RESUMEN
We are reporting a short and convenient pathway for the synthesis of novel ß-carboline-bisindole hybrid compounds from relatively cheap and commercially available chemicals such as tryptamine, dialdehydes and indoles. These newly designed compounds can also be prepared in high yields with the tolerance of many functional groups under mild conditions. Notably, these ß-carboline-bisindole hybrid compounds exhibited some promising applications as anticancer agents against the three common cancer cell lines MCF-7 (breast cancer), SK-LU-1 (lung cancer), and HepG2 (liver cancer). The two best compounds 5 b and 5 g inhibited the aforementioned cell lines with the same IC50 range of the reference Ellipticine at less than 2â µM. A molecular docking study to gain more information about the interactions between the synthesized molecules and the kinase domain of the EGFR was performed. Therefore, this finding can have significant impacts on the development of future research in medicinal chemistry and drug discovery.
RESUMEN
Discovering new solutions for crop protection is a major challenge for the next decades as a result of the ecotoxicological impact of classical fungicides, the emergence of fungicide resistances, and the consequence of climate change on pathogen distribution. Previous work on fungal mutants deficient in the unfolded protein response (UPR) supported that targeting this pathway is a promising plant disease control strategy. In particular, we showed that the UPR is involved in fungal virulence by altering cell protection against host defense compounds, such as phytoalexins and phytoanticipins. In this study, we evaluated natural products targeting fungal IRE1 protein (UPR effector) and consequently increasing fungal susceptibility to plant defenses. Developing an in vitro cell-based screening assay allowed for the identification of seven potential IRE1 inhibitors with a focus on polyhydroxylated prenylated xanthones. Inhibition of hac1 mRNA splicing, which is mediated by IRE1, was then validated for the most active compound, namely, γ-mangostin 3. To study the mode of interaction between the binding site of IRE1 and active xanthones, molecular docking was also undertaken, revealing similar and novel interactions between the known inhibitor and the binding site. Eventually, active xanthones applied at subtoxic doses induced a significant reduction in necrosis size for leaves of Brassica oleracea inoculated with Alternaria brassicicola and Botrytis cinerea.
Asunto(s)
Productos Biológicos , Fungicidas Industriales , Protección de Cultivos , Simulación del Acoplamiento Molecular , Sitios de Unión , Proteínas Fúngicas/genética , Fungicidas Industriales/farmacología , Proteínas Serina-Treonina QuinasasRESUMEN
Nine compounds including a new one, garcichaudiic acid (1), were isolated from the bark of G. gaudichaudii and their structures were characterized mainly by 1 D and 2 D NMR experiments. The antioxidant capacity of the isolated compounds was determined using DPPH radical scavenging assay and the anti-hyperglycemic activity was assessed by measuring the inhibitory effect against α-glucosidase. Among them, compound 4 showed higher antioxidant activity than the positive control, ascorbic acid, while both compounds 1 and 7 exhibited more significant α-glucosidase inhibitory activity than the reference drug acarbose. Molecular docking analysis of the bioactive compounds was also performed to examine the binding modes and key interactions with the catalytic site.
Asunto(s)
Antioxidantes , Garcinia , Antioxidantes/química , alfa-Glucosidasas/metabolismo , Inhibidores de Glicósido Hidrolasas/química , Simulación del Acoplamiento Molecular , Garcinia/químicaRESUMEN
Insulin degrading enzyme (IDE) is a zinc metalloprotease that cleaves numerous substrates among which amyloid-ß and insulin. It has been linked through genetic studies to the risk of type-2 diabetes (T2D) or Alzheimer's disease (AD). Pharmacological activation of IDE is an attractive therapeutic strategy in AD. While IDE inhibition gave paradoxal activity in glucose homeostasis, recent studies, in particular in the liver suggest that IDE activators could be also of interest in diabetes. Here we describe the discovery of an original series of IDE activators by screening and structure-activity relationships. Early cellular studies show that hit 1 decreases glucose-stimulating insulin secretion. Docking studies revealed it has an unprecedented extended binding to the polyanion-binding site of IDE. These indole-based pharmacological tools are activators of both Aß and insulin hydrolysis by IDE and could be helpful to explore the multiple roles of IDE.
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Indoles/farmacología , Insulisina/metabolismo , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Indoles/química , Ratones , Modelos Moleculares , Estructura Molecular , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
Endogenous long-chain metabolites of vitamin E (LCMs) mediate immune functions by targeting 5-lipoxygenase (5-LOX) and increasing the systemic concentrations of resolvin E3, a specialized proresolving lipid mediator. SAR studies on semisynthesized analogues highlight α-amplexichromanol (27a), which allosterically inhibits 5-LOX, being considerably more potent than endogenous LCMs in human primary immune cells and blood. Other enzymes within lipid mediator biosynthesis were not substantially inhibited, except for microsomal prostaglandin E2 synthase-1. Compound 27a is metabolized by sulfation and ß-oxidation in human liver-on-chips and exhibits superior metabolic stability in mice over LCMs. Pharmacokinetic studies show distribution of 27a from plasma to the inflamed peritoneal cavity and lung. In parallel, 5-LOX-derived leukotriene levels decrease, and the inflammatory reaction is suppressed in reconstructed human epidermis, murine peritonitis, and experimental asthma in mice. Our study highlights 27a as an orally active, LCM-inspired drug candidate that limits inflammation with superior potency and metabolic stability to the endogenous lead.
