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Synthesis and Biological Evaluation of Novel 1H-Benzo[d]imidazole Derivatives as Potential Anticancer Agents Targeting Human Topoisomerase I.

ABSTRACT: Small molecules that modulate biological functions are targets of modern-day drug discovery efforts. A new series of novel 1H-benzo[d]imidazoles (BBZs) were designed and synthesized with different functional groups at the phenyl ring and variable lengths of the alkyl chain at the piperazine end as anticancer agents. We identified human topoisomerase I (Hu Topo I) as a probable target of these molecules through a computational study and DNA relaxation assay, a functional assay of the Hu Topo I enzyme. UV absorption, fluorescence, and circular dichroism spectroscopy were used to study interactions between BBZ and DNA. Out of 16 compounds, 11a, 12a, and 12b showed strong binding affinity and thermal stabilization of AT sequence-specific DNA. BBZs were screened against a panel of 60 human cancer cell lines at National Cancer Institute, USA. Most potent molecules 11a, 12a, and 12b showed 50% growth inhibition (GI₅₀) in a concentration range from 0.16 to 3.6 μM cancer cells. Moreover, 12b showed 50% inhibition of the relaxation of DNA by Hu Topo I at 16 μM. Furthermore, flow cytometry revealed that 11a, 12a, and 12b cause prominent G2M arrest of cancer cells. In view of the above, we propose that 12b deserves to be further evaluated for its therapeutic use as an anticancer agent.

SUBMITTER: Pandey S

PROVIDER: S-EPMC8793051 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Synthesis and Biological Evaluation of Novel 1H-Benzo[d]imidazole Derivatives as Potential Anticancer Agents Targeting Human Topoisomerase I.

Pandey Stuti S Tripathi Pragya P Parashar Palak P Maurya Vikas V Malik Md Zubbair MZ Singh Raja R Yadav Pooja P Tandon Vibha V

ACS omega 20220110 3

Small molecules that modulate biological functions are targets of modern-day drug discovery efforts. A new series of novel 1H-benzo[d]imidazoles (BBZs) were designed and synthesized with different functional groups at the phenyl ring and variable lengths of the alkyl chain at the piperazine end as anticancer agents. We identified human topoisomerase I (Hu Topo I) as a probable target of these molecules through a computational study and DNA relaxation assay, a functional assay of th ...[more]

PMID: 35097282

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Project description:Repositioning of already approved medications through repurposing or re-profiling for new medical uses after certain structural modifications is a novel approach in drug discovery. Fluoroquinolone antibiotics are one of the cardinal agents investigated for potential anticancer activities. In this work, levofloxacin was repositioned for anticancer activities. A series of levofloxacin-based compounds were designed and synthesized through the derivatization of levofloxacin's carboxylic acid functionality. The newly synthesized compounds were screened for cytotoxic activities against breast, liver, and leukemia cancer cell lines. Their effect on normal cells was also investigated. The target compounds were evaluated for their proliferative inhibitory activity toward topoisomerase II beta polymerization. Compound 5 showed higher inhibitory activity against a breast cancer cell line (MCF-7) with IC50 = 1.4 μM and lesser side effects on a normal breast cell line (MCF-10a) with IC50 = 30.40 μM than reference drugs. The best activity against a liver cancer cell line (Hep3B) was exhibited by compounds 3c, 4b, 5, 7, 8, 13a and 13c with IC50 values ranging from 0.43 to 8.79 μM. Regarding the effect of compounds 5 and 13a on a leukemia cancer cell line (L-SR), their IC50 values were 0.96 and 3.12 μM, respectively. Compounds 3c and 5 showed Topo2β inhibitory effects on Hep3B cells (81.33% and 83.73%, respectively), which was better than levofloxacin and etoposide as reference drugs. Cytometry cell cycle analysis revealed that compounds 3c and 5 arrested the cell cycle at the S phase (37.56% and 39.09%, respectively). Compounds 3c and 5 exhibited an elevation in active caspase-3 levels by 4.9 and 4.5 folds, respectively. Molecular modeling simulation of compounds 3c and 5 demonstrated energy scores (-29.77 and -20.46 kcal mol-1, respectively) more than those of the reference drugs as they interact with the most essential amino acids required for good affinity towards human topoisomerase II beta enzyme (PDB ID: 3QX3). Physicochemical characteristics of the most promising cytotoxic compounds 3c and 5 were investigated and compared to etoposide and levofloxacin as reference drugs. However, they showed high gastrointestinal absorption and could not penetrate the blood-brain barrier.

Dataset Information

Synthesis and Biological Evaluation of Novel 1H-Benzo[d]imidazole Derivatives as Potential Anticancer Agents Targeting Human Topoisomerase I.

Publications

Synthesis and Biological Evaluation of Novel 1<i>H</i>-Benzo[<i>d</i>]imidazole Derivatives as Potential Anticancer Agents Targeting Human Topoisomerase I.

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