RESUMEN
Imidazoline-based small molecule inhibitors of p53-MDM2 interaction intended for the treatment of p53 wild-type tumors are the promising structures for design of anticancer drugs. Based on fragment approach we have investigated a key role of substituents in cis-imidazoline core for biological activity of nutlin family compounds. Although the necessity of the substituents in the phenyl rings of cis-imidazoline has been shown, there are no studies in which the replacements of a halogen by other substituents have been investigated. A series of simple cis-imidazoline derivatives containing halogen, hydroxy and alkoxy-substituents were synthesized. The biological activity of the compounds was studied using assays of cytotoxicity (MTT) and p53 level. It was found that the hydroxyl-derivatives were not cytotoxic whereas the alkoxy analogues were the same or more active as halogen-substituted compounds in cell viability test. The synthesized alkoxy derivatives induced an increase of p53 level and did not promote necrotic cell death in the concentration up to 40⯵M.
Asunto(s)
Diseño de Fármacos , Imidazolinas/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Células A549 , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Imidazolinas/síntesis química , Imidazolinas/química , Estructura Molecular , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/químicaRESUMEN
Glycogen synthase kinase 3ß (GSK-3ß) is a widely investigated molecular target for numerous diseases including Alzheimer's disease, cancer, and diabetes mellitus. Inhibition of GSK-3ß activity has become an attractive approach for treatment of diabetes and cancer. We report the discovery of novel GSK-3ß inhibitors of 3-arylidene-2-oxindole scaffold with promising activity. The most potent compound 3a inhibits GSK-3ß with IC50 4.19â¯nM. In a cell-based assay 3a shows no significant leucocyte toxicity at 10⯵M and is moderately cytotoxic against A549 cells. Compound 3a demonstrated high antidiabetic efficacy in obese streptozotocin-treated rats improving glucose tolerance at a dose of 50â¯mg/kg body weight thus representing an interesting lead for further optimization.
Asunto(s)
Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Oxindoles/química , Inhibidores de Proteínas Quinasas/síntesis química , Células A549 , Animales , Sitios de Unión , Dominio Catalítico , Supervivencia Celular/efectos de los fármacos , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/tratamiento farmacológico , Prueba de Tolerancia a la Glucosa , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Oxindoles/farmacología , Oxindoles/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Ratas , Relación Estructura-ActividadRESUMEN
Mixed simplified structures containing the paclitaxel and eleutherobin pharmacophore moieties were analyzed using molecular docking techniques and synthesized based on adamantane and 8-oxabicyclo[3.2.1]octane scaffolds. The crucial role of substituents' stereochemistry in biological activity is discussed. At micromolar concentrations the selected analogues interfered with tubulin dynamics in vitro and in a living organism. Furthermore, new compounds were cytotoxic against human tumour cell lines. The simplified eleutherobin analogues may be considered as prototypes of a new class of antitumour agents.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Diterpenos/síntesis química , Diterpenos/farmacología , Adamantano/química , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Sitios de Unión , Línea Celular Tumoral , Técnicas de Química Sintética , Diterpenos/química , Diterpenos/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Octanos/química , Conformación Proteica , Erizos de Mar/efectos de los fármacos , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismoRESUMEN
New 5-acetamido-substituted melatonin derivatives were efficiently synthesized in excellent yields via Knoevenagel condensation. The relative binding affinity of new synthesized compounds to MT3 receptor was tested via enzymatic assays and the X-ray structures of the most potent compounds were determined in complex with MT3.
Asunto(s)
Acetamidas/química , Melatonina/farmacología , Receptores de Melatonina/antagonistas & inhibidores , Cristalografía por Rayos X , Humanos , Ligandos , Melatonina/síntesis química , Melatonina/química , Modelos Moleculares , Estructura MolecularRESUMEN
The mol-ecule of the title compound, C(12)H(16)O(5), has crystallographically imposed mirror symmetry with the mirror plane passing through the endocyclic O atom and the mid-point of the double bond. In the crystal, mol-ecules are linked by C-Hâ¯O hydrogen bonds, forming chains running along the a axis.
RESUMEN
The title compound, 3C(7)H(9)ClO(3)·CHCl(3), crystallizes with mol-ecules of 3-exo-chloro-8-oxabicyclo-[3.2.1]oct-6-ene-2,4-diol (A) and chloro-form in a 3:1 ratio, in the space group R3m. Mol-ecules of A straddle a crystallographic mirror plane, whereas the chloro-form mol-ecules (C and H atoms) lie additionally on the threefold axis. The mol-ecules of A are linked into right- and left-helical chains by means of O-Hâ¯O hydrogen bonds, thus forming columns running along the c axis. Six inter-penetrated columns form a channel in which the solvent mol-ecules (chloro-form) are located.