Solvent-controlled Rh-catalysed hydrodehalogenation and construction of phenanthridinone skeleton from a common precursor in one-step sequence and the antitumor activity of its derivatives.

Herein, we report a solvent-controlled, operationally convenient and highly efficient rhodium(II)-catalysed protocol enabling hydrodehalogenation and phenanthridinone skeleton construction from 2-halobenzamide. This methodology facilitates the hydrodehalogenation of diverse 2-halobenzamides using isopropanol, providing quantitative yields without further purification. Furthermore, this strategy allows the direct and efficient conversion of 2‑halobenzamides into phenanthridinones by aprotic solvent. Additionally, a series of phenanthridinone derivatives were synthesised and evaluated for their inhibitory activities against tyrosyl-DNA phosphodiesterase 1 (TDP1) and topoisomerase IB (TOP1), as well as their cytotoxicity. Compound 3a showed potent TDP1 inhibitory activity (IC50 = 4.5 ± 0.4 μM) and synergistic effect with topotecan and radiosensitising effect in HCT116 cells by stabilising cellular TDP1 cleavage complexes (TDP1cc). Compound 3c exhibited strong TOP1 inhibition (+++) and induced the formation of cellular TOP1 cleavage complexes (TOP1cc) and DNA damage, and consequently triggered apoptosis. In vivo studies indicated that 3c exhibits antitumor efficacy in HCT116 xenograft model.