Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Nov 26;17(12):1593.
doi: 10.3390/ph17121593.

In Silico Evaluation of Some Computer-Designed Fluoroquinolone-Glutamic Acid Hybrids as Potential Topoisomerase II Inhibitors with Anti-Cancer Effect

Octavia-Laura Oancea  1 , Șerban Andrei Gâz  1 , Gabriel Marc  2 , Ioana-Andreea Lungu  3 , Aura Rusu  4
Affiliations

In Silico Evaluation of Some Computer-Designed Fluoroquinolone-Glutamic Acid Hybrids as Potential Topoisomerase II Inhibitors with Anti-Cancer Effect

Octavia-Laura Oancea et al. Pharmaceuticals (Basel). .

Abstract

Background/Objectives: Fluoroquinolones (FQs) are topoisomerase II inhibitors with antibacterial activity, repositioned recently as anti-cancer agents. Glutamic acid (GLA) is an amino acid that affects human metabolism. Since an anti-cancer mechanism of FQs is human topoisomerase II inhibition, it is expected that FQ-GLA hybrids can act similarly. Methods: We designed 27 hypothetical hybrids of 6 FQs and GLA through amide bonds at the 3- and 7-position groups of FQs or via ethylenediamine/ethanolamine linkers at the carboxyl group of the FQ. Hydroxamic acid derivatives were also theoretically formulated. Computational methods were used to predict their physicochemical, pharmacokinetic, or toxicological properties and their anti-cancer activity. For comparison, etoposide was used as an anti-cancer agent inhibiting topoisomerase II. Molecular docking assessed whether the hybrids could interact with the human topoisomerase II beta in the same binding site and interaction sites as etoposide. Results: All the hybrids acted as potential topoisomerase II inhibitors, demonstrating possible anti-cancer activity on several cancer cell lines. Among all the proposed hybrids, MF-7-GLA would be the ideal candidate as a lead compound. The hybrid OF-3-EDA-GLA and the hydroxamic acid derivatives also stood out. Conclusions: Both FQs and GLA have advantageous structures for obtaining hybrids with favourable properties. Improvements in the hybrids' structure could lead to promising results.

Keywords: anti-cancer potential; computational methods; docking study; etoposide; fluoroquinolones; glutamic acid; huma topoisomerase II beta-DNA complex; hybrids.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The structures of type II topoisomerase inhibitors: (a) doxorubicin, (b) epirubicin, (c) vosaroxin, (d) A-65281, (e) merbarone, (f) mitoxantrone, (g) amsacrine, (h) etoposide, (i) teniposide.
Figure 2
Figure 2
The basic core of the FQs structure.
Figure 3
Figure 3
Comparison of the docked pose (yellow) and the original ligand (red) structures.
Figure 4
Figure 4
The interactions of etoposide with the residues of the enzyme–DNA complex binding site—3D (left) and 2D (right) structures.
Figure 5
Figure 5
The interactions of the ligand (the hybrid OF-3-EDA-GLA) with the residues of the enzyme–DNA complex binding site—3D (left) and 2D (right) structures.
Figure 6
Figure 6
The interactions of the ligand (the hybrid MF-7-GLA) with the residues of the enzyme–DNA complex binding site—3D (left) and 2D (right) structures.
Figure 7
Figure 7
The overlay of binding poses of the hybrids OF-3-EDA-GLA (black) and MF-7-GLA (purple).
Figure 8
Figure 8
Synthesis proposal for hybrid MF-7-GLA.
Figure 9
Figure 9
The general structures of each class of hybrids.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Yadav V., Talwar P. Repositioning of Fluoroquinolones from Antibiotic to Anti-Cancer Agents: An Underestimated Truth. Biomed. Pharmacother. 2019;111:934–946. doi: 10.1016/j.biopha.2018.12.119. - DOI - PubMed
    1. Aranha O., Grignon R., Fernandes N., McDonnell T., Wood D., Sarkar F. Suppression of Human Prostate Cancer Cell Growth by Ciprofloxacin Is Associated with Cell Cycle Arrest and Apoptosis. Int. J. Oncol. 2003;22:787–794. doi: 10.3892/ijo.22.4.787. - DOI - PubMed
    1. Aranha O., Wood D.P., Sarkar F.H. Ciprofloxacin Mediated Cell Growth Inhibition, S/G2-M Cell Cycle Arrest, and Apoptosis in a Human Transitional Cell Carcinoma of the Bladder Cell Line. Clin. Cancer Res. 2000;6:891–900. - PubMed
    1. Perucca P., Savio M., Cazzalini O., Mocchi R., Maccario C., Sommatis S., Ferraro D., Pizzala R., Pretali L., Fasani E., et al. Structure–Activity Relationship and Role of Oxygen in the Potential Antitumour Activity of Fluoroquinolones in Human Epithelial Cancer Cells. J. Photochem. Photobiol. B Biol. 2014;140:57–68. doi: 10.1016/j.jphotobiol.2014.07.006. - DOI - PubMed
    1. Morgan D.O. Principles of CDK Regulation. Nature. 1995;374:131–134. doi: 10.1038/374131a0. - DOI - PubMed

LinkOut - more resources