DNA topoisomerase II-mediated interaction of doxorubicin and daunorubicin congeners with DNA

A. Bodley, Leroy-Fong Liu, M. Israel, R. Seshadri, Y. Koseki, F. C. Giuliani, S. Kirschenbaum, R. Silber, M. Potmesil

Research output: Contribution to journalArticle

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Abstract

Three groups of doxorubicin and daunorubicin analogues, differing by their substituents on the chromophore and sugar moieties, were used in this study. The 3'-N-unsubstituted (Group 1), 3'-N-acyl (Group 2), and 3'-N-alkyl (Group 3) analogues were tested for: (a) in vivo antitumor activity and in vitro cytotoxicity; (b) cellular or tissue uptake and metabolic conversion; (c) strength of DNA intercalation; and (d) interaction with DNA topoisomerase II (topo-II). Compounds of Group 1 were cytotoxic, were strongly intercalative, and, except for those with C-14 side chain substitution, induced the formation of topo-II-DNA cleavable complexes. As shown previously, esterolysis of C-14-acyl substituents was required to yield a metabolite which can interact with topo-II in the purified system. The C-14-substituted compounds of Group 2 and their C-14-unsubstituted metabolites were cytotoxic. These drugs were weak intercalators, and the C-14-unsubstituted congeners induced cleavable complex formation in the purified system, but with reduced potency relative to doxorubicin. The type of the 3'-N-position substituent determined whether Group 3 analogues were cytotoxic and strong intercalators, or less active and nonintercalating. Although C-14-unsubstituted intercalators of Group 3 did not form cleavable complexes in the purified system, they were cytotoxic. The study shows that DNA intercalation is required but not sufficient for the activity by topo-II-targeted anthracyclines. In addition to the planar chromophore which is involved in intercalation, two other domains of the anthracycline molecule are important for the interaction with topo-II: (a) substitution of the C-14 position totally inhibits drug activity in the purified system, but enhances cytotoxicity by aiding drug uptake and presumably acting on other cellular targets; and (b) substitutions on the 3'-N position of the sugar ring can, depending on the nature of the substituent, inhibit intercalation and/or topo-II-targeting activity. These findings may provide guidance for the synthesis and development of new active analogues.

Original languageEnglish
Pages (from-to)5969-5978
Number of pages10
JournalCancer Research
Volume49
Issue number21
Publication statusPublished - 1989
Externally publishedYes

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Type II DNA Topoisomerase
Daunorubicin
Doxorubicin
Intercalating Agents
DNA
Anthracyclines
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Bodley, A., Liu, L-F., Israel, M., Seshadri, R., Koseki, Y., Giuliani, F. C., ... Potmesil, M. (1989). DNA topoisomerase II-mediated interaction of doxorubicin and daunorubicin congeners with DNA. Cancer Research, 49(21), 5969-5978.

DNA topoisomerase II-mediated interaction of doxorubicin and daunorubicin congeners with DNA. / Bodley, A.; Liu, Leroy-Fong; Israel, M.; Seshadri, R.; Koseki, Y.; Giuliani, F. C.; Kirschenbaum, S.; Silber, R.; Potmesil, M.

In: Cancer Research, Vol. 49, No. 21, 1989, p. 5969-5978.

