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

@article{Antony2006BisindenoisoquinolineBB,
  title={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},
  author={Smitha Antony and Keli Agama and Zehong Miao and Melinda G. Hollingshead and Susan L. Holbeck and Mollie H. Wright and Lyuba Varticovski and Muthukaman Nagarajan and Andrew Ian Morrell and Mark Cushman and Yves Pommier},
  journal={Molecular Pharmacology},
  year={2006},
  volume={70},
  pages={1109 - 1120}
}
Indenoisoquinolines are topoisomerase (Top) I inhibitors developed to overcome some of the limitations of camptothecins and expand their anticancer spectrum. Bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}-propane bis(trifluoroacetate) (NSC 727357) is a novel dimeric indenoisoquinoline derivative with potent antiproliferative activity in the NCI-60 cell line panel, promising hollow fiber activity (score of 32) and activity against xenografts. Submicromolar… Expand
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TLDR
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References

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In an attempt to design and synthesize potential anticancer agents acting by inhibition of topoisomerase I (top1), a new series of indenoisoquinolines was prepared and tested for cytotoxicity inExpand
Synthesis of cytotoxic indenoisoquinoline topoisomerase I poisons.
TLDR
The potencies of the indenoisoquinolines as top1 inhibitors did not correlate with their potencies as cytotoxicity agents, as some of the most cytotoxic agents had little if any effect on top1. Expand
Cellular Topoisomerase I Inhibition and Antiproliferative Activity by MJ-III-65 (NSC 706744), an Indenoisoquinoline Topoisomerase I Poison
TLDR
One of the idenoisoquinoline derivatives, MJ-III-65 (NSC 706744), is identified with both similarities and differences from CPT, which exhibits antitumor activity in mouse tumor xenografts and limited cross-resistance was observed in camptothecin-resistant cell lines. Expand
Synthesis and biological evaluation of bisindenoisoquinolines as topoisomerase I inhibitors.
TLDR
The biological results for substituted compounds revealed a disagreement between the structure-activity relationships of monomeric indenoisoquinolines and bisindenoisOquinoline as Top1 inhibitors, but cytotoxicity was maintained for both series of compounds. Expand
Synthesis and mechanism of action studies of a series of norindenoisoquinoline topoisomerase I poisons reveal an inhibitor with a flipped orientation in the ternary DNA-enzyme-inhibitor complex as determined by X-ray crystallographic analysis.
TLDR
The X-ray crystal structure of norindenoisoquinoline 14 in complex with topoisomerase I and DNA has been solved, providing insight into the structure-activity relationships within this class of new anticancer agents. Expand
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TLDR
The results suggest mechanisms whereby intercalating agents interfere with the normal function of human top1, and propose a model with the +1 base rotated out of the duplex, and in which the intercalated adduct prevents religation of the corresponding nucleotide at the 5' end of the cleaved DNA. Expand
Synthesis and anticancer activity of simplified indenoisoquinoline topoisomerase I inhibitors lacking substituents on the aromatic rings.
TLDR
There were also variations in the DNA cleavage pattern seen with camptothecin vs the indenoisoquinolines, which indicates that these two classes of topoisomerase I inhibitors are likely to target the cancer cell genome differently, resulting in different spectra of anticancer activity. Expand
Design, synthesis, and biological evaluation of indenoisoquinoline topoisomerase I inhibitors featuring polyamine side chains on the lactam nitrogen.
TLDR
One of the monoamine analogues, which features a bis(2-hydroxyethyl)amino group in the side chain, proved to be one of the most cytotoxic indenoisoquinoline synthesized to date, with a GI50 mean-graph midpoint of 0.07 microM in the NIH human cancer cell culture screen, and topoisomerase I inhibitory activity comparable to that of camptothecin. Expand
Position-specific trapping of topoisomerase II by benzo[a]pyrene diol epoxide adducts: Implications for interactions with intercalating anticancer agents
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  • Chemistry, Medicine
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TLDR
These results identify specific binding sites for intercalators that result in trapping of Top2, a potential mechanism for poisoned DNA cleavage by bulky polycyclic aromatic hydrocarbon DE adducts. Expand
Differential induction of topoisomerase I-DNA cleavage complexes by the indenoisoquinoline MJ-III-65 (NSC 706744) and camptothecin: base sequence analysis and activity against camptothecin-resistant topoisomerases I.
TLDR
This study shows the specific molecular interactions of MJ-III-65 with top1 and demonstrates that MJ- III-65 is a potentially useful top1 inhibitor that enhances and traps top1 cleavage sites not sensitive to CPTs. Expand
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