Bisindenoisoquinoline Bis-1,3-{(5,6-dihydro-5,11-diketo-11<i>H</i>-indeno[1,2-<i>c</i>]isoquinoline)-6-propylamino}propane bis(trifluoroacetate) (NSC 727357), a DNA Intercalator and Topoisomerase Inhibitor with Antitumor Activity

Antony, Smitha; Agama, Keli; Hollingshead, Melinda G.; Holbeck, Susan L.; Wright, Mollie H.; Varticovski, Lyuba; Nagarajan, Muthukaman; Morrell, Andrew; Cushman, Mary; Pommier, ﻿Yves

doi:10.1124/mol.106.024372

Cited by 36 publications

(40 citation statements)

References 42 publications

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“…Consistent with previously published results (37), CPT-induced cell killing is p53 dependent (see ref. 26 for details). Loss of cell viability measured by cytotoxicity assay at 24 h of exposure to CPT showed an IC 50 of f5 nmol/L for cells with wildtype p53 (TK6), whereas an IC 50 of f300 nmol/L was observed for p53-null NH32 cells (data published in ref.…”

Section: -Fold Inmentioning

confidence: 99%

“…Loss of cell viability measured by cytotoxicity assay at 24 h of exposure to CPT showed an IC 50 of f5 nmol/L for cells with wildtype p53 (TK6), whereas an IC 50 of f300 nmol/L was observed for p53-null NH32 cells (data published in ref. 26). Similar to CPT, dependence on p53 was observed for both NSC 725776 and NSC 724998 (see Fig.…”

Section: -Fold Inmentioning

confidence: 99%

“…Cell cycle analyses of HT29 cells treated with 0.01, 0.05, 0.1, or 0.5 Amol/L of NSC 725776 or NSC 724998 were done with a FACScan flow cytometer (Becton Dickinson; refs. 13,26). Cell cycle distributions were calculated using ModFit LT software (Verity Software House, Inc.).…”

Section: Drugsmentioning

confidence: 99%

“…For reversal, after 1 h of drug treatment, the cells were cultured in drug-free medium for the appropriate time. DPCs were analyzed under nondeproteinizing, DNA-denaturing conditions using protein-adsorbing filters and the DPC frequencies were calculated as described previously (13,26).…”

Section: Drugsmentioning

confidence: 99%

“…As the indenoisoquinolines advance among the first candidates for phase 0 clinical trials (23), g-H2AX can be used as a clinical marker for monitoring the efficacy of NSC 725776 and NSC 724998. (18,26).…”

Section: Introductionmentioning

confidence: 99%

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Novel Indenoisoquinolines NSC 725776 and NSC 724998 Produce Persistent Topoisomerase I Cleavage Complexes and Overcome Multidrug Resistance

et al. 2007

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Camptothecin (CPT) derivatives are effective anticancer drugs, especially against solid tumors. As CPTs are chemically unstable and have clinical limitations, we have synthesized indenoisoquinolines as novel topoisomerase I (Top1) inhibitors. We presently report two indenoisoquinoline derivatives, NSC 725776 and NSC 724998, which have been selected for therapeutic development. Both are potent Top1 inhibitors and induce Top1 cleavage at unique genomic positions compared with CPT. Consistent with Top1 poisoning, protein-linked DNA breaks were detected in cells treated with NSC 725776 and NSC 724998 at nanomolar concentrations. Those druginduced protein-linked DNA breaks persisted longer after drug removal than those produced by CPT. Studies in human cells in culture show that NSC 725776 and NSC 724998 exert antiproliferative activity at submicromolar concentrations. Furthermore, NSC 725776 and NSC 724998 show crossresistance in cells deficient or silenced for Top1, which is consistent with their selective Top1 targeting. Similar to other known Top1 inhibitors, NSC 725776-treated and NSC 724998-treated cells show an arrest of cell cycle progression in both S and G 2 -M and a dependence on functional p53 for their cytotoxicity. Dose-dependent ;-H2AX foci formation was readily observed in cells treated with NSC 725776 and NSC 724998. These ;-H2AX foci were detectable at pharmacologically relevant doses for up to 24 h and thus could be used as biomarkers for clinical trials (phase 0). [Cancer Res 2007; 67(21):10397-405]

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Section: -Fold Inmentioning

confidence: 99%

Section: -Fold Inmentioning

confidence: 99%

Section: Drugsmentioning

confidence: 99%

Section: Drugsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel Indenoisoquinolines NSC 725776 and NSC 724998 Produce Persistent Topoisomerase I Cleavage Complexes and Overcome Multidrug Resistance

et al. 2007

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Cobalt‐Catalyzed Dual Annulation of o‐Halobenzaldimine with Alkyne: A Powerful Route toward Bioactive Indenoisoquinolinones

Liu

Hsieh

Korivi

et al. 2015

Chemistry A European J

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A cobalt-catalyzed dual annulation reaction for the synthesis of variously substituted indenoisoquinolinones from 2-bromobenzaldehydes, amines, and methyl 2-(ethynyl)benzoates has been developed. This method could also be applied to the synthesis of an array of highly functionalized bioactive indenoisoquinolinones and their derivatives. A possible mechanism of the cobalt catalysis is proposed, involving imine formation from bromobenzaldehyde and the amine, followed by a series of oxidative addition, alkyne insertion, cyclization reactions, and carbon-carbon double-bond migration. The regioselective alkyne insertion plays an important role for the success of the second annulation.

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Topoisomerases: Resistance versus Sensitivity, How Far We Can Go?

Bansal

Bajaj

Pandey

et al. 2016

Medicinal Research Reviews

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DNA topoisomerases are ubiquitously present remarkable molecular machines that help in altering topology of DNA in living cells. The crucial role played by these nucleases during DNA replication, transcription, and recombination vis-à-vis less sequence similarity among different species makes topoisomerases unique and attractive targets for different anticancer and antibacterial drugs. However, druggability of topoisomerases by the existing class of molecules is increasingly becoming questationable due to resistance development predominated by mutations in the corresponding genes. The current scenario facing a decline in the development of new molecules further comprises an important factor that may challenge topoisomerase-targeting therapy. Thus, it is imperative to wisely use the existing inhibitors lest with this rapid rate of losing grip over the target we may not go too far. Furthermore, it is important not only to design new molecules but also to develop new approaches that may avoid obstacles in therapies due to multiple resistance mechanisms. This review provides a succinct account of different classes of topoisomerase inhibitors, focuses on resistance acquired by mutations in topoisomerases, and discusses the various approaches to increase the efficacy of topoisomerase inhibitors. In a later section, we also suggest the possibility of using bisbenzimidazoles along with efflux pump inhibitors for synergistic bactericidal effects.

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Bisindenoisoquinoline Bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}propane bis(trifluoroacetate) (NSC 727357), a DNA Intercalator and Topoisomerase Inhibitor with Antitumor Activity

Cited by 36 publications

References 42 publications

Novel Indenoisoquinolines NSC 725776 and NSC 724998 Produce Persistent Topoisomerase I Cleavage Complexes and Overcome Multidrug Resistance

Novel Indenoisoquinolines NSC 725776 and NSC 724998 Produce Persistent Topoisomerase I Cleavage Complexes and Overcome Multidrug Resistance

Cobalt‐Catalyzed Dual Annulation of o‐Halobenzaldimine with Alkyne: A Powerful Route toward Bioactive Indenoisoquinolinones

Topoisomerases: Resistance versus Sensitivity, How Far We Can Go?

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