Synthesis, biological evaluation, and molecular docking study of 3-(3′-heteroatom substituted-2′-hydroxy-1′-propyloxy) xanthone analogues as novel topoisomerase IIα catalytic inhibitor

Jun, Kyu Yeon; Lee, Eun Young; Jung, Mi Ja; Lee, Ok Hee; Lee, Eung Seok; Choo, Hea Young Park; Na, Younghwa; Kwon, Young Joo

doi:10.1016/j.ejmech.2011.01.011

Cited by 49 publications

(39 citation statements)

References 33 publications

(40 reference statements)

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“…We also measured the ATP hydrolysis activity of human topoisomerase IIα in the presence or absence of daurinol using the malachite green method to confirm that daurinol inhibits topoisomerase IIα by targeting its ATPase domain. Both daurinol and novobiocin (a topoisomerase II inhibitor that blocks ATP binding) (12,18) significantly inhibited the ATP hydrolysis activity of human topoisomerase IIα (Fig. 4).…”

Section: Daurinol Does Not Inhibit Human Topoisomerase I Catalytic Acmentioning

confidence: 99%

“…Briefly, the standard reaction mixture (20 µl) contained 50 mM Tris-HCl (pH 8.0), 150 mM NaCl, 10 mM MgCl 2 , 0.5 mM dithiothreitol, 30 µg/ml BSA, 200 ng of supercoiled DNA (pHOT-1), 2.0 µl of human topoisomerase IIα (TopoGEN, Inc.); and 100 µM daurinol or 400 µM novobiocin dissolved in DMSO. The final concentration of DMSO was 1%, and novobiocin was used as a positive control (12,13). The reaction was initiated by adding ATP at a final concentration of 2 mM (Sigma) and was incubated at 37˚C for 30 min.…”

Section: Measurement Of Human Topoisomerase I Catalytic Activitymentioning

confidence: 99%

“…The DNA-dependent ATP hydrolysis activity of human topoisomerase IIα was determined by quantifying hydrolyzed inorganic phosphate using the malachite green assay with slight modifications (10)(11)(12). Briefly, the standard reaction mixture (20 µl) contained 50 mM Tris-HCl (pH 8.0), 150 mM NaCl, 10 mM MgCl 2 , 0.5 mM dithiothreitol, 30 µg/ml BSA, 200 ng of supercoiled DNA (pHOT-1), 2.0 µl of human topoisomerase IIα (TopoGEN, Inc.); and 100 µM daurinol or 400 µM novobiocin dissolved in DMSO.…”

Section: Measurement Of Human Topoisomerase I Catalytic Activitymentioning

confidence: 99%

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Daurinol, a catalytic inhibitor of topoisomerase IIα, suppresses SNU-840 ovarian cancer cell proliferation through cell cycle arrest in S phase

Kang

Nho

Kim

et al. 2014

International Journal of Oncology

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Abstract. Daurinol, a lignan from the ethnopharmacological plant Haplophyllum dauricum, was recently reported to be a novel topoisomerase II inhibitor and an alternative to the clinical anticancer agent etoposide based on a colorectal cancer model. In the present study, we elucidated the detailed biochemical mechanism underlying the inhibition of human topoisomerase IIα by daurinol based on a molecular docking study and in vitro biochemical experiments. The computational simulation predicted that daurinol binds to the ATP-binding pocket of topoisomerase IIα. In a biochemical assay, daurinol (10-100 µM) inhibited the catalytic activity of topo isomerase IIα in an ATP concentration-dependent manner and suppressed the ATP hydrolysis activity of the enzyme. However, daurinol did not inhibit topoisomerase I activity, most likely because topoisomerase I does not contain an ATP-binding domain. We also evaluated the anti-proliferative activity of daurinol in ovarian, small cell lung and testicular cancer cells, common target cancers treated with etoposide. Daurinol potently inhibited SNU-840 human ovarian cancer cell proliferation through cell cycle arrest in S phase, while etoposide induced G2/M phase arrest. Daurinol induced the increased expression of cyclin E, cyclin A and E2F-1, which are important proteins regulating S phase initiation and progression. Daurinol did not induce abnormal cell and nuclear enlargement in SNU-840 cells, in contrast to etoposide. Based on these data, we suggest that daurinol is a potential anticancer drug candidate for the treatment of human ovarian cancer with few side effects. IntroductionTopoisomerases are essential enzymes in all organisms that are involved in the topological homeostasis of DNA molecules during DNA replication, transcription and chromosomal segregation. Topoisomerases are classified into two classes, topoisomerase I and II, which create single and double-strand breaks, respectively. Because topoisomerases are crucial enzymes in DNA replication, they have served as primary targets for the development of anticancer agents (1,2). Topoisomerase II inhibitors such as etoposide, teniposide and doxorubicin have been extensively used in clinical cancer treatment. However, these agents also have undesirable side effects, including immunosuppression, myelosuppression, gastrointestinal toxicity and the development of secondary leukemia (3). Thus, the discovery of new topoisomerase inhibitors with fewer side effects from natural products has received a great deal of attention (4,5).Daurinol is a natural arylnaphthalene lignan isolated from the traditional medicinal plant Haplophyllum dauricum (6). According to an ethnopharmacological study, this plant has been used to treat tumors in Russia (7). The chemical structure of daurinol is similar to that of the clinical anticancer agent VP-16 (also known as etoposide phosphate). Recently, we suggested that daurinol could be a promising antitumor agent with minimal side effects, compared to etoposide, based on in vitro and in vivo resu...

