Design, synthesis, and biological evaluation of novel ciprofloxacin derivatives as potential anticancer agents targeting topoisomerase II enzyme

Swedan, Hadeer K.; Kassab, Asmaa E.; Gedawy, Ehab M.; Elmeligie, Salwa E.

doi:10.1080/14756366.2022.2136172

Cited by 16 publications

(8 citation statements)

References 73 publications

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“…It is well known that the CPX, as all FQs, are a bacterial topoisomerase inhibitor [6,69]. However, due to the presence of these enzymes in the human body, in the last years many experimental researches have been pointed the potential of this drug and its derivatives to also inhibit human topoisomerases [12,[70][71][72][73][74][75][76]. Recently, in order to better understand the action mechanisms and the main differences between the interactions in TOPO-II of the two organisms, some theoretical investigations have already been done [77,78].…”

Section: Resultsmentioning

confidence: 99%

Structural parameters of the interaction between ciprofloxacin and human topoisomerase-II β enzyme: toward new 19F NMR Chemical Shift probes

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Ramalho

Gonçalves

2022

Preprint

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New tools for cancer diagnosis are being studied day by day, since early diagnosis can be crucial for a successful treatment. In this context, the use of NMR probes constitutes an efficient way of diagnosis. In this work, we investigated the use of ciprofloxacin to indirectly label the overexpression of topoisomerase-II enzymes by changes in 19F NMR chemical shifts of ciprofloxacin. Increased topoisomerase-II expression has been associated with cancer occurrence, mainly with aggressive forms of breast cancer, thus constituting a promising molecular target for new tumor cell identifiers. Using DFT calculations, a spectroscopy analysis of ciprofloxacin in different chemical environments, evaluating the solvent and enzymatic effects was performed. Our results point that the ciprofloxacin forms a stable complex with the enzyme, and the main intermolecular interactions between ciprofloxacin and human topoisomerase-IIβ are hydrogen bonds, following by pi-pi stacking and electrostatic interactions. Also, a shift of 6.04 ppm occurs in the 19F NMR signal when ciprofloxacin is interacting with the human topoi-somerase-IIβ enzyme, and that this parameter may be a possible indirect marker to indicate the overexpression of these enzymes in the body.

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Section: Resultsmentioning

confidence: 99%

Structural parameters of the interaction between ciprofloxacin and human topoisomerase-II β enzyme: toward new 19F NMR Chemical Shift probes

Sales

Ramalho

Gonçalves

2022

Preprint

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“…Topoisomerase activity was investigated using topoisomerase II kit (Human DNA Topoisomerase II eia Kit MBS942146) following manufacturer information. [41] Topoisomerase II activity was measured by the conversion of supercoiled plasmid DNA to relaxed DNA by recombinant Topo II. A mixture of 100 ng of supercoiled pBR322 plasmid DNA (Fermentas, USA) and 2 units of human DNA Topo II (USB Corp., USA) was incubated with and without the prepared compounds in the assay buffer (10 mM Tris-HCl pH 7.9) containing 50 mM NaCl, 4 mM MgCl2, 1 mM EDTA, 1 mM ATP, and 15 mg/ml bovine serum albumin for 30 min at 37 °C.…”

Section: Enzyme Targetingmentioning

confidence: 99%

“…Topoisomerase activity was investigated using topoisomerase II kit (Human DNA Topoisomerase II eia Kit MBS942146) following manufacturer information [41] . Topoisomerase II activity was measured by the conversion of supercoiled plasmid DNA to relaxed DNA by recombinant Topo II.…”

Section: Experimental Partmentioning

confidence: 99%

Design and Synthesis of Benzenesulfonamides Coupled with Piperidine, Morpholine, and N,N‐Dimethylethanamine Moieties as Apoptotic Inducers through VEGFR2 and Topoisomerase II Inhibition

Albujuq,

Althumayri,

Alharbi

et al. 2023

ChemistrySelect

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Novel hybrid series of benzenesulfonamide coupled with piperidine, morpholine, and N,N‐dimethylethanamine moieties at sulfonyl group were designed through pharmacophore hybridization, synthesized, and evaluated for cancer treatment. Benzenesulfonamide‐based derivatives had been synthesized, structurally elucidated, and biologically evaluated as potent VEGFR2 kinase and topoisomerase II inhibitors with cytotoxicity against MCF‐7 and HepG2 cells. Interestingly, the most cytotoxic compound against MCF‐7 and HepG2 cells exhibited promising IC50 values of 0.08 and 0.186 μM, respectively, compared to Doxorubicin as the reference drug with IC50 values of 7.67 and 8.28 μM. It exhibited promising dual enzyme inhibition VEGFR2 and Topoisomerase II with IC50 values of 13.24 nM and 8.3 μM compared to Sorafenib and Doxorubicin as standard drugs. It significantly stimulated total apoptotic breast cancer cell death by 55.25‐fold (34.26 % compared to 0.62 for the control), arresting the cell cycle at S‐phase, which affected the apoptosis‐mediated genes through upregulating P53, Bax, caspases 3, 8, and 9 and downregulating the anti‐apoptotic gene Bcl‐2. A molecular docking study was conducted to confirm the binding affinity of the designed compounds towards VEGFR2 and Topoisomerase II proteins with good binding energy and interactive modes as their co‐crystallized ligands.

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“…A popular broad-spectrum uoroquinolone antibiotic called cipro oxacin has shown anticancer action in many cancer cell lines. In cancer cells, it has been demonstrated to stop the cell cycle, break DNA double strands, and trigger apoptosis [5,6].…”

Section: Introductionmentioning

confidence: 99%

The Assessment of cytotoxicity, apoptosis inducing activity and molecular docking of a new ciprofloxacin derivative in human leukemic cells

Pashapour,

Dehghan-Nayeri,

Babaei

et al. 2023

Preprint

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The fluoroquinolone class of antibiotics includes derivatives of the drug ciprofloxacin. These substances have recently been advocated for the treatment of cancer. In the current study, we examined the cytotoxicity and apoptosis-inducing potential of a novel synthetic ciprofloxacin derivative in the human myeloid leukemia KG1-a cell line. With an IC50 of 25µM, this ciprofloxacin derivative, 7-(4-(2-(benzhydryloxy)-2-oxoethyl) piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4 dihydroquinoline-3- carboxylic acid (4-BHPCP), was an active drug. Through Hoechst 33258 staining and Annexin V/PI double staining experiments, the apoptotic activity of the 4-BHPCP was assessed morphologically. Real-time quantitative PCR was used to assess changes in the expression level of certain apoptosis-related genes, including Bcl-2, Bax, and Survivin (qRT PCR). The results of the qRT PCR analysis demonstrated that 4-BHPCP promotes apoptosis in the KG1-a cell line by down-regulating Survivin and Bcl2, up-regulating Bax, and increasing the Bax/Bcl2 transcripts in a time-dependent manner. These results imply that this novel chemical may be a promising therapy option for acute myeloid leukemia.

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Design, synthesis, and biological evaluation of novel ciprofloxacin derivatives as potential anticancer agents targeting topoisomerase II enzyme

Cited by 16 publications

References 73 publications

Structural parameters of the interaction between ciprofloxacin and human topoisomerase-II β enzyme: toward new 19F NMR Chemical Shift probes

Structural parameters of the interaction between ciprofloxacin and human topoisomerase-II β enzyme: toward new 19F NMR Chemical Shift probes

Design and Synthesis of Benzenesulfonamides Coupled with Piperidine, Morpholine, and N,N‐Dimethylethanamine Moieties as Apoptotic Inducers through VEGFR2 and Topoisomerase II Inhibition

The Assessment of cytotoxicity, apoptosis inducing activity and molecular docking of a new ciprofloxacin derivative in human leukemic cells

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