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Inhibition of DNA Topoisomerase Type II? (TOP2A) by Mitoxantrone and Its Halogenated Derivatives: A Combined Density Functional and Molecular Docking Study.

ABSTRACT: In this study, mitoxantrone and its halogenated derivatives have been designed by density functional theory (DFT) to explore their structural and thermodynamical properties. The performance of these drugs was also evaluated to inhibit DNA topoisomerase type II? (TOP2A) by molecular docking calculation. Noncovalent interactions play significant role in improving the performance of halogenated drugs. The combined quantum and molecular mechanics calculations revealed that CF3 containing drug shows better preference in inhibiting the TOP2A compared to other modified drugs.

SUBMITTER: Abu Saleh M

PROVIDER: S-EPMC4754470 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Inhibition of DNA Topoisomerase Type IIα (TOP2A) by Mitoxantrone and Its Halogenated Derivatives: A Combined Density Functional and Molecular Docking Study.

Abu Saleh Md M Solayman Md M Hoque Mohammad Mazharol MM Khan Mohammad A K MA Sarwar Mohammed G MG Halim Mohammad A MA

BioMed research international 20160215

In this study, mitoxantrone and its halogenated derivatives have been designed by density functional theory (DFT) to explore their structural and thermodynamical properties. The performance of these drugs was also evaluated to inhibit DNA topoisomerase type IIα (TOP2A) by molecular docking calculation. Noncovalent interactions play significant role in improving the performance of halogenated drugs. The combined quantum and molecular mechanics calculations revealed that CF3 containing drug shows ...[more]

PMID: 27088089

Similar Datasets

Maternal topoisomerase II alpha, not topoisomerase II beta, enables embryonic development of zebrafish top2a-/- mutants.

Project description:BackgroundGenetic alterations in human topoisomerase II alpha (TOP2A) are linked to cancer susceptibility. TOP2A decatenates chromosomes and thus is necessary for multiple aspects of cell division including DNA replication, chromosome condensation and segregation. Topoisomerase II alpha is also required for embryonic development in mammals, as mouse Top2a knockouts result in embryonic lethality as early as the 4-8 cell stage. The purpose of this study was to determine whether the extended developmental capability of zebrafish top2a mutants arises from maternal expression of top2a or compensation from its top2b paralogue.ResultsHere, we describe bloody minded (blm), a novel mutant of zebrafish top2a. In contrast to mouse Top2a nulls, zebrafish top2a mutants survive to larval stages (4-5 day post fertilization). Developmental analyses demonstrate abundant expression of maternal top2a but not top2b. Inhibition or poisoning of maternal topoisomerase II delays embryonic development by extending the cell cycle M-phase. Zygotic top2a and top2b are co-expressed in the zebrafish CNS, but endogenous or ectopic top2b RNA appear unable to prevent the blm phenotype.ConclusionsWe conclude that maternal top2a enables zebrafish development before the mid-zygotic transition (MZT) and that zebrafish top2a and top2b are not functionally redundant during development after activation of the zygotic genome.

| S-EPMC3287258 | biostudies-literature

Inhibition of human DNA topoisomerase II? by two novel ellipticine derivatives.

Project description:Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) is an antineoplastic agent that intercalates into DNA and alters topoisomerase II activity. Unfortunately, this compound displays a number of adverse properties. Therefore, to investigate new ellipticine-based compounds for their potential as topoisomerase II-targeted drugs, we synthesized two novel derivatives, N-methyl-5-demethyl ellipticine (ET-1) and 2-methyl-N-methyl-5-demethyl ellipticinium iodide (ET-2). As determined by DNA decatenation and cleavage assays, ET-1 and ET-2 act as catalytic inhibitors of human topoisomerase II? and are both more potent than the parent compound. Neither compound impairs the ability of the type II enzyme to bind its DNA substrate. Finally, the potency of ET-1 and ET-2 as catalytic inhibitors of topoisomerase II? appears to be related to their ability to intercalate into the double helix.

| S-EPMC4785065 | biostudies-literature

QSAR and docking studies on xanthone derivatives for anticancer activity targeting DNA topoisomerase II?.

Project description:Due to the high mortality rate in India, the identification of novel molecules is important in the development of novel and potent anticancer drugs. Xanthones are natural constituents of plants in the families Bonnetiaceae and Clusiaceae, and comprise oxygenated heterocycles with a variety of biological activities along with an anticancer effect. To explore the anticancer compounds from xanthone derivatives, a quantitative structure activity relationship (QSAR) model was developed by the multiple linear regression method. The structure-activity relationship represented by the QSAR model yielded a high activity-descriptors relationship accuracy (84%) referred by regression coefficient (r(2)=0.84) and a high activity prediction accuracy (82%). Five molecular descriptors - dielectric energy, group count (hydroxyl), LogP (the logarithm of the partition coefficient between n-octanol and water), shape index basic (order 3), and the solvent-accessible surface area - were significantly correlated with anticancer activity. Using this QSAR model, a set of virtually designed xanthone derivatives was screened out. A molecular docking study was also carried out to predict the molecular interaction between proposed compounds and deoxyribonucleic acid (DNA) topoisomerase II?. The pharmacokinetics parameters, such as absorption, distribution, metabolism, excretion, and toxicity, were also calculated, and later an appraisal of synthetic accessibility of organic compounds was carried out. The strategy used in this study may provide understanding in designing novel DNA topoisomerase II? inhibitors, as well as for other cancer targets.

