanos , Desoxicitidina/farmacología , Línea Celular Tumoral , Neoplasias Pancreáticas/patología , FN-kappa B/metabolismo , Apoptosis , Proliferación CelularRESUMEN
Tyrosinase is an important rate-limiting enzyme in melanin biosynthesis. To find potential tyrosinase inhibitors with anti-melanogenic activity, a series of indole-thiazolidine-2,4-dione derivatives 5a~5z were synthesized by incorporating indole with thiazolidine-2,4-dione into one compound and assayed for their biological activities. All compounds displayed tyrosinase inhibitory activities and 5w had the highest anti-tyrosinase inhibitory activity with an IC50 value of 11.2 µM. Inhibition kinetics revealed 5w as a mixed-type tyrosinase inhibitor. Fluorescence quenching results indicated that 5w quenched tyrosinase fluorescence in a static process. CD spectra and 3D fluorescence spectra results suggested that the binding of 5w with tyrosinase could change the conformation and microenvironment of tyrosinase. Molecular docking also represented the binding between 5w and tyrosinase. Moreover, 5w could inhibit tyrosinase activity and melanogenesis both in B16F10 cells and the zebrafish model. Therefore, compound 5w could serve as a tyrosinase inhibitor with anti-melanogenic activity.
Asunto(s)
Inhibidores Enzimáticos , Monofenol Monooxigenasa , Animales , Simulación del Acoplamiento Molecular , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Pez Cebra/metabolismo , Indoles/farmacología , MelaninasRESUMEN
To provide clinical evidence for the management of hypoxic-ischemic encephalopathy (HIE) by analyzing the role of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) and colony-stimulating factor-1 (CSF1) in the disease. We purchased 15 Sprague-Dawley (SD) rat pups and randomized them into five groups (n=3), of which one group was untreated as the control group and the other four were modeled by HIE. After modeling, a group was treated as a model group without any treatment, another group was injected with sLOX-1-silencing lentiviral vector (sLOX-1-si group), and the third and fourth were injected with CSF1-silencing lentiviral vector (CSF1-si group) and an equal amount of normal saline (blank group), respectively. After the corresponding intervention, the rat tissue in each group was obtained to observe the pathological injury by HE and TUNEL staining. In addition, sLOX-1, CSF1, 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE) levels in brain tissue of each group were determined. The model group showed more severe pathological damage of the hippocampus and higher neuronal apoptosis than the control group. Besides, higher sLOX-1 and CSF1 levels and lower 5-HT, DA and NE contents were identified in the model group versus the control group (P<0.05). Compared with the blank group, sLOX-1-si and CSF1-si groups showed significantly alleviated hippocampal damage, inhibited neuronal apoptosis, reduced 5-HT, DA, NE, Bax, and cl-caspase-3, and increased Bcl-2 (P<0.05). Silencing sLOX-1 and CSF1 expression ameliorated the pathological injury of HIE and inhibited neuronal apoptosis.
Asunto(s)
Hipoxia-Isquemia Encefálica , Ratas , Animales , Hipoxia-Isquemia Encefálica/tratamiento farmacológico , Hipoxia-Isquemia Encefálica/metabolismo , Hipoxia-Isquemia Encefálica/patología , Animales Recién Nacidos , Ratas Sprague-Dawley , Serotonina , Apoptosis , Receptores Depuradores de Clase ERESUMEN
A catalytic asymmetric 1,3-acyloxy shift/polyene cyclization cascade has been achieved with good enantioselectivities under the catalysis of the chiral Au(I) reagent. The synthetic utility of this method has been showcased by the catalytic asymmetric total syntheses of (+)-2-ketoferruginol, (+)-fleuryinol B, and (+)-salviol. Notably, the first enantioselective total synthesis of (-)-erythroxylisin A has also been realized in 15 steps.
RESUMEN
In this study, we designed and synthesized a novel class of 1,3,4-oxadiazolyl-containing ß-carboline derivatives, i.e., compounds f1â¼f35 as potential α-glucosidase inhibitors. All the synthesized compounds possessed outstanding α-glucosidase inhibitory activity with the IC50 values in the range of 3.07-15.49 µM, representing that they are 36â¼183-fold more active than a positive control, acarbose (IC50 = 564.28 µM). Among them, compound f26 exhibited the highest α-glucosidase inhibitory activity (IC50 = 3.07 µM) and was demonstrated to function as a reversible and noncompetitive inhibitor. Mechanistic studies by means of 3D fluorescence spectra, CD spectra and molecular docking suggested that complexation of compound f26 with α-glucosidase through hydrogen bonds and hydrophobic interactions, led to changes in the conformation and secondary strictures of α-glucosidase and further the inhibition of the enzymatic activity. In vivo results showed that oral administration of compound f26 (50 mg/kg/day) could obviously reduce the levels of fasting blood glucose and improve glucose tolerance and dyslipidemia in diabetic mice. The present findings suggest that compound f26 is exploitable as a potential lead compound for the development of new α-glucosidase inhibitors with antidiabetic activity.