Research output: Contribution to journalArticle

Bodley, A, Liu, L-F, Israel, M, Seshadri, R, Koseki, Y, Giuliani, FC, Kirschenbaum, S, Silber, R & Potmesil, M 1989, 'DNA topoisomerase II-mediated interaction of doxorubicin and daunorubicin congeners with DNA', Cancer Research, vol. 49, no. 21, pp. 5969-5978.
Bodley A, Liu L-F, Israel M, Seshadri R, Koseki Y, Giuliani FC et al. DNA topoisomerase II-mediated interaction of doxorubicin and daunorubicin congeners with DNA. Cancer Research. 1989;49(21):5969-5978.
Bodley, A. ; Liu, Leroy-Fong ; Israel, M. ; Seshadri, R. ; Koseki, Y. ; Giuliani, F. C. ; Kirschenbaum, S. ; Silber, R. ; Potmesil, M. / DNA topoisomerase II-mediated interaction of doxorubicin and daunorubicin congeners with DNA. In: Cancer Research. 1989 ; Vol. 49, No. 21. pp. 5969-5978.
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abstract = "Three groups of doxorubicin and daunorubicin analogues, differing by their substituents on the chromophore and sugar moieties, were used in this study. The 3'-N-unsubstituted (Group 1), 3'-N-acyl (Group 2), and 3'-N-alkyl (Group 3) analogues were tested for: (a) in vivo antitumor activity and in vitro cytotoxicity; (b) cellular or tissue uptake and metabolic conversion; (c) strength of DNA intercalation; and (d) interaction with DNA topoisomerase II (topo-II). Compounds of Group 1 were cytotoxic, were strongly intercalative, and, except for those with C-14 side chain substitution, induced the formation of topo-II-DNA cleavable complexes. As shown previously, esterolysis of C-14-acyl substituents was required to yield a metabolite which can interact with topo-II in the purified system. The C-14-substituted compounds of Group 2 and their C-14-unsubstituted metabolites were cytotoxic. These drugs were weak intercalators, and the C-14-unsubstituted congeners induced cleavable complex formation in the purified system, but with reduced potency relative to doxorubicin. The type of the 3'-N-position substituent determined whether Group 3 analogues were cytotoxic and strong intercalators, or less active and nonintercalating. Although C-14-unsubstituted intercalators of Group 3 did not form cleavable complexes in the purified system, they were cytotoxic. The study shows that DNA intercalation is required but not sufficient for the activity by topo-II-targeted anthracyclines. In addition to the planar chromophore which is involved in intercalation, two other domains of the anthracycline molecule are important for the interaction with topo-II: (a) substitution of the C-14 position totally inhibits drug activity in the purified system, but enhances cytotoxicity by aiding drug uptake and presumably acting on other cellular targets; and (b) substitutions on the 3'-N position of the sugar ring can, depending on the nature of the substituent, inhibit intercalation and/or topo-II-targeting activity. These findings may provide guidance for the synthesis and development of new active analogues.",
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AU - Seshadri, R.

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AU - Giuliani, F. C.

AU - Kirschenbaum, S.

AU - Silber, R.

AU - Potmesil, M.

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N2 - Three groups of doxorubicin and daunorubicin analogues, differing by their substituents on the chromophore and sugar moieties, were used in this study. The 3'-N-unsubstituted (Group 1), 3'-N-acyl (Group 2), and 3'-N-alkyl (Group 3) analogues were tested for: (a) in vivo antitumor activity and in vitro cytotoxicity; (b) cellular or tissue uptake and metabolic conversion; (c) strength of DNA intercalation; and (d) interaction with DNA topoisomerase II (topo-II). Compounds of Group 1 were cytotoxic, were strongly intercalative, and, except for those with C-14 side chain substitution, induced the formation of topo-II-DNA cleavable complexes. As shown previously, esterolysis of C-14-acyl substituents was required to yield a metabolite which can interact with topo-II in the purified system. The C-14-substituted compounds of Group 2 and their C-14-unsubstituted metabolites were cytotoxic. These drugs were weak intercalators, and the C-14-unsubstituted congeners induced cleavable complex formation in the purified system, but with reduced potency relative to doxorubicin. The type of the 3'-N-position substituent determined whether Group 3 analogues were cytotoxic and strong intercalators, or less active and nonintercalating. Although C-14-unsubstituted intercalators of Group 3 did not form cleavable complexes in the purified system, they were cytotoxic. The study shows that DNA intercalation is required but not sufficient for the activity by topo-II-targeted anthracyclines. In addition to the planar chromophore which is involved in intercalation, two other domains of the anthracycline molecule are important for the interaction with topo-II: (a) substitution of the C-14 position totally inhibits drug activity in the purified system, but enhances cytotoxicity by aiding drug uptake and presumably acting on other cellular targets; and (b) substitutions on the 3'-N position of the sugar ring can, depending on the nature of the substituent, inhibit intercalation and/or topo-II-targeting activity. These findings may provide guidance for the synthesis and development of new active analogues.

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