Antitumor Agents, 130. Novel 4β-Arylamino Derivatives of 3',4'-Didemethoxy-3',4'-dioxo-4-deoxypodophyllotoxin as Potent Inhibitors of Human DNA Topoisomerase II

Zhang, Yi Lin; Shen, Ya Ching; Wang, Zhe Qing; Chen, Hong Xing; Guo, Xin; Cheng, Yung Chi; Lee, Kuo Hsiung̀

doi:10.1021/np50086a011

Cited by 28 publications

(10 citation statements)

References 15 publications

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“…CPT is known to stabilize topoisomerase I resulting in formation of dsDNA breaks during the S phase (Tsao et al, 1993). Etoposide stabilizes topoisomerase II (Zhang et al, 1992). The other chemical genotoxins cause speci®c types of DNA damages.…”

Section: Complementary Involvement Of Wrn and Blm In Dna Repairmentioning

confidence: 99%

Werner and Bloom helicases are involved in DNA repair in a complementary fashion

et al. 2002

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Werner syndrome (WS) is a recessive disorder characterized by premature senescence. Bloom syndrome (BS) is a recessive disorder characterized by short stature and immunode®ciency. A common characteristic of both syndromes is genomic instability leading to tumorigenesis. WRN and BLM genes causing WS and BS, encode proteins that are closely related to the RecQ helicase. We produced WRN 7/7, BLM 7/7 and WRNmutants in the chicken B-cell line DT40. WRN 7/7 cells showed hypersensitivities to genotoxic agents, such as 4-nitroquinoline 1-oxide, camptothecin and methyl methanesulfonate. They also showed a threefold increase in targeted integration rate of exogenous DNAs, but not in sister chromatid exchange (SCE) frequency. BLM 7/7 cells showed hypersensitivities to the genotoxic agents as well as ultraviolet (UV) light, in addition to a 10-fold increase in targeted integration rate and an 11-fold increase in SCE frequency. In WRN 7/7 /BLM 7/7 cells, synergistically increased hypersensitivities to the genotoxic agents were observed whereas both SCE frequencies and targeted integration rates were partially diminished compared to the single mutants. Chromosomal aberrations were also synergistically increased in WRN 7/7 / BLM 7/7 cells when irradiated with UV light in late S to G 2 phases. These results suggest that both WRN and BLM may be involved in DNA repair in a complementary fashion.

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Section: Complementary Involvement Of Wrn and Blm In Dna Repairmentioning

confidence: 99%

Werner and Bloom helicases are involved in DNA repair in a complementary fashion

et al. 2002

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“…Figure 3 shows the inhibition of the DNA relaxation activity of TOPO II with the potency order etoposide <EQ<CLQ. EQ and other orthoquinone derivatives of etoposide have shown greater inhibition of this enzyme than etoposide [11].…”

Section: Density Functional (Dft) Calculationsmentioning

confidence: 95%

“…EQ has been proposed to bind covalently both DNA and proteins [10]. In fact, several orthoquinone derivatives of EQ were found to be better TOPO II inhibitors than etoposide [11]. Thiol-reactive quinones and other thiol-reactive compounds such as N-ethylmaleimide (NEM), disulphiram and organic sulphides were shown to induce TOPO II-mediated DNA cleavage which suggests the possibility that cellular DNA damage could occur indirectly through thiolation of TOPO II [12,13].…”

Section: Introductionmentioning

confidence: 99%

Thiols oxidation and covalent binding of BSA by cyclolignanic quinones are enhanced by the magnesium cation

Alegrı́a

Sanchez-Cruz

Kumar

et al. 2008

Free Radical Research

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A novel cyclolignanic quinone, 7-acetyl-3′,4′-didemethoxy-3′,4′-dioxopodophyllotoxin (CLQ), inhibits topoisomerase II (TOPO II) activity. The extent of this inhibition was greater than that produced by the etoposide quinone (EQ) or etoposide. Glutathione (GSH) reduces EQ and CLQ to their corresponding semiquinones under anaerobic conditions. The latter were detected by EPR spectroscopy in the presence of MgCl 2 but not in its absence. Semiquinone EPR spectra change with quinone/GSH mol ratio, suggesting covalent binding of GSH to the quinones. Quinone-GSH covalent adducts were isolated and identified by ESI-MS. These orthoquinones also react with nucleophilic groups from BSA to bind covalently under anaerobic conditions. BSA thiol consumption and covalent binding by these quinones are enhanced by MgCl 2 . Complex formation between the parent quinones and Mg +2 was also observed. Density functional calculations predict the observed blueshifts in the absorption spectra peaks and large decreases in the partial negative charge of electrophilic carbons at the quinone ring when the quinones are complexed to Mg +2 . These observations suggest a possible role of Mg +2 chelation by these quinones in increasing TOPO II thiol and/or amino/imino reactivity with these orthoquinones.