Asunto(s)
Diabetes Mellitus Experimental , Inhibidores de Glicósido Hidrolasas , Ratones , Animales , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , alfa-Glucosidasas/metabolismo , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/tratamiento farmacológico , Carbolinas/farmacología , Estructura MolecularRESUMEN
Paeonol, as one effective tyrosinase inhibitor, had been used as food preservative and clinical medication for skin disorders. In this study, the inhibition mechanism and binding behavior of paeonol to tyrosinase and its anti-browning property were investigated using multi-spectroscopic and molecular docking methods. Activity assay and kinetic results confirmed paeonol as a reversible mixed-type tyrosinase inhibitor. Results of the mechanistic studies were clarified using fluorescence quenching, synchronous fluorescence, CD spectra and 3D fluorescence, and showed that the binding of paeonol to tyrosinase might change the chromophore microenvironment and conformation of tyrosinase to inhibit enzyme catalytic activity. Molecular docking results revealed the detailed binding between paeonol and tyrosinase. Moreover, paeonol could prevent the browning of fresh-cut apples, as well as inhibiting PPO and POD activities and increasing APX activity. All above findings established a reliable basis for the inhibitory mechanism of paeonol against tyrosinase and therefore contributed to its application in anti-browning.
Asunto(s)
Malus , Monofenol Monooxigenasa , Simulación del Acoplamiento Molecular , Acetofenonas/farmacología , Acetofenonas/química , Malus/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , CinéticaRESUMEN
Tyrosinase plays crucial roles in mediating the production of melanin pigment; thus, its inhibitors could be useful in preventing melanin-related diseases. To find potential tyrosinase inhibitors, a series of cinnamic acid-eugenol esters (c1~c29) was synthesized and their chemical structures were confirmed by 1H NMR, 13C NMR, HRMS, and FT-IR, respectively. The biological evaluation results showed that all compounds c1~c29 exhibited definite tyrosinase inhibitory activity; especially, compound c27 was the strongest tyrosinase inhibitor (IC50: 3.07 ± 0.26 µM), being ~4.6-fold stronger than the positive control, kojic acid (IC50: 14.15 ± 0.46 µM). Inhibition kinetic studies validated compound c27 as a reversible mixed-type inhibitor against tyrosinase. Three-dimensional fluorescence and circular dichroism (CD) spectra results indicated that compound c27 could change the conformation and secondary structure of tyrosinase. Fluorescence-quenching results showed that compound c27 quenched tyrosinase fluorescence in the static manner with one binding site. Molecular docking results also revealed the binding interactions between compound c27 and tyrosinase. Therefore, cinnamic acid-eugenol esters, especially c27, could be used as lead compounds to find potential tyrosinase inhibitors.
Asunto(s)
Eugenol , Melaninas , Eugenol/farmacología , Cinética , Simulación del Acoplamiento Molecular , Espectroscopía Infrarroja por Transformada de Fourier , Monofenol Monooxigenasa , Ésteres/farmacologíaRESUMEN
To find potential α-glucosidase inhibitors, indolo[1,2-b]isoquinoline derivatives (1-20) were screened for their α-glucosidase inhibitory effects. All derivatives presented potential α-glucosidase inhibitory effects with IC50 values of 3.44 ± 0.36~41.24 ± 0.26 µM compared to the positive control acarbose (IC50 value: 640.57 ± 5.13 µM). In particular, compound 11 displayed the strongest anti-α-glucosidase activity, being ~186 times stronger than acarbose. Kinetic studies found that compounds 9, 11, 13, 18, and 19 were all reversible mix-type inhibitors. The 3D fluorescence spectra and CD spectra results revealed that the interaction between compounds 9, 11, 13, 18, and 19 and α-glucosidase changed the conformational changes of α-glucosidase. Molecular docking and molecular dynamics simulation results indicated the interaction between compounds and α-glucosidase. In addition, cell cytotoxicity and drug-like properties of compound 11 were also investigated.
Asunto(s)
Acarbosa , alfa-Glucosidasas , Estructura Molecular , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , alfa-Glucosidasas/metabolismo , Cinética , Inhibidores de Glicósido Hidrolasas/farmacología , IsoquinolinasRESUMEN
A palladium catalyzed annulation of o-iodo-anilines with propargyl alcohols for the synthesis of substituted quinolines has been developed. The reaction tolerates diverse functional groups under mild conditions, providing direct access to 2,4-disubstituted quinolines from easily available starting materials. A broad range of 2,4-disubstituted quinolines were efficiently prepared in good to excellent yields.
RESUMEN
Efficient access to the synthesis of lactam-derived quinoline through a bicyclic amidine-triggered cyclization reaction from readily prepared o-alkynylisocyanobenzenes has been developed. The reaction was initiated by nucleophilic attack of the bicyclic amidines to o-alkynylisocyanobenzenes, subsequently with intramolecular cyclization to produce a DBU-quinoline-based amidinium salt, followed by hydrolysis to afford the lactam-derived quinoline in moderate to good yields.
Asunto(s)
Lactamas , Quinolinas , Ciclización , Amidinas , HidrólisisRESUMEN
Naproxen is widely used for anti-inflammatory treatment but it can lead to serious side effects. To improve the anti-inflammatory activity and safety, a novel naproxen derivative containing cinnamic acid (NDC) was synthesized and used in combination with resveratrol. The results showed that the combination of NDC and resveratrol at different ratios have a synergistic anti-inflammatory efficacy in RAW264.7 macrophage cells. It was indicated that the combination of NDC and resveratrol at a ratio of 2:1 significantly inhibited the expression of carbon monoxide (NO), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), induced nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2) and reactive oxygen species (ROS) without detectable side effects on cell viability. Further studies revealed that these anti-inflammatory effects were mediated by the activation of nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K)/protein kinase B (Akt) signaling pathways, respectively. Taken together, these results highlighted the synergistic NDC and resveratrol anti-inflammatory activity that could be further explored as a strategy for the treatment of inflammatory disease with an improved safety profile.