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

Abstract

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).

Highlights

• Two novel series of dibenzo[b,f]azepines were designed and synthesised based on the rigidification principle in drug design.

• The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines.

• 5e was the most active anti-topo II congener (IC₅₀ = 6.36 ± 0.36 µM).

• 5e was evaluated against leukaemia SR cells and its cytotoxic effect was confirmed (IC₅₀ = 13.05 ± 0.62 µM).

• In vivo studies of 5e significantly inhibited tumour proliferation by 62.7% and decreased tumour volume to 30.1 mm³ compared to doxorubicin treatment.

Graphical Abstract

Keywords:

• Dibenzo[bf]azepines
• rigidification
• ring closure
• topoisomerase II
• in vivo
• SAR

Acknowledgement

The authors extend their appreciation to the Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2022R25), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

Author contributions

Conceptualisation: Mohammed Farrag El-Behairy and Ahmed A. Al-Karmalawy; Data curation: Mohammed Farrag El-Behairy, Walaa Hamada Abd-Allah, Mohamed M. Khalifa, Mohamed S. Nafie, Mohamed A. Saleh, Wagdy M. Eldehna, and Ahmed A. Al-Karmalawy; Visualisation: Walaa Hamada Abd-Allah and Mohamed M. Khalifa; Methodology: Mohammed Farrag El-Behairy, Walaa Hamada Abd-Allah, Mohamed M. Khalifa, Mohamed S. Nafie, and Ahmed A. Al‐Karmalawy; Validation: Walaa Hamada Abd-Allah, Mohamed M. Khalifa, and Ahmed A. Al-Karmalawy; Supervision: Ahmed A. Al-Karmalawy; Writing – review and editing: Mohammed Farrag El-Behairy, Walaa Hamada Abd-Allah, Mohamed M. Khalifa, Mohamed S. Nafie, Mohamed A. Saleh, Wagdy M. Eldehna, and Ahmed A. Al‐Karmalawy. Finally, all authors revised and approved the final submitted version of the manuscript.

Disclosure statement

The authors declare that there is no conflict of interest.

Additional information

Funding

This work was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2022R25), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.