PUBLICATION
A forward chemical screen using zebrafish embryos with novel 2-substituted 2H-chromene derivatives
- Authors
- Torregroza, I., Evans, T., and Das, B.C.
- ID
- ZDB-PUB-090217-27
- Date
- 2009
- Source
- Chemical Biology & Drug Design 73(3): 339-345 (Journal)
- Registered Authors
- Evans, Todd
- Keywords
- biological screening, chemical biology, chemical genetics, chemical structure, kinase/phosphatase
- MeSH Terms
-
- Animals
- Benzopyrans/chemical synthesis
- Benzopyrans/chemistry
- Benzopyrans/pharmacology*
- Drug Evaluation, Preclinical/methods
- Embryonic Development/drug effects
- MAP Kinase Signaling System
- Receptors, Transforming Growth Factor beta/agonists*
- Receptors, Transforming Growth Factor beta/antagonists & inhibitors*
- Receptors, Transforming Growth Factor beta/metabolism
- Signal Transduction
- Small Molecule Libraries
- Zebrafish/embryology*
- PubMed
- 19207470 Full text @ Chem. Biol. Drug Des.
Citation
Torregroza, I., Evans, T., and Das, B.C. (2009) A forward chemical screen using zebrafish embryos with novel 2-substituted 2H-chromene derivatives. Chemical Biology & Drug Design. 73(3):339-345.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping