Highly potent naphthofuran-based retinoic acid receptor agonists

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Molecular Pharmacology

Background:

• Arotinoids are a class of compounds with diverse biological activities.
• Retinoic acid receptors (RARs) play crucial roles in cellular differentiation, proliferation, and apoptosis.
• Developing novel RAR agonists is important for therapeutic applications.

Purpose of the Study:

• To synthesize a novel series of arotinoids with benzofuran or naphthofuran scaffolds.
• To evaluate the synthesized compounds as agonists for retinoic acid receptor (RAR) subtypes.

Main Methods:

• A three-step synthetic strategy involving Sonogashira coupling, iodine-induced 5-endo-dig cyclization, and Suzuki/Sonogashira coupling.
• Characterization of synthesized benzofuran and naphthofuran arotinoids.
• In vitro assays to determine the agonist activity of compounds against RAR subtypes.

Main Results:

• Efficient synthesis of arotinoids with central benzofuran or naphthofuran ring structures.
• Most 3-substituted naphthofuran arotinoids demonstrated potent RAR agonist activity.
• Activities were observed in the nanomolar range for potent compounds.
• 5,7-di-tert-butylbenzofurans with specific substitution patterns showed reduced activity.

Conclusions:

• The developed synthetic route provides access to novel arotinoid structures.
• The synthesized naphthofuran arotinoids are potent agonists of RAR subtypes.
• These findings may lead to the development of new therapeutic agents targeting RAR-mediated pathways.