Synthesis and biological evaluation of pyrano and furano fused ring isoflavene derivatives

Abstract

Idronoxil (IDX) is a clinically tested isoflavene with anticancer and anti-inflammatory activity. While it has shown favourable safety and efficacy profiles in early trials, further optimisation is needed to improve its potency and pharmacokinetic properties. Structural modifications at the C6 and C7 positions of IDX have yielded promising leads; however, dual functionalisation of these sites remains underexplored. In this study, we report the synthesis of novel fused-ring IDX derivatives incorporating coumarin, pyran, and furan moieties via Pechmann and Knoevenagel condensations, Rap–Stoermer cyclisations, and [4 + 2] cycloaddition reactions involving o-quinone methide intermediates. A selection of analogues with differing functionality was evaluated for anticancer activity across prostate (PC-3), neuroblastoma (SKN-BE(2)C), and triple-negative breast cancer (MDA-MB-231) cell lines. These findings establish synthetic strategies for the incorporation of various fused rings to isoflavene scaffolds and offer insights for structure–activity optimisation.