2. Academic Validation
  3. Hit-to‑lead optimization of new carbazoles as potential anticancer agents via targeting human topoisomerase II

Hit-to‑lead optimization of new carbazoles as potential anticancer agents via targeting human topoisomerase II

  • Bioorg Chem. 2025 Nov:166:109070. doi: 10.1016/j.bioorg.2025.109070.
Pritam Maity 1,  Farman Ahmad 1,  Poonam Yadav 2,  Madhurendra Kumar Katiyar 1,  Joydeep Chatterjee 1,  Umashanker Navik 3,  Raj Kumar 4
Affiliations

Affiliations

  • 1 Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, School of Health Sciences, Central University of Punjab, Bathinda 151401, India.
  • 2 Department of Pharmacology, School of Health Sciences, Central University of Punjab, Bathinda 151401, India.
  • 3 Department of Pharmacology, School of Health Sciences, Central University of Punjab, Bathinda 151401, India. Electronic address: [email protected].
  • 4 Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, School of Health Sciences, Central University of Punjab, Bathinda 151401, India. Electronic address: [email protected].
PMID: 41086725 DOI: 10.1016/j.bioorg.2025.109070
Abstract

Prostate and breast cancers are the major concerns among Cancer patients. This study represents the development of new carbazoles as Anticancer agents by interfering with topoisomerases II (topoII). Fifteen rationally designed carbazoles (4a-4o) were initially synthesized and screened for Anticancer activities against different Cancer cell lines. The promising hit compound 4f was further optimized by modifying the carbazole scaffold at positions 1, 3, 4, and 9, which led to the synthesis of its derivatives 5a-5j, 6a-6d and 7a-7d. Interestingly, 5a (IC50 = 8.47 ± 0.29 μM) and 6a (IC50 = 5.35 ± 0.30 μM) showed selective and improved Anticancer activities than 4f (IC50 = 10.20 ± 0.44 μM and 8.564 ± 0.55 μM) in MCF-7 and PC-3 cells, respectively. Both compounds increased the ROS generation, depolarized the mitochondrial membrane, induced Apoptosis via increased relative Bax/Bcl2 ratio, and arrested the cell cycle at G2/M phase. The selective human topoII inhibition further supported their Anticancer mechanism. The in silico molecular docking and MD simulation studies aided their binding analysis in topoII and claimed them as potential topoII inhibitors.

Keywords

Breast cancer; Carbazole; Lead optimization; Prostate cancer; Topoisomerases.

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