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Laura Baranello Fedor Kouzine Damian Wojtowicz Kairong Cui Teresa M. Przytycka Keji Zhao David Levens 《International journal of molecular sciences》2014,15(7):13111-13122
Genomic DNA is under constant assault by endogenous and exogenous DNA damaging agents. DNA breakage can represent a major threat to genome integrity but can also be necessary for genome function. Here we present approaches to map DNA double-strand breaks (DSBs) and single-strand breaks (SSBs) at the genome-wide scale by two methods called DSB- and SSB-Seq, respectively. We tested these methods in human colon cancer cells and validated the results using the Topoisomerase II (Top2)-poisoning agent etoposide (ETO). Our results show that the combination of ETO treatment with break-mapping techniques is a powerful method to elaborate the pattern of Top2 enzymatic activity across the genome. 相似文献
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Flores LV Staples AM Mackay H Howard CM Uthe PB Sexton JS Buchmueller KL Wilson WD O'Hare C Kluza J Hochhauser D Hartley JA Lee M 《Chembiochem : a European journal of chemical biology》2006,7(11):1722-1729
The synthesis and DNA-binding properties of a novel naphthalimide-polyamide hairpin (3) designed to target the inverted CCAAT box 2 (ICB2) site on the topoisomerase IIalpha (topoIIalpha) promoter are described. The polyamide component of 3 was derived from the minor-groove binder, 2, and tailored to bind to the 5'-TTGGT sequence found in and flanking ICB2. The propensity of mitonafide 4 to intercalate between G-C base pairs was exploited by the incorporation of a naphthalimide moiety at the N terminus of 2. Hybrid 3 targeted 5'-CGATTGGT and covered eight contiguous base pairs, which included the underlined ICB2 site. DNase I footprinting analysis with the topoIIalpha promoter sequence demonstrated that 3 bound selectively to the ICB2 and ICB3 sites. Thermal-denaturation studies confirmed these results, and the highest degree of stabilization was found for ICB2 and -3 in preference to ICB1 (4.1, 4.6, and 0.6 degrees C, respectively). CD studies confirmed minor-groove binding and suggested a 1:1 binding stoichiometry. Emission-titration experiments established intercalative binding. Surface plasmon resonance results showed strong binding to ICB2 (2.5x10(7) M(-1)) with no observable binding to ICB1. Furthermore, the binding constant of 3 to ICB2 was larger than that of the parent polyamide 2. The increased binding affinity was primarily due to a reduction in the dissociation-rate constant of the polyamide-DNA complex, which can be attributed to the N-terminal naphthalimide moiety. In addition, the binding site of 3 was larger than that of 2, which innately improved sequence selectivity. We conclude that the polyamide-naphthalimide 3 selectively binds to the ICB2 site by simultaneous intercalation and minor-groove binding, and warrants further investigation as a model compound for the regulation of topoIIalpha gene expression. 相似文献
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Dr. Michael S. Christodoulou Dr. Franco Zunino Dr. Valentina Zuco Dr. Stella Borrelli Dr. Daniela Comi Dr. Gabriele Fontana Dr. Marisa Martinelli Prof. Dr. James B. Lorens Dr. Lasse Evensen Prof. Dr. Maurizio Sironi Dr. Stefano Pieraccini Prof. Dr. Lisa Dalla Via Prof. Dr. Ornella Maria Gia Prof. Dr. Daniele Passarella 《ChemMedChem》2012,7(12):2134-2143
The introduction of a methylenthiol group at position 7 of camptothecin was carried out in four steps. This preparation also yielded the corresponding disulfide, which behaves as a prodrug due to its reactivity with glutathione. Assessment of their antiproliferative activities, investigations of their mechanism of action, and molecular modeling analysis indicated that the 7‐modified camptothecin derivatives described herein maintain the biological activity and drug–target interactions of the parent compound. 相似文献
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Yu XM Ramiandrasoa F Guetzoyan L Pradines B Quintino E Gadelle D Forterre P Cresteil T Mahy JP Pethe S 《ChemMedChem》2012,7(4):587-605
New N‐alkylaminoacridine derivatives attached to nitrogen heterocycles were synthesized, and their antimalarial potency was examined. They were tested in vitro against the growth of Plasmodium falciparum, including chloroquine (CQ)‐susceptible and CQ‐resistant strains. This biological evaluation has shown that the presence of a heterocyclic ring significantly increases the activity against P. falciparum. The best compound shows a nanomolar IC50 value toward parasite proliferation on both CQ‐susceptible and CQ‐resistant strains. The antimalarial activity of these new acridine derivatives can be explained by the two mechanisms studied in this work. First, we showed the capacity of these compounds to inhibit heme biocrystallization, a detoxification process specific to the parasite and essential for its survival. Second, in our search for alternative targets, we evaluated the in vitro inhibitory activity of these compounds toward Sulfolobus shibatae topoisomerase VI‐mediated DNA relaxation. The preliminary results obtained reveal that all tested compounds are potent DNA intercalators, and significantly inhibit the activity of S. shibatae topoisomerase VI at concentrations ranging between 2.0 and 2.5 μM . 相似文献