Asunto(s)
Araquidonato 5-Lipooxigenasa/metabolismo , Descubrimiento de Drogas , Inflamación/tratamiento farmacológico , Inhibidores de la Lipooxigenasa/farmacología , Vitamina E/farmacología , Administración Oral , Araquidonato 5-Lipooxigenasa/genética , Relación Dosis-Respuesta a Droga , Humanos , Inflamación/metabolismo , Inhibidores de la Lipooxigenasa/administración & dosificación , Inhibidores de la Lipooxigenasa/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Vitamina E/administración & dosificación , Vitamina E/metabolismoRESUMEN
Modulation of major histocompatibility complex (MHC) expression using drugs has been proposed to control immunity. Phytochemical investigations on Garcinia species have allowed the isolation of bioactive compounds such as polycyclic polyprenylated acylphloroglucinols (PPAPs). PPAPs such as guttiferone J (1), display anti-inflammatory and immunoregulatory activities while garcinol (4) is a histone acetyltransferases (HAT) p300 inhibitor. This study reports on the isolation, identification and biological characterization of two other PPAPs, i.e., xanthochymol (2) and guttiferone F (3) from Garcinia bancana, sharing structural analogy with guttiferone J (1) and garcinol (4). We show that PPAPs 1-4 efficiently downregulated the expression of several MHC molecules (HLA-class I, -class II, MICA/B and HLA-E) at the surface of human primary endothelial cells upon inflammation. Mechanistically, PPAPs 1-4 reduce MHC proteins by decreasing the expression and phosphorylation of the transcription factor STAT1 involved in MHC upregulation mediated by IFN-γ. Loss of STAT1 activity results from inhibition of HAT CBP/p300 activity reflected by a hypoacetylation state. The binding interactions to p300 were confirmed through molecular docking. Loss of STAT1 impairs the expression of CIITA and GATA2 but also TAP1 and Tapasin required for peptide loading and transport of MHC. Overall, we identified new PPAPs issued from Garcinia bancana with potential immunoregulatory properties.
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Garcinia/química , Floroglucinol/análogos & derivados , Floroglucinol/farmacología , Compuestos Policíclicos/farmacología , Transportador de Casetes de Unión a ATP, Subfamilia B, Miembro 2/metabolismo , Acilación , Benzofenonas/química , Benzofenonas/aislamiento & purificación , Benzofenonas/farmacología , Regulación hacia Abajo/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Factor de Transcripción GATA2/metabolismo , Humanos , Interferón gamma/metabolismo , Complejo Mayor de Histocompatibilidad/efectos de los fármacos , Complejo Mayor de Histocompatibilidad/genética , Proteínas de Transporte de Membrana/metabolismo , Simulación del Acoplamiento Molecular , Proteínas Nucleares/metabolismo , Floroglucinol/química , Floroglucinol/aislamiento & purificación , Compuestos Policíclicos/química , Compuestos Policíclicos/aislamiento & purificación , Prenilación , Cultivo Primario de Células , Factor de Transcripción STAT1/metabolismo , Terpenos/química , Terpenos/farmacología , Transactivadores/metabolismo , Factores de Transcripción p300-CBP/antagonistas & inhibidores , Factores de Transcripción p300-CBP/químicaRESUMEN
Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring.
Asunto(s)
Amidas/farmacología , Antiinflamatorios no Esteroideos/farmacología , Araquidonato 5-Lipooxigenasa/metabolismo , Diseño de Fármacos , Inhibidores de la Lipooxigenasa/farmacología , Vitamina E/análogos & derivados , Amidas/síntesis química , Amidas/química , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Relación Dosis-Respuesta a Droga , Humanos , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Vitamina E/síntesis química , Vitamina E/química , Vitamina E/farmacologíaRESUMEN
Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13'-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8-49 nM) that inhibit 5-lipoxygenase in human leukocytes. α-T-13'-COOH accumulates in immune cells and inflamed murine exudates, selectively inhibits the biosynthesis of 5-lipoxygenase-derived lipid mediators in vitro and in vivo, and efficiently suppresses inflammation and bronchial hyper-reactivity in mouse models of peritonitis and asthma. Together, our data suggest that the immune regulatory and anti-inflammatory functions of α-tocopherol depend on its endogenous metabolite α-T-13'-COOH, potentially through inhibiting 5-lipoxygenase in immune cells.