RESUMEN
A series of twenty seven oxa/azaspiro[4,5]trienone derivatives were synthesized and their anticancer properties have been explored. GI50 values of all these compounds were evaluated against four types of human cancer cell lines, i.e. MCF-7 (breast), DU-145 (prostate), A549 (lung) and HepG2 (liver). Five compounds of the series exhibited good anticancer potential against MCF-7 with GI50 values less than 2 µM. Detailed biological studies of the two representative compounds 9b and 9e revealed that they arrest cell cycle in G0/G1 phase and induce mitochondria mediated apoptosis, that was further confirmed by measurement of mitochondrial membrane potential (ΔΨm), intracellular ROS generation, caspase 9 activity and Annexin V-FITC assay. Furthermore, western blot analysis suggested that these compounds up-regulate the levels of p53, p21, p27 and Bax, and down-regulate the level of Bcl-2 confirming the apoptosis inducing properties.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Diseño de Fármacos , Furanos/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Pirroles/farmacología , Compuestos de Espiro/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Furanos/síntesis química , Furanos/química , Humanos , Mitocondrias/metabolismo , Estructura Molecular , Pirroles/síntesis química , Pirroles/química , Especies Reactivas de Oxígeno/metabolismo , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
An efficient synthesis of a new series of tamoxifen mimics is described by employing iodine catalyzed ipsocyclization strategy followed by Suzuki coupling. A molecular docking studies of the synthesized compounds 11a-n and 12 in estrogen receptor (ER-α) showed that the scaffolds are fitting well in the groove, thereby suggesting them as promising antiproliferative agents for estrogen dependent breast cancer lines. All compounds were tested in vitro against breast cancer cell lines-ER positive, MCF-7; ER negative, MDA-MB-231; and control mammary epithelial cells, MEpiC. The biological results showed that most of the compounds are active against MCF-7 with IC50 values less than 6.5µM which corroborate the results of molecular docking studies.
Asunto(s)
Ácidos Borónicos/química , Tamoxifeno/análogos & derivados , Sitios de Unión , Ácidos Borónicos/síntesis química , Ácidos Borónicos/toxicidad , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Catálisis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/química , Receptor alfa de Estrógeno/química , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Paladio/química , Estructura Terciaria de Proteína , Tamoxifeno/síntesis química , Tamoxifeno/toxicidadRESUMEN
The link between PDE4 and apoptosis prompted us to design and synthesize for the first time a series of novel 1-thienyl pyrroloquinoxalines as potential PDE4 inhibitors/apoptotic agents. A ligand-free Pd-catalyzed C-N cross-coupling/cyclization strategy has been developed for the rapid and milder access to this class of compounds some of which showed interesting pharmacological properties when tested in vitro and in zebrafish embryos.
Asunto(s)
Apoptosis/efectos de los fármacos , Paladio/química , Inhibidores de Fosfodiesterasa 4/farmacología , Pirroles/farmacología , Quinoxalinas/farmacología , Tiofenos/farmacología , Animales , Catálisis , Ciclización , Relación Dosis-Respuesta a Droga , Estructura Molecular , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/química , Pirroles/síntesis química , Pirroles/química , Quinoxalinas/síntesis química , Quinoxalinas/química , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/química , Pez Cebra/embriologíaRESUMEN
An unprecedented AlCl3-mediated method has been developed involving aromatic C-H bond addition to an alkyne and heteroarylation of an arene in a single pot leading to densely functionalized novel olefins, e.g. 2-(2,2-diarylvinyl)-3-arylquinoxalines, as potential inhibitors of sirtuins.
Asunto(s)
Alquenos/química , Compuestos de Aluminio/química , Antineoplásicos/farmacología , Cloruros/química , Embrión no Mamífero/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Quinoxalinas/farmacología , Sirtuinas/antagonistas & inhibidores , Cloruro de Aluminio , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Quinoxalinas/síntesis química , Quinoxalinas/química , Sirtuinas/metabolismo , Relación Estructura-Actividad , Pez CebraRESUMEN
Novel pyrano[4,3-b]pyran-5(4H)-one based small molecules were designed as potential inhibitors of sirtuins (i.e., yeast sir2, a homolog of human SIRT1). Elegant synthesis of these compounds was performed via a multi-step sequence consisting of MCR, Sandmeyer type iodination, Sonogashira type coupling followed by iodocyclization and then Pd-mediated various C-C bond forming reactions. The overall strategy involved the construction of a pyran ring followed by the fused pyranone moiety and subsequent functionalization at C-8 position of the resultant core pyrano[4,3-b]pyran-5(4H)-one framework. The crystal structure analysis of a representative iodolactonized product (6d) is presented. Some of the synthesized compounds showed promising inhibitory activities when tested against yeast sir2 in vitro. The compound 6g showed dose dependent inhibition (IC50=78.05µM) of yeast sir2 and good interactions with this protein in silico.