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

Autor: Mohammed Farrag El-Behairy, Walaa Hamada Abd-Allah, Mohamed M. Khalifa, Mohamed S. Nafie, Mohamed A. Saleh, Mohammed S. Abdel-Maksoud, Tarfah Al-Warhi, Wagdy M. Eldehna, Ahmed A. Al‐Karmalawy
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 38, Iss 1 (2023)
Druh dokumentu: article
ISSN: 14756366
1475-6374
1475-6366
DOI: 10.1080/14756366.2022.2157825
Popis: 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).
Databáze: Directory of Open Access Journals
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