DNA Topoisomerase II-mediated Interaction of Doxorubicin and Daunorubicin Congeners with DNA

Annette Bodley, Leroy F. Liu, Mervyn Israel