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Benzo[b]tryptanthrin Inhibits MDR1, Topoisomerase Activity,and Reverses Adriamycin Resistance in Breast Cancer Cells
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Dr. Kyu‐Yeon Jun So‐Eun Park Jing Lu Liang Prof. Yurngdong Jahng Prof. Youngjoo Kwon 《ChemMedChem》2015,10(5):827-835
Tryptanthrin is an indoloquinazoline alkaloid isolated from indigo. Tryptanthrin and its benzo‐annulated derivative, benzo[b]tryptanthrin, inhibit both topoisomerases I (topo I) and II (topo II) and cause cytotoxicity in several human cancer cell lines. From diverse assessment methods, including cleavage complex stabilization, comet, DNA unwinding/intercalation, topo II ATPase inhibition, ATP competition for topo II, and wound‐healing assays, we determined that the mode of action of benzo[b]tryptanthrin is as a DNA non‐intercalative and ATP‐competitive topo I and II dual catalytic inhibitor. Benzo[b]tryptanthrin induced apoptosis through the cleavage of caspase‐3 and PARP in HCT15 colon cancer cells. Additionally, benzo[b]tryptanthrin reversed adriamycin resistance by down‐regulation of multidrug resistance protein 1 (MDR1) in adriamycin‐resistant MCF7 breast cancer cells (MCF7adr) with more potent inhibitory activity than tryptanthrin. Taken together, derivatization by benzo‐annulation of tryptanthrin ameliorated the MDR‐reversing effect of tryptanthrin and may pave the way to the discovery of a novel potent adjuvant agent for chemotherapy. 相似文献
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目的 研究小干扰RNA片段(shRNA)对三氧化二砷(ATO)耐药的白血病细胞株K562/AS2细胞的Topo Ⅱα、TopoⅡβ基因表达及其功能的影响.方法 设计并合成针对Topo Ⅱα和TopoⅡβ基因序列的shRNA各3对,在脂质体的介导下转染K562/AS2细胞;用荧光实时定量聚合酶链反应(PCR)分析Topo Ⅱα、TopoⅡβmRNA的表达水平;流式细胞术检测Topo Ⅱα、TopoⅡβ蛋白表达.结果 针对Topo Ⅱα-shRNA、TopoⅡβ的shRNA作用于K562/AS2细胞24 h后,Topo ⅡαmRNA水平和蛋白水平最大下调为(78.22±0.01)%、(31.17±1.27)%(P<0.05),TopoⅡβmRNA水平和蛋白水平最大下调为(57.36 ±0.01)%、(23.98 ± 1.22)%(P<0.05).结论 转染24 h后针对TopoⅡ的shRNA可抑制对ATO耐药的白血病细胞株K562/AS2细胞TopoⅡ基因的表达. 相似文献
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Anthracyclines are ranked among the most effective chemotherapeutics against cancer. They are glycoside drugs comprising the amino sugar daunosamine linked to a hydroxy anthraquinone aglycone, and act by DNA intercalation, oxidative stress generation and topoisomerase II poisoning. Regardless of their therapeutic value, multidrug resistance and severe cardiotoxicity are important limitations of anthracycline treatment that have prompted the discovery of novel analogues. This review covers the most clinically relevant anthracyclines and their development over decades, since the first discovered natural prototypes to recent semisynthetic and synthetic derivatives. These include registered drugs, drug candidates undergoing clinical trials, and compounds under pre-clinical investigation. The impact of the structural modifications on antitumour activity, toxicity and resistance profile is addressed. 相似文献
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Aleksandra Kowalczyk Agata Paneth Damian Trojanowski Piotr Paneth Jolanta Zakrzewska-Czerwiska Pawe Stczek 《International journal of molecular sciences》2021,22(8)
Compounds targeting bacterial topoisomerases are of interest for the development of antibacterial agents. Our previous studies culminated in the synthesis and characterization of small-molecular weight thiosemicarbazides as the initial prototypes of a novel class of gyrase and topoisomerase IV inhibitors. To expand these findings with further details on the mode of action of the most potent compounds, enzymatic studies combined with a molecular docking approach were carried out, the results of which are presented herein. The biochemical assay for 1-(indol-2-oyl)-4-(4-nitrophenyl) thiosemicarbazide (4) and 4-benzoyl-1-(indol-2-oyl) thiosemicarbazide (7), showing strong inhibitory activity against Staphylococcus aureus topoisomerase IV, confirmed that these compounds reduce the ability of the ParE subunit to hydrolyze ATP rather than act by stabilizing the cleavage complex. Compound 7 showed better antibacterial activity than compound 4 against clinical strains of S. aureus and representatives of the Mycobacterium genus. In vivo studies using time-lapse microfluidic microscopy, which allowed for the monitoring of fluorescently labelled replisomes, revealed that compound 7 caused an extension of the replication process duration in Mycobacterium smegmatis, as well as the growth arrest of bacterial cells. Despite some similarities to the mechanism of action of novobiocin, these compounds show additional, unique properties, and can thus be considered a novel group of inhibitors of the ATPase activity of bacterial type IIA topoisomerases. 相似文献
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