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Molecular docking analysis of α-Topoisomerase II with δ-Carboline derivatives as potential anticancer agents.

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| S-EPMC8340707 | biostudies-literature

Density Functional Theory, Chemical Reactivity, Pharmacological Potential and Molecular Docking of Dihydrothiouracil-Indenopyridopyrimidines with Human-DNA Topoisomerase II.

Project description:In this work, three computational methods (Hatree-Fock (HF), Møller-Plesset 2 (MP2), and Density Functional Theory (DFT)) using a variety of basis sets are used to determine the atomic and molecular properties of dihydrothiouracil-based indenopyridopyrimidine (TUDHIPP) derivatives. Reactivity descriptors of this system, including chemical potential (µ), chemical hardness (?), electrophilicity (?), condensed Fukui function and dual descriptors are calculated at B3LYP/6-311++ G (d,p) to identify reactivity changes of these molecules in both gas and aqueous phases. We determined the molecular electrostatic surface potential (MESP) to determine the most active site in these molecules. Molecular docking study of TUDHIPP with topoisomerase II ? and ? is performed, predicting binding sites and binding energies with amino acids of both proteins. Docking studies of TUDHIPP versus etoposide suggest their potential as antitumor candidates. We have applied Lipinski, Veber's rules and analysis of the Golden triangle and structure activity/property relationship for a series of TUDHIPP derivatives indicate that the proposed compounds exhibit good oral bioavailability. The comparison of the drug likeness descriptors of TUDHIPP with those of etoposide, which is known to be an antitumor drug, indicates that TUDHIPP can be considered as an antitumor drug. The overall study indicates that TUDHIPP has comparable and even better descriptors than etoposide proposing that it can be as effective antitumor drug, especially 2H, 6H and 7H compounds.

| S-EPMC7072893 | biostudies-literature

Design and synthesis of DNA-intercalative naphthalimide-benzothiazole/cinnamide derivatives: cytotoxicity evaluation and topoisomerase-II? inhibition.

Project description:A new series of different naphthalimide-benzothiazole/cinnamide derivatives were designed, synthesized and tested for their in vitro cytotoxicity on selected human cancer cell lines. Among them, derivatives 4a and 4b with the 6-aminobenzothiazole ring and 5g with the cinnamide ring displayed potent cytotoxic activity against colon (IC50: 3.715 and 3.467 ?M) and lung cancer (IC50: 4.074 and 3.890 ?M) cell lines when compared to amonafide (IC50: 5.459 and 7.762 ?M). Later, the DNA binding studies for these selected derivatives (by CD, UV/vis, fluorescence spectroscopy, DNA viscosity, and molecular docking) suggested that these new derivatives significantly intercalate between two strands of DNA. In addition, the most potent derivatives 4a and 4b were also found to inhibit DNA topoisomerase-II.

| S-EPMC6350626 | biostudies-literature

Halogenated imidazole derivatives block RNA polymerase II elongation along mitogen inducible genes.

Project description:BackgroundAberrant activation of protein kinases is one of the essential oncogenic driving forces inherent to the process of tumorigenesis. The protein kinase CK2 plays an important role in diverse biological processes, including cell growth and proliferation as well as in the governing and transduction of prosurvival signals. Increased expression of CK2 is a hallmark of some cancers, hence its antiapoptotic properties may be relevant to cancer onset. Thus, the designing and synthesis of the CK2 inhibitors has become an important pursuit in the search for cancer therapies.ResultsUsing a high-throughput microarray approach, we demonstrate that two potent inhibitors of CK2, 4,5,6,7-tetrabromo-benzimidazole (TBBz) and 2-Dimethyloamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), blocked mitogen induced mRNA expression of immediate early genes. Given the impact of these inhibitors on the process of transcription, we investigated their effects on RNA Polymerase II (RNAPII) elongation along the mitogen inducible gene, EGR1 (early growth response 1), using chromatin immunoprecipitation (ChIP) assay. ChIP analysis demonstrated that both drugs arrest RNAPII elongation. Finally, we show that CDK9 kinase activity, essential for the triggering of RNAPII elongation, was blocked by TBBz and to lesser degree by DMAT.ConclusionsOur approach revealed that small molecules derived from halogenated imidazole compounds may decrease cell proliferation, in part, by inhibiting pathways that regulate transcription elongation.

| S-EPMC2824761 | biostudies-literature

Expression of the Topoisomerase II Alpha (TOP2A) Gene in Lung Adenocarcinoma Cells and the Association with Patient Outcomes.

