RESUMEN
Polycomb repressive complex 2 (PRC2) catalyzes the methylation of histone H3 lysine 27 (H3K27) and the enrichment of its catalytic product H3K27me3 is responsible for the silencing of tumor suppressor genes and the blocking of transcripts related to immunity and cell terminal differentiation. Aberrations of PRC2 components, such as mutation and overexpression, have been observed in various cancers, which makes PRC2 a potential therapeutic target for cancer. Up to now, targeting the enhancer of zeste homolog 2 (EZH2), the catalytic subunit of PRC2, represents the main strategy in the development of PRC2 inhibitors. Although significant progress has been made, new problems also emerge, e.g. the drug resistance caused by secondary mutations. In recent years, more and more efforts have shifted to another new strategy - targeting embryonic ectoderm development (EED) to disrupt its major interactions with other components, which are necessary to the PRC2 function, and some promising results have been obtained. This review summarizes the recent development of EED inhibitors as possible chemotherapy for cancer treatment, which could help accelerate future related research work.
RESUMEN
Eleven new compounds including five bisabolane (1-5) and three oplopane (6-8) sesquiterpenoids, a pair of benzopyran enantiomers (9 & 10) and a benzofuran derivative (11), along with six known sesquiterpenoid co-metabolites (12-17), have been obtained from the flower buds of Tussilago farfara. Their structures were elucidated by comprehensive spectroscopic analyses and comparison with structurally related known analogues. The absolute configurations of all the compounds except 11 were unequivocally assigned by various techniques, including Mosher's method and time-dependent density functional theory (TD-DFT) based calculations of 13C NMR and electronic circular dichroism (ECD) data. The C-8 absolute configuration on the sidechain of this group of bisabolane sesquiterpenoids was assigned for the first time. Our bioassays have established that compounds 3, 4, 13 and 14 showed significant α-glucosidase inhibitory activities, while 6, 8 and 14 displayed moderate antiproliferative effects against two human tumor cell lines A549 and MDA-MB-231. Further flow cytometric analysis revealed that 14 effectively induced cell apoptosis and arrested cell cycle at the S/G2 phases in A549 cells, in a dose-dependent manner.
Asunto(s)
Sesquiterpenos/química , Tussilago/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Dicroismo Circular , Flores/química , Flores/metabolismo , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/aislamiento & purificación , Inhibidores de Glicósido Hidrolasas/metabolismo , Inhibidores de Glicósido Hidrolasas/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/metabolismo , Sesquiterpenos/farmacología , Estereoisomerismo , Tussilago/metabolismo , alfa-Glucosidasas/química , alfa-Glucosidasas/metabolismoRESUMEN
Two new ergostane-type steroids (1 and 2) have been isolated from the fruiting body of a medicinal macro fungus Ganoderma lingzhi. The structures including the absolute configurations of them were elucidated by a combination of different spectroscopic analyses especially 13C NMR and ECD calculations. Compound 2 features an unusual 1,2-dioxolane moiety. Our bioassays revealed that the two steroids showed remarkable cytotoxicity against human A549 (lung) and MCF-7 (breast) tumor cell lines, with IC50 values ranging from 5.15 to 8.57 µg/mL.