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Research ArticleArticle

Probing the Role of Linker Substituents in Bisdioxopiperazine Analogs for Activity against Wild-Type and Mutant Human Topoisomerase IIα

Axelle Renodon-Cornière, Tina K. Sørensen, Peter B. Jensen, John L. Nitiss, Birgitte Søkilde, Maxwell Sehested and Lars H. Jensen
Molecular Pharmacology May 2003, 63 (5) 1159-1168; DOI: https://doi.org/10.1124/mol.63.5.1159
Axelle Renodon-Cornière
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Tina K. Sørensen
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Peter B. Jensen
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John L. Nitiss
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Birgitte Søkilde
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Maxwell Sehested
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Lars H. Jensen
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Abstract

The bisdioxopiperazines are catalytic inhibitors of eukaryotic type II DNA topoisomerases capable of trapping these enzymes as a salt-stable closed-clamp complex on circular DNA. The various bisdioxopiperazine analogs differ from each other because of structural differences in the linker connecting the two dioxopiperazine rings. Although the composition of this linker region has been found to be important for potency, the structural basis for this is largely unknown. To elucidate the role of the linker region in drug action, we have analyzed the effect of different linker substituents in otherwise identical analogs by studying their interaction with wild-type and mutant human topoisomerase IIα. Two mutations, L169I and R162Q, displayed differential sensitivity toward closely related analogs, suggesting that the linker region in these compounds plays a highly specific role in protein drug interaction. The finding that the L169I mutation, which probably represents a subtle structural change, was sufficient to confer resistance further emphases the importance of this region of the protein for bisdioxopiperazine inhibition of topoisomerase II. Comparing the sensitivity profiles of different bisdioxopiperazines against wild-type and mutant proteins with that of mitindomide, we observed a spectrum of sensitivity closely resembling that of ICRF-154, a bisdioxopiperazine with no linker substituents. We discuss the implications of these observations for the understanding of the mechanism of bisdioxopiperazine action on topoisomerase II.

Footnotes

  • This work was supported by a European Community Marie Curie Fellowship (HPMF-CT-2000-00501) (to A.R.-C.); the Toyota Foundation, Danish Cancer Society, H:S Research Council (to T.K.S.); The Danielsen Foundation, The National Cancer Institute grant CA52814 (to J.L.N.) and core grant CA21765 (to J.L.N.), and The American Lebanese Syrian Associated Charities (to J.L.N.).

  • Abbreviations:
    ICRF-187
    (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane
    ICRF-154
    4,4′-(1,2-ethanediyl)-bis(2,6-piperazinedione)
    ICRF-193
    meso-4,4′-(2,3-butanediyl)-bis(2,6-piperazinedione)
    ICRF-202
    2,6-piperazinedione, 4,4′-(1-ethyl-2-methyl-1,2-ethanediyl)bis-,(R*,S*)-(.+ −.)-
    AMP-PNP
    adenylylimidodiphosphate
    BSA
    bovine serum albumin
    kDNA
    kinetoplast DNA
    SPR
    surface plasmon resonance
    • Received July 24, 2002.
    • Accepted February 6, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (5)
Molecular Pharmacology
Vol. 63, Issue 5
1 May 2003
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Research ArticleArticle

Probing the Role of Linker Substituents in Bisdioxopiperazine Analogs for Activity against Wild-Type and Mutant Human Topoisomerase IIα

Axelle Renodon-Cornière, Tina K. Sørensen, Peter B. Jensen, John L. Nitiss, Birgitte Søkilde, Maxwell Sehested and Lars H. Jensen
Molecular Pharmacology May 1, 2003, 63 (5) 1159-1168; DOI: https://doi.org/10.1124/mol.63.5.1159

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Research ArticleArticle

Probing the Role of Linker Substituents in Bisdioxopiperazine Analogs for Activity against Wild-Type and Mutant Human Topoisomerase IIα

Axelle Renodon-Cornière, Tina K. Sørensen, Peter B. Jensen, John L. Nitiss, Birgitte Søkilde, Maxwell Sehested and Lars H. Jensen
Molecular Pharmacology May 1, 2003, 63 (5) 1159-1168; DOI: https://doi.org/10.1124/mol.63.5.1159
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