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Section: Daurinol Does Not Inhibit Human Topoisomerase I Catalytic Acmentioning

confidence: 99%

Section: Measurement Of Human Topoisomerase I Catalytic Activitymentioning

confidence: 99%

Section: Measurement Of Human Topoisomerase I Catalytic Activitymentioning

confidence: 99%

See 1 more Smart Citation

Daurinol, a catalytic inhibitor of topoisomerase IIα, suppresses SNU-840 ovarian cancer cell proliferation through cell cycle arrest in S phase

Kang

Nho

Kim

et al. 2014

International Journal of Oncology

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“…As an alternative, the use of catalytic inhibitors of Top2 could also prevent DNA cleavage and reduce drug-induced chromosomal rearrangements. Recent studies reported the synthesis of new derivatives such as the purine analog quinoline aminopurine compound 1 (Chène et al, 2009), thiosemicarbazones (Huang et al, 2010), N-fused imidazoles (Baviskar et al, 2011), or xanthone analogs (Jun et al, 2011), which inhibit the catalytic activity of Top2␣ by an ATPcompetitive mechanism. Apart from quinoline aminopurine compound 1, which inhibits both isoforms (Chène et al, 2009), it is not known whether these derivatives also inhibit the catalytic activity of Top2␤, which is expressed in postmitotic cells (Watanabe et al, 1994;Lyu and Wang, 2003) and nonproliferating tissues such as the adult heart (Capranico et al, 1992).…”

Section: Top2α Top2βmentioning

confidence: 99%

The Polyphenolic Ellagitannin Vescalagin Acts As a Preferential Catalytic Inhibitor of the α Isoform of Human DNA Topoisomerase II

Auzanneau¹,

Montaudon²,

Jacquet³

et al. 2012

Mol Pharmacol

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Polyphenolic ellagitannins are natural compounds that are often associated with the therapeutic activity of plant extracts used in traditional medicine. They display cancer-preventing activity in animal models by a mechanism that remains unclear. Potential targets have been proposed, including DNA topoisomerases II (Top2). Top2␣ and Top2␤, the two isoforms of the human Top2, play a crucial role in the regulation of replication, transcription, and chromosome segregation. They are the target of anticancer agents used in the clinic such as anthracyclines (e.g., doxorubicin) or the epipodophyllotoxin etoposide. It was recently shown that the antitumor activity of etoposide was due primarily to the inhibition of Top2␣, whereas inhibition of Top2␤ was responsible for the development of secondary malignancies, pointing to the need for more selective Top2␣ inhibitors. Here, we show that the polyphenolic ellagitannin vescalagin preferentially inhibits the decatenation activity of Top2␣ in vitro, by a redox-independent mechanism. In CEM cells, we also show that transient small interfering RNA-mediated downregulation of Top2␣ but not of Top2␤ conferred a resistance to vescalagin, indicating that the ␣ isoform is a preferential target. We further confirmed that Top2␣ inhibition was due to a catalytic inhibition of the enzyme because it did not induce DNA double-strand breaks in CEM-treated cells but prevented the formation of Top2␣-rather than Top2␤-DNA covalent complexes induced by etoposide. To our knowledge, vescalagin is the first example of a catalytic inhibitor for which cytotoxicity is due, at least in part, to the preferential inhibition of Top2␣.

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“…Xanthonescan also binds and shows anticancer activity by forming a stable binding complex with N-terminal ATP-binding domain of topo IIα (Jun et al, 2011) like novobiocin (Larsen et al, 2003), cyclothialidine (Boehm et al, 2000) and salvicine (Hu et al, 2006). Xanthone fights competitively with ATP to binds with the ATP binding site on topo IIα and directly hampers the energy driven rapid kinetics which lead to a higher topo IIα catalytic inhibitory activity.…”

Section: Introductionmentioning

confidence: 99%

Design and docking of novel series of hybrid xanthones as anti-cancer agent to target human DNA topoisomerase 2-alpha

Nainwal

Parida

Das

et al. 2014

Bangladesh J Pharmacol

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Topoisomerase (topo) IIα is a homodimeric protein catalyzes topological vicissitudes by adding or by soothing super coiling transpiration, occurs in human DNA during DNA replication as an outcome chromosome segregation and condensation occurs during meiosis I and recombination. To prevent the cleavage and religation activity we administered novel hybrid substituted Xanthone series of drugs. The toxicity prediction showed outstanding results which impetus to study its anticancer activities by targeting topoisomerase (topo) IIα. We developed the homology model of the topoisomerase (topo) IIα due to the unavailability of 3D structure in the Protein Data Bank. Structural assessment of the modeled protein and confirmed the quality of the model. The ligands were docked using Autodock4.2 software and binding energy was reported. The compound XM9, XN2, XM7, XLNU and XNS scored lowest binding energy and highest binding affinity. The interaction sites and the hydrogen bond were observed.

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Synthesis, biological evaluation, and molecular docking study of 3-(3′-heteroatom substituted-2′-hydroxy-1′-propyloxy) xanthone analogues as novel topoisomerase IIα catalytic inhibitor

Cited by 49 publications

References 33 publications

Daurinol, a catalytic inhibitor of topoisomerase IIα, suppresses SNU-840 ovarian cancer cell proliferation through cell cycle arrest in S phase

Daurinol, a catalytic inhibitor of topoisomerase IIα, suppresses SNU-840 ovarian cancer cell proliferation through cell cycle arrest in S phase

The Polyphenolic Ellagitannin Vescalagin Acts As a Preferential Catalytic Inhibitor of the α Isoform of Human DNA Topoisomerase II

Design and docking of novel series of hybrid xanthones as anti-cancer agent to target human DNA topoisomerase 2-alpha

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