This article is based on a poster originally authored by Nermeen Ali, Mina Adly, Azza Taher, Heather Coleman, Fakher Ahmed, Ashraf Mahmoud, Mohamed Salem and Rana El-Masry, which was presented at ELRIG Drug Discovery 2024 in affiliation with Ulster University, Cairo University, October 6 university and University for Modern Sciences and Arts.
This poster is being hosted on this website in its raw form, without modifications. It has not undergone peer review but has been reviewed to meet AZoNetwork's editorial quality standards. The information contained is for informational purposes only and should not be considered validated by independent peer assessment.
Introduction
Fluoroquinolones are a class of compounds with known antimicrobial properties, but their potential as anticancer agents remains underexplored.1,2 DNA topoisomerase has been identified as important molecular targets for anticancer drugs.3
Objective
This study aims to design and synthesize novel fluoroquinolone analogs derived from Ciprofloxacin hydrazide, with the goal of discovering potent and selective anticancer agents. These compounds are specifically designed to inhibit the Topoisomerase II enzyme, a critical player in DNA replication and cell cycle regulation, thereby serving as a promising target for anticancer therapies.
Method
A series of fluoroquinolone analogs were synthesized and subjected to the NCI-60 Human Tumour Cell Line Screening assay to assess their cytotoxicity. The most potent compounds were further tested in a five-dose assay. Topoisomerase II inhibition assays were conducted to elucidate the mechanism of action. Selectivity was assessed by comparing the cytotoxic effects on cancerous NCI-60 cell lines versus normal mammalian Vero cells. Cell cycle analysis was performed on MCF-7 cells to investigate the effects on cell cycle distribution.
Results
The novel derivatives demonstrated a remarkable reduction in cell proliferation across most tested cell lines, with IC50 values significantly lower than Etoposide, exhibiting 4-12 folds greater cytotoxicity.
Derivative I, in particular, displayed high selectivity for cancer cells, with markedly reduced toxicity to Vero cells (CC50 = 349.03 µM) compared to its potent cytotoxic effect on cancer cells (Mean GI50 = 9.06 µM). Topoisomerase II inhibition assays confirmed that Ciprofloxacin hydrazide derivatives are potent inhibitors of the enzyme. Furthermore, cell cycle analysis revealed that the most active Ciprofloxacin hydrazide derivatives induced cell cycle arrest at the G2/M phase in MCF-7 cells.
Graphs
Image Credit: Image courtesy of Nermeen Ali, in partnership with ELRIG (UK) Ltd.
Image Credit: Image courtesy of Nermeen Ali, in partnership with ELRIG (UK) Ltd.
Image Credit: Image courtesy of Nermeen Ali, in partnership with ELRIG (UK) Ltd.
Image Credit: Image courtesy of Nermeen Ali, in partnership with ELRIG (UK) Ltd.
Cell study results. Source: Ulster University
| |
Ciprofloxacin |
Ciprofloxacin
hydrazide
derivatives I |
Ciprofloxacin
hydrazide
derivatives
II, III |
Etoposide |
Mean GI50 of
NCI-60 cell lines
(µM) |
3.30 |
9.06 |
2.45 |
2.85 |
CC50 of Vero cell
line (µM) |
30.62 |
349.03 |
43.45 |
|
Full NCI panel SI
(using mean GI50) |
9.28 |
38.52 |
17.73 |
Conclusion
A new series of fluoroquinolone-based compounds were designed and synthesized as potential anticancer agents. A single-dose NCI 60 cell line screen revealed that most of these novel derivatives exhibited significant potency across the tested lines.
The five-dose assay demonstrated broad-spectrum cytotoxicity comparable to Etoposide, with several compounds showing remarkable reductions in cell proliferation across most tested cell lines.
These derivatives achieved IC50 values significantly lower than Etoposide, resulting in up to 4- to 12-fold greater cytotoxicity. In the normal VERO cell line cytotoxicity assay, most compounds were found to be selectively more toxic to cancer cell lines than to normal cells.
Cell cycle analysis further revealed that the most active compounds disrupted the cell cycle phase distribution in MCF-7 cells, inducing arrest in the G2/M phase. Additionally, a Topoisomerase II inhibition assay confirmed that these target molecules exhibit potent inhibitory activity against the Topoisomerase II enzyme, supporting their proposed mechanism of action.
In conclusion, these findings suggest that these compounds are potential candidates for the development of new anti-cancer agents. Future work will focus on designing additional analogs to establish a more advanced structure-activity relationship and optimize their therapeutic potential.
References
- Sung, H., et al. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a Cancer Journal for Clinicians, [online] 71(3), pp.209–249. https://doi.org/10.3322/caac.21660..
- Bray, F., et al. (2024). Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A cancer journal for clinicians, 74(3), pp.229–263. https://doi.org/10.3322/caac.21834.
- Buzun, K., et al. (2020). DNA topoisomerases as molecular targets for anticancer drugs. Journal of Enzyme Inhibition and Medicinal Chemistry, 35(1), pp.1781–1799. https://doi.org/10.1080/14756366.2020.1821676.
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