Project description:BACKGROUND This study was carried out to analyze TOP2A expression in lung adenocarcinoma (LUAD) and to assess its value in clinical diagnosis and prognosis. MATERIAL AND METHODS The Cancer Genome Atlas (TCGA) database was used to study the relationship of TOP2A expression with the progression and prognosis of LUAD. For a further elucidation of the value of TOP2A in LUAD, the effect of TOP2A knockout on cell viability and related protein expression of LUAD cell line A549 in vitro was investigated by using RNA interference, MTT, flow cytometry, RT-PCR, and western blot analysis. RESULTS According to the results of database analysis, TOP2A expression in LUAD was higher than that in normal lung tissues. There was a strong correlation of TOP2A expression with clinicopathological and epidemiological parameters of LUAD. The survival rate of LUAD patients with high TOP2A expression was lower than that of patients with low expression (P<0.001). The expression of TOP2A in A549 cells was higher than that in Beas-2B cells. After decreased expression of TOP2A in A549 cells, the proliferation of A549 cells was downregulated and the apoptosis rate was increased. It was further verified that TOP2A low expression exerts a role in LUAD through activation of the ERK/JNK/p-P38/CHOP signaling pathway. CONCLUSIONS The findings from this study showed that TOP2A expression was upregulated in a human lung adenocarcinoma cell line, and this finding was supported by bioinformatics analysis. Further studies are required to determine whether TOP2A expression is a prognostic biomarker and potential therapeutic target in patients with lung adenocarcinoma.

| S-EPMC7774312 | biostudies-literature

Topoisomerase II inhibition involves characteristic chromosomal expression patterns.

Project description:BACKGROUND: The phenomenon of co-localization of transcriptionally upregulated genes showing similar expression levels is known across all eukaryotic genomes. We recently mapped the Aroclor 1254-regulated transcriptome back onto the genome and provided evidence for the statistically significant co-localization of regulated genes. They did, however, not always show similar expression levels, and many of the regulated genes were, in fact, repressed. RESULTS: In this study, we were able to reproduce this observation with microarray data stemming from 1) human hepatocytes treated with the gyrase and potential topoisomerase II inhibitor trovafloxacin, 2) human hepatocytes treated with the topoisomerase II inhibitor doxorubicin and 3) mouse lymphoma cells treated with the topoisomerase II inhibitor etoposide. We found statistically significant co-localization of regulated gene pairs--induced and repressed--within the window size of 0-100 kbp. Notably, by using microarray data stemming from lung tissue of a mouse transgenic line overexpressing the transcription factor c-myc, which served as a negative control, we found regulated genes to be located with regard to each other nearly in the same way as genes distributed randomly all over the genome (0-100 kbp). CONCLUSION: We suggest topoisomerase II inhibition by Aroclor 1254, trovafloxacin, doxorubicin, and etoposide to be responsible for significant co-localization of regulated genes through the inability of the stabilized enzyme complexes to religate DNA. Within the permanently opened chromatin domains, neighbored genes might be allowed to be regulated. Overexpression of c-myc, however, does not inhibit topoisomerase II activity. Consequently, the enzyme is able to perform its normal function of transiently breaking and rejoining the DNA double strand. As a result, exclusively target genes are regulated.

| S-EPMC2488358 | biostudies-literature

Halogenated Flavonoid Derivatives Display Antiangiogenic Activity.

Project description:Antiangiogenic agents attenuate tumours' growth and metastases and are therefore beneficial as an adjuvant or standalone cancer regimen. Drugs with dual antiproliferative and antiangiogenic activities can achieve anticancer efficacy and overcome acquired resistance. In this study, synthetic flavones (5a,b) with reported anticancer activity, and derivatives (4b and 6a), exhibited significant inhibition of endothelial cell tube formation (40-55%, 12 h) at 1 µM, which is comparable to sunitinib (50% inhibition at 1 µM, 48 h). Flavones (4b, 5a,b and 6a) also showed 25-37% reduction in HUVECs migration at 10 µM. In a Western blotting assay, 5a and 5b subdued VEGFR2 phosphorylation by 37% and 57%, respectively, suggesting that VEGFR2 may be their main antiangiogenic target. 5b displayed the best docking fit with VEGFR2 in an in silico study, followed by 5a, emphasizing the importance of the 7-hydroxyl group accompanied by a 4-C=S for activity. Conversely, derivatives with a 4-carbonyl moiety fitted poorly into the target's binding pocket, suggesting that their antiangiogenic activity depends on a different target. This study provides valuable insight into the Structure Activity Relationships (SAR) and modes of action of halogenated flavones with VEGFR2 and highlights their therapeutic potential as antiangiogenic/anticancer lead compounds.

| S-EPMC9331694 | biostudies-literature

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