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“…Estes compostos agem inibindo a religação do DNA e induzem a ligação de proteínas em suas quebras, e constituemse como parte integrante em quimioterapia de primeira linha para uma grande variedade de tumores sólidos e hematológicos (Sampaio et al, 2006). O etoposídeo, derivado semi-sintético da lignana podofi lotoxina, apresenta papel importante no tratamento clínico como potente agente quimioterapêutico para uma variedade de tumores, incluindo carcinomas, câncer testicular e linfomas (Zhang et al, 1992). Na tentativa de descobrir novos inibidores da topoisomerase, diversas classes de produtos naturais têm sido testadas e descritas na literatura nos últimos anos.…”

Section: Introductionunclassified

Rubrofusarina, um policetídeo natural inibidor da topoisomerase II-α humana

Branco¹,

Pinto²,

Braz‐Filho³

et al. 2008

Rev. bras. farmacogn.

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RESUMO:Este trabalho descreve o efeito inibitório de rubrofusarina (5,6-diidroxi-8-metoxi-2-metilbenzo[g]cromen-4-ona, 1) sobre a enzima DNA topoisomerase II-humana. Rubrofusarina mostrou total inibição da enzima topisomerase II-na concentração de 120 M. Este resultado é semelhante ao observado com etoposida, utilizada como controle positivo. Para a realização deste teste, rubrofusarina foi isolada de Senna macranthera var. nervosa (Voguel) Irwin & Barnebyem e caracterizada por métodos espectroscópicos, incluindo RMN 2D, do produto natural bem como de seu derivado monoacetilado.Unitermos: Rubrofusasina, topoisomerase, Senna macranthera, Fabaceae.ABSTRACT: "Rubrofusarin, a natural polyketide as new human topoisomerase IIinhibitor". This work describes the inhibitory effect of rubrofusarin (5,6-dihydroxy-8-methoxy-2-methylbenzo[g]cromen-4-one, 1) against human DNA topoisomerase II-. The results for relaxation assays showed total inhibition of topisomerase II-by rubrofusarin at 120 M. This result is comparable to the one observed with etoposide as positive control. For this study, rubrofusarin was isolated from Senna macranthera var. nervosa (Voguel) Irwin & Barnebyem and characterized by spectral data, including 2D NMR, as well as its acetylated derivative.Keywords: Rubrofusarin, topoisomerase, Senna macranthera, Fabaceae. INTRODUÇÃOAs topoisomerases são enzimas nucleares que controlam e modifi cam o estado topológico do DNA. Estas enzimas nucleares são classifi cadas em tipo I e II, de acordo com seus mecanismos e propriedades físicas, em células de mamíferos. A topoisomerase II (Topo II), dímero de tamanho aproximado de 170 kDa e existente nas isoformas ou , é responsável pela quebra da fi ta dupla de DNA levando a eventos como liberação da fi ta de DNA enovelada, transcrição, condensação dos cromossomos e recombinação (Sampaio et al., 2006;Hande, 2006). As topoisomerases, durante a proliferação celular, participam da manutenção e replicação do DNA. Quando estas funções são desativadas, as células fi cam vulneráveis. Além disso, em tecidos tumorais a expressão das DNA-Topo I e II é maior do que nas células de metabolismo normal (Kellner et al., 2000). Assim, as topoisomerases são alvos importantes no desenvolvimento de novas drogas, principalmente para as que apresentam atividade anticâncer e antiviral (De Vita Jr et al., 1997).Na medicina destacam-se os compostos das classes das antraciclinas e das epipodofi lotoxinas como potentes inibidores da topoisomerase II. Estes compostos agem inibindo a religação do DNA e induzem a ligação de proteínas em suas quebras, e constituemse como parte integrante em quimioterapia de primeira linha para uma grande variedade de tumores sólidos e hematológicos (Sampaio et al., 2006). O etoposídeo, derivado semi-sintético da lignana podofi lotoxina, apresenta papel importante no tratamento clínico como potente agente quimioterapêutico para uma variedade de tumores, incluindo carcinomas, câncer testicular e linfomas (Zhang et al., 1992). Na tentativa de descobrir novos inibidores da...

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Antitumor Agents, 130. Novel 4β-Arylamino Derivatives of 3',4'-Didemethoxy-3',4'-dioxo-4-deoxypodophyllotoxin as Potent Inhibitors of Human DNA Topoisomerase II

Cited by 28 publications

References 15 publications

Werner and Bloom helicases are involved in DNA repair in a complementary fashion

Werner and Bloom helicases are involved in DNA repair in a complementary fashion

Thiols oxidation and covalent binding of BSA by cyclolignanic quinones are enhanced by the magnesium cation

Rubrofusarina, um policetídeo natural inibidor da topoisomerase II-α humana

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