RESUMEN
Nrf2-mediated activation of ARE regulates expression of cytoprotective enzymes against oxidative stress, inflammation, and carcinogenesis. We have discovered a novel structure (1) as an ARE inducer via luciferase reporter assay to screen the in-house database of our laboratory. The potency of 1 was evaluated by the expression of NQO-1, HO-1, and nuclear translocation of Nrf2 in HCT116 cells. In vivo potency of 1 was studied using AOM-DSS models, showing that the development of colorectal adenomas was significantly inhibited. Administration with 1 lowered the expression of IL-6, IL-1ß, and promoted Nrf2 nuclear translocation. These results indicated that 1 is a potent Nrf2/ARE activator, both in vitro and in vivo. Forty-one derivatives were synthesized for SAR study, and a more potent compound 17 was identified. To our knowledge, this is a potent ARE activator. Besides, its novel structure makes it promising for further optimization.
Asunto(s)
Adenoma/prevención & control , Antineoplásicos/farmacología , Elementos de Respuesta Antioxidante/genética , Neoplasias Colorrectales/prevención & control , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Transporte Activo de Núcleo Celular/efectos de los fármacos , Adenoma/inducido químicamente , Adenoma/patología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Azoximetano , Western Blotting , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Neoplasias Colorrectales/inducido químicamente , Neoplasias Colorrectales/patología , Sulfato de Dextran , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HCT116 , Hemo-Oxigenasa 1/metabolismo , Células Hep G2 , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos Químicos , Estructura Molecular , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologíaRESUMEN
When exposed to electrophiles, human colorectal cancer cells (HCT116) counteract oxidative stress through activating NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. To identify new activators, luciferase reporter gene assay was used to screen in-house database of our laboratory, leading to a novel α-pyrone compound 1 as a hit. 2 with 2-fluoro phenyl group exhibited the strongest ARE inductive activity in the first round structure-activity relationship (SAR) study. Biological studies showed the compound induced nuclear translocation of Nrf2 preceded by phosphorylation of ERK1/2. The data encouraged us to use 2 as lead and 20 derivatives were synthesized to discuss a more detailed SAR, leading to a more potent compound 9, which can be the starting compound for further modification.