Design and synthesis of novel rigid dibenzo[b,f]azepines through ring closure technique as promising anticancer candidates against leukaemia and acting as selective topoisomerase II inhibitors and DNA intercalators

In this research, two novel series of dibenzo[b,f]azepines (14 candidates) were designed and synthesised based on the rigidification principle and following the reported doxorubicin's pharmacophoric features. The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. Further, the promising candidates (5a-g) were evaluated for their ability to inhibit topoisomerase II, where 5e was noticed to be the most active congener. Moreover, its cytotoxicity was evaluated against leukaemia SR cells. Also, 5e arrested the cell cycle at the G1 phase and increased the apoptosis ratio by 37.34%. Furthermore, in vivo studies of 5e showed the inhibition of tumour proliferation and the decrease in its volume. Histopathology and liver enzymes were examined as well. Besides, molecular docking, physicochemical, and pharmacokinetic properties were carried out. Finally, a SAR study was discussed to open the gate for further optimisation of the most promising candidate (5e).

Automated summary

Based on the rigidification principle and doxorubicin's pharmacophoric features, two novel series of dibenzo[b,f]azepines (14 candidates) were designed and synthesised. The anti-proliferative activity and topoisomerase II inhibition ability of the promising candidates (5a-g) were evaluated, with 5e identified as the most active congener. Moreover, 5e exhibited cytotoxicity against leukaemia SR cells, arrested the cell cycle at the G1 phase, increased apoptosis ratio, and showed inhibition of tumor proliferation and volume decrease in in vivo studies.