RESUMEN
Acridone based synthetic and natural products with inherent anticancer activity advancing the research and generating a large number of structurally diversified compounds. In this sequence we have designed, synthesized a series of tetracyclic acridones with amide framework viz., 3-(alkyloyl/ aryloyl/ heteroaryloyl/ heteroaryl)-2,3-dihydropyrazino[3,2,1-de]acridin-7(1H)-ones and screened for their in vitro anti-cancer activity. The in vitro study revealed that compounds with cyclopropyl-acetyl, benzoyl, p-hydroxybenzoyl, p-(trifluoromethyl)benzoyl, p-fluorobenzoyl, m-fluorobenzoyl, picolinoyl, 6-methylpicolinoyl and 3-nicotinoyl groups are active against HT29, MDAMB231 and HEK293T cancer cell lines. The molecular docking studies performed for them against 4N5Y, HT29 and 2VWD revealed the potential ligand-protein binding interactions among the neutral aminoacid of the enzymes and carbonyl groups of the title compounds with a binding energy ranging from - 8.1394 to - 6.9915 kcal/mol. In addition, the BSA protein binding assay performed for them has confirmed their interaction with target proteins through strong binding to BSA macromolecule. The additional studies like ADMET, QSAR, bioactivity scores, drug properties and toxicity risks ascertained them as newer drug candidates. This study had added a new collection of piperazino fused acridone derivatives to the existing array of other nitrogen heterocyclic fused acridone derivatives as anticancer agents.
Asunto(s)
Acridonas/química , Acridonas/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Unión Proteica/fisiología , Línea Celular , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales/métodos , Células HEK293 , Células HT29 , Humanos , Simulación del Acoplamiento Molecular/métodos , Relación Estructura-Actividad CuantitativaRESUMEN
Biological evaluation of 3,4-dihydroxy piperidines as α-glucosidase inhibitors is being reported for the first time. Forty-five derivatives (amides, di-amides and sulfonamides) were made using cis and trans 3,4-dihydroxy piperidines to evaluate their α-glucosidase inhibition activity. Polar groups (-OH, -NH2) on phenyl ring having derivatives 5i, 5l, 7g, 7i &12j showed excellent activity compared to standard references. Acarbose, Voglibose and Miglitol were used as standard references. Molecular docking simulations were done for compounds to identify important binding modes responsible for inhibition activity of α-glucosidase.
Asunto(s)
Inhibidores de Glicósido Hidrolasas/farmacología , Piperidinas/farmacología , alfa-Glucosidasas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/química , Humanos , Modelos Moleculares , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Relación Estructura-ActividadRESUMEN
A new series of Deacetylsarmentamide A and B derivatives, amides and sulfonamides of 3,4-dihydroxypyrrolidines as α-glucosidase inhibitors were designed and synthesized. The biological screening test against α-glucosidase showed that some of these compounds have the positive inhibitory activity against α-glucosidase. Saturated aliphatic amides were more potent than the olefinic amides. Among all the compounds, 5o/6o having polar -NH2 group, 10f/11f having polar -OH group on phenyl ring displayed 3-4-fold more potent than the standard drugs. Acarbose, Voglibose and Miglitol were used as standard references. The promising compounds 6i, 5o, 6o, 10a, 11a, 10f and 11f have been identified. Molecular docking simulations were done for compounds to identify important binding modes responsible for inhibition activity of α-glucosidase.
Asunto(s)
Inhibidores de Glicósido Hidrolasas/farmacología , Pirrolidinas/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Pirrolidinas/síntesis química , Pirrolidinas/química , Saccharomyces cerevisiae/enzimología , Relación Estructura-Actividad , alfa-Glucosidasas/metabolismoRESUMEN
An efficient acid catalyzed methodology has been employed to synthesize a variety of aza-flavanones and their α-glucosidase inhibitory activity is evaluated using acarbose, miglitol and voglibose as reference standards. Molecular modeling studies were performed for all compounds to identify the important binding modes responsible for the inhibition activity of α-glucosidase which helped find key interactions between the enzyme and the active compounds. Among all the compounds 5g, 5r and 5w have shown high α-glucosidase inhibition activity compared to standard reference drugs and have been identified as promising potential antidiabetic agents. This study is the first biological evaluation of aza-flavanones as α-glucosidase inhibitors.
RESUMEN
Sortilin is a type I membrane glycoprotein belonging to the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors and is most abundantly expressed in the central nervous system. Sortilin has emerged as a key player in the regulation of neuronal viability and has been implicated as a possible therapeutic target in a range of disorders. Here, the identification of AF40431, the first reported small-molecule ligand of sortilin, is reported. Crystals of the sortilin-AF40431 complex were obtained by co-crystallization and the structure of the complex was solved to 2.7â Å resolution. AF40431 is bound in the neurotensin-binding site of sortilin, with the leucine moiety of AF40431 mimicking the binding mode of the C-terminal leucine of neurotensin and the 4-methylumbelliferone moiety of AF40431 forming π-stacking with a phenylalanine.
Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular/antagonistas & inhibidores , Proteínas Adaptadoras del Transporte Vesicular/química , Cumarinas/química , Leucina/análogos & derivados , Bibliotecas de Moléculas Pequeñas/química , Proteínas Adaptadoras del Transporte Vesicular/genética , Sitios de Unión , Cristalización , Cristalografía por Rayos X , Células HEK293 , Humanos , Leucina/química , Ligandos , Neurotensina/química , Fenilalanina/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relación Estructura-ActividadRESUMEN
The identification of the novel, selective, orally bioavailable Sortilin inhibitor AF38469 is described. Structure-activity relationships and syntheses are reported, along with an X-ray crystal structure of the sortilin-AF38469 protein-inhibitor complex.