RESUMEN
A new series of 1,3-diketone, heterocyclic and α,ß-unsaturated derivatives were synthesized and evaluated for their AhR antagonist activity using zebrafish and mammalian cells. Compounds 1b, 2c, 3b and 5b showed significant AhR antagonist activity in a transgenic zebrafish model. Among them, compound 3b, and 5b were found to have excellent AhR antagonist activity with IC50 of 3.36â¯nM and 8.3â¯nM in a luciferase reporter gene assay. In stem cell proliferation assay, compound 5b elicited marked HSC expansion.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Chalconas/farmacología , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Proteínas de Pez Cebra/antagonistas & inhibidores , Animales , Células COS , Proliferación Celular/efectos de los fármacos , Chalconas/síntesis química , Chlorocebus aethiops , Humanos , Células Madre/efectos de los fármacos , Pez CebraRESUMEN
Pyruvate dehydrogenase kinase 4 (PDK4) activation is associated with metabolic diseases including hyperglycemia, insulin resistance, allergies, and cancer. Structural modifications of hit anthraquinone led to the identification of a new series of allosteric PDK4 inhibitors. Among this series, compound 8c showed promising in vitro activity with an IC50 value of 84 nM. Good metabolic stability, pharmacokinetic profiles, and possible metabolites were suggested. Compound 8c improved glucose tolerance in diet-induced obese mice and ameliorated allergic reactions in a passive cutaneous anaphylaxis mouse model. Additionally, compound 8c exhibited anticancer activity by controlling cell proliferation, transformation, and apoptosis. From the molecular docking studies, compound 8c displayed optimal fitting in the lipoamide binding site (allosteric) with a full fitness, providing a new scaffold for drug development toward PDK4 inhibitors.
