title: A forward chemical screen using zebrafish embryos with novel 2-substituted 2H-chromene derivatives.
abstract: We synthesized 2-substituted 2H-chromene derivatives from salicylaldehyde using potassium vinylic borates in the presence of secondary amines. Our goal was to generate novel compounds that might modulate transforming growth factor-beta signaling, based on limited rational design. Potassium vinyl trifluoroborates react with salicylaldehydes at 80 degrees C in the presence of a secondary amine and produce 2-substituted 2H-chromene derivatives with a 70-90% yield. A small library of these compounds, predicted to potentially interact with transforming growth factor-beta receptors, was screened for bioactivity in living zebrafish embryos. We found that the related compounds differentially affect development, and demonstrate one compound that produces severe body axis alterations in early embryogenesis and at lower doses affects specifically cardiovascular development. This compound modulates specifically a Smad-independent transforming growth factor-beta-regulated mitogen-activated protein kinase pathway, namely p-SAPK/JNK. These compounds, as suggested by our biological assays, may prove useful to manipulate developmental programs and develop therapeutic tools.
authors.affiliation: Department of Developmental & Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Torregroza
authors.forename: Todd
authors.initials: T
authors.lastname: Evans
authors.forename: Bhaskar C
authors.initials: BC
authors.lastname: Das
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D047108:Embryonic Development / Q000187:drug effects; D020935:MAP Kinase Signaling System; D018125:Receptors, Transforming Growth Factor beta / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries; D015027:Zebrafish / Q000196:embryology*
chemical_list: D001578:Benzopyrans; D018125:Receptors, Transforming Growth Factor beta; D054852:Small Molecule Libraries