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A new group of thiazolidine-2,4-dione derivatives of ciprofloxacin having butyryl linker 3a-l was synthesized via an alkylation of thiazolidine-2,4-diones with butyryl ciprofloxacin with yield range 48–77% andfully characterized by various spectroscopic and analytical tools. Anti-cancer screening outcomes indicated that 3a and 3i possess antiproliferative activities against human melanoma LOX IMVI cancer cell line with IC 50 values of 26.7 ± 1.50 and 25.4 ± 1.43 µM, respectively, using doxorubicin and cisplatin as positive controls with an IC 50 of 7.03 ± 0.40 and 5.07 ± 0.29 µM, respectively. Additionally, compound 3j showed promising anticancer activity against human renal cancer A498 cell line with IC 50 value of 33.9 ± 1.91 µM while doxorubicin and cisplatin showed IC 50 values of 3.59 ± 0.20 and 7.92 ± 0.45, respectively. On the other hand, compound 3i did not show considerable anti-bacterial activity against S. aureus , E. coli and P. aeruginosa , a nd only moderate activity against K. pneumoniae with only a tenth of the activity of ciprofloxacin, confirming the cytotoxicity observed. Mechanistically, compound 3i inhibited both topoisomerase I and II with IC 50 of 4.77 ± 0.26 and 15 ± 0.81 µM. Furthermore, it induced cell cycle arrest at S phase in melanoma LOX IMVI cells. Moreover, 3i provoked substantial levels of early, late apoptosis and necrosis in melanoma LOX IMVI cell line comparable to that induced by doxorubicin. Furthermore, compound 3i increased the expression level of active caspase-3 by 49 folds higher in LOX IMVI cell, increased protein expression level of Bax more than the control by 3 folds and inhibited PARP-1by 33% in LOX IMVI. All results were supported by theoretical docking studies on both tested enzymes confirming potential cytotoxicity for the synthesized hybrids.

Several reviews of inhibitors of topoisomerase II have been published, covering research before 2018. Therefore, this review is focused primarily on more recent publications with relevant points from the earlier literature. Topoisomerase II is an established target for anticancer drugs, which are further subdivided into poisons and catalytic inhibitors. While most of the topoisomerase II-based drugs in clinical use are mostly topoisomerase II poisons, their mechanism of action has posed severe concern due to DNA damaging potential, including the development of multi-drug resistance. As a result, we are beginning to see a gradual paradigm shift towards non-DNA damaging agents, such as the lesser studied topoisomerase II catalytic inhibitors. In addition, this review describes some novel selective catalytic topoisomerase II inhibitors. The ultimate goal is to bring researchers up to speed by curating and delineating new scaffolds as the leads for the optimization and development of new potent, safe, and selective agents for the treatment of cancer.

The current study has yielded promising results in the evaluation of a new ciprofloxacin-chalcone hybrid (CP derivative) for its anticancer activity as potential Topoisomerases (Topo) I and II inhibitors. The in vitro results showed that the CP derivative significantly suppressed the growth of HCT-116 and LOX IMVI cells, with IC50 values of 5.0 μM and 1.3 μM, respectively, outperforming Staurosporine, which had IC50 values of 8.4 μM and 1.6 μM, respectively. Flow cytometry analysis revealed that the new CP derivative triggered apoptosis and cell cycle arrest at the G2/M phase, associated with the up-regulation of pro-apoptotic genes (Bax and Caspase 9) and downregulation of the anti-apoptotic gene (Bcl-2). Further investigations showed that the CP derivative inhibited Topo I and II enzymes, as expected molecular targets; docking studies further supported its dual inhibitory action on Topo I and II. These findings suggest that the ciprofloxacin-chalcone hybrid could be a promising lead compound for developing new anticancer therapy.

Breast cancer is a prevalent type of cancer worldwide, leading to both high incidence and mortality, and hence, effective and safe drugs are needed. Because of this, the use of natural products and their derivatives has become a popular strategy for developing new chemotherapeutic agents. In this study, 17 new sesquiterpene-aryl derivatives were synthesized using (−)-drimenol as the starting material. The cytotoxicity of these semi-synthetic derivatives was determined in MCF-7 cells, a breast cancer model, and in a non-tumor cell line, MCF-10, to evaluate selectivity. The results show that five of these sesquiterpene derivatives had IC50 values between 9.0 and 25 µM. Of these, compound 14c stands out for its higher cytotoxicity in MCF-7 cells but lower cytotoxicity in MCF-10 cells, being more selective than daunorubicin (selective index values of 44 and 28, respectively). In addition, compound 14c induced oxidative stress in MCF-7 cells, activated caspases-3/7, and selectively inhibited topoisomerase II (TOP2) versus topoisomerase I (TOP1) in MCF-7 cells. In silico studies allowed us to propose a binding mode for 14c to the TOP2 DNA complex to validate the experimental results. Therefore, this study demonstrated the importance of aryl-sesquiterpene structures and their promising profiles in the search for new bioinspired antitumor drugs in natural products.

To shed light on the significance of thiazole derivatives in the advancement of cancer medication and to contribute to therapeutic innovation, we have designed the synthesis and antiproliferative activity investigation of 5-(1,3-dioxoisoindolin-2-yl)-7-(4-nitrophenyl)-2-thioxo-3,7-dihydro-2H-pyrano[2,3-d] thiazole-6-carbonitrile, the structure of thiazole derivative was confirmed by spectroscopic techniques UV, IR and NMR. The cytotoxic activity (in vitro) of the new hybrid synthesized compound on five human cancer cell lines; human liver hepatocellular carcinoma (HepG-2), colorectal carcinoma (HCT-116), breast adenocarcinoma (MCF-7), and epithelioid carcinoma (Hela), and a normal human lung fibroblast (WI-38) was studied using MTT assay. The compound exhibited a strong cytotoxicity effect against HepG-2 and MCF-7. The interaction of the newly synthesized compound with calf-thymus DNA (CT-DNA) was investigated at pH 7.2 by using UV–Vis absorption measurements, also, molecular docking was carried out to investigate the DNA binding affinity of the proposed compound with the prospective target, DNA (PDB ID: 1d12). Finally, molecular docking was carried out to examine the binding patterns with the prospective target, DNA-Topo II complex (PDB-code: 3QX3). Results indicated that the investigated compound strongly binds to CT-DNA via intercalative mode, and correlated with those obtained from molecular docking and in agreement with that of in vitro cytotoxicity activity.

Cancers that appear pathologically similar often respond differently to the same drug regimens. Methods to better match patients to drugs are in high demand. We demonstrate a promising approach to identify robust molecular markers for targeted treatment of acute myeloid leukemia (AML) by introducing: data from 30 AML patients including genome-wide gene expression profiles and in vitro sensitivity to 160 chemotherapy drugs, a computational method to identify reliable gene expression markers for drug sensitivity by incorporating multi-omic prior information relevant to each gene’s potential to drive cancer. We show that our method outperforms several state-of-the-art approaches in identifying molecular markers replicated in validation data and predicting drug sensitivity accurately. Finally, we identify SMARCA4 as a marker and driver of sensitivity to topoisomerase II inhibitors, mitoxantrone, and etoposide, in AML by showing that cell lines transduced to have high  SMARCA4 expression reveal dramatically increased sensitivity to these agents. Identification of markers of drug response is essential for precision therapy. Here the authors introduce an algorithm that uses prior information about each gene’s importance in AML to identify the most predictive gene-drug associations from transcriptome and drug response data from 30 AML samples.

Type II topoisomerases (TOP2s) resolve the topological problems of DNA by transiently cleaving both strands of a DNA duplex to form a cleavage complex through which another DNA segment can be transported. Several widely prescribed anticancer drugs increase the population of TOP2 cleavage complex, which leads to TOP2-mediated chromosome DNA breakage and death of cancer cells. We present the crystal structure of a large fragment of human TOP2β complexed to DNA and to the anticancer drug etoposide to reveal structural details of drug-induced stabilization of a cleavage complex. The interplay between the protein, the DNA, and the drug explains the structure-activity relations of etoposide derivatives and the molecular basis of drug-resistant mutations. The analysis of protein-drug interactions provides information applicable for developing an isoform-specific TOP2-targeting strategy.

Zygophyllum coccineum, an edible halophytic plant, is part of the traditional medicine chest in the Mediterranean region for symptomatic relief of diabetes, hypertension, wound healing, burns, infections, and rheumatoid arthritis pain. The current study aimed to characterize Z. coccineum phytoconstituents, and the evaluations of the anti-microbial-biofilm, and anti-cancers bioactivities of the plant’s mother liquor, i.e., aqueous-ethanolic extract, and its subsequent fractions. The in silico receptors interaction feasibility of Z. coccineum major constituents with Staph GyraseB, and human topoisomerase-IIβ (h-TOP-IIβ) were conducted to confirm the plant’s anti-microbial and anti-cancer biological activities. Thirty-eight secondary metabolites of flavonoids, stilbene, phenolic acids, alkaloids, and coumarin classes identified by LC-ESI-TOF-MS spectrometric analysis, and tiliroside (kaempferol-3-O-(6′′′′-p-coumaroyl)-glucoside, 19.8%), zygophyloside-F (12.78%), zygophyloside-G (9.67%), and isorhamnetin-3-O-glucoside (4.75%) were identified as the major constituents. A superior biofilm obliteration activity established the minimum biofilm eradication concentration (MBEC) for the chloroform fraction at 3.9–15.63 µg/mL, as compared to the positive controls (15.63–31.25 µg/mL) against all the microbial strains that produced the biofilm under study, except the Aspergillus fumigatus. The aqueous-ethanolic extract showed cytotoxic effects with IC50 values at 3.47, 3.19, and 2.27 µg/mL against MCF-7, HCT-116, and HepG2 cell-lines, respectively, together with the inhibition of h-TOP-IIβ with IC50 value at 45.05 ng/mL in comparison to its standard referral inhibitor (staurosporine, IC50, 135.33 ng/mL). This conclusively established the anti-cancer activity of the aqueous-ethanolic extract that also validated by in silico receptor-binding predicted energy levels and receptor-site docking feasibility of the major constituents of the plant’s extract. The study helped to authenticate some of the traditional phytomedicinal properties of the anti-infectious nature of the plant.

This research presents the design and synthesis of a novel series of phthalazine derivatives as Topo II inhibitors, DNA intercalators, and cytotoxic agents. In vitro testing of the new compounds against HepG-2, MCF-7, and HCT-116 cell lines confirmed their potent cytotoxic activity with low IC 50 values. Topo II inhibition and DNA intercalating activities were evaluated for the most cytotoxic members. IC 50 values determination demonstrated Topo II inhibitory activities and DNA intercalating affinities of the tested compounds at a micromolar level. Amongst, compound 9d was the most potent member. It inhibited Topo II enzyme at IC 50 value of 7.02 ± 0.54 µM with DNA intercalating IC 50 of 26.19 ± 1.14 µM. Compound 9d was then subjected to an in vivo antitumor examination. It inhibited tumour proliferation reducing solid tumour volume and mass. Additionally, it restored liver enzymes, proteins, and CBC parameters near-normal, indicating a remarkable amelioration in their functions along with histopathological examinations.

Bacteria have evolved resistance to nearly all known antibacterials, emphasizing the need to identify antibiotics that operate via novel mechanisms. Here we report a class of allosteric inhibitors of DNA gyrase with antibacterial activity against fluoroquinolone-resistant clinical isolates of Escherichia coli . Screening of a small-molecule library revealed an initial isoquinoline sulfonamide hit, which was optimized via medicinal chemistry efforts to afford the more potent antibacterial LEI-800. Target identification studies, including whole-genome sequencing of in vitro selected mutants with resistance to isoquinoline sulfonamides, unanimously pointed to the DNA gyrase complex, an essential bacterial topoisomerase and an established antibacterial target. Using single-particle cryogenic electron microscopy, we determined the structure of the gyrase–LEI-800–DNA complex. The compound occupies an allosteric, hydrophobic pocket in the GyrA subunit and has a mode of action that is distinct from the clinically used fluoroquinolones or any other gyrase inhibitor reported to date. LEI-800 provides a chemotype suitable for development to counter the increasingly widespread bacterial resistance to fluoroquinolones. Global antibiotic scarcity looms owing to bacterial resistance. Now the discovery of a class of allosteric inhibitors targeting DNA gyrase—essential for bacteria—yields a compound LEI-800 that exhibits activity against fluoroquinolone-resistant E. coli . The compound’s unique mode of action, revealed through cryo-EM, makes it a promising candidate for countering bacterial resistance.