Dibenzofuran annulated 1-azepines: Synthesis and cytotoxicity

Abstract

The 2,3,4,5-tetrahydro-1H-benzo[2,3]benzofuro[6,5-b]azepine skeleton was built starting from dibenzofuran via 3-aminodibenzofuran, creating the 5-methylene-substituted azepine ring by an intramolecular Heck cyclization. Subsequent modifications led to the endocyclic 4,5-unsaturated analog, the dihydro product, and N-methyl and N-acylated derivatives. All the compounds were obtained in high yields and were fully characterized. Preliminary proliferation assays in a wild-type and a cisplatin-resistant human ovarian carcinoma cell line (A2780 and A2780cisR respectively) indicated that these compounds are moderately cytotoxic, with no significant differences associated with cisplatin resistance. The N-acetyl-5-methylene analog 3 (IC₅₀ = 10 μM), the only one with an exocyclic double bond in conjugation with a benzene ring, was at least twice as active as any other member of the series, suggesting that this structural feature might be associated with higher cytotoxicity.

GRAPHICAL ABSTRACT

Keywords:

• 1-Azepines
• cytotoxicity
• DEPT NMR
• dibenzofuran
• intramolecular Heck cyclization

Additional information

Funding

Authors TY and BKC are grateful to CONICYT (Chile) for providing funds through FONDECYT postdoctoral grant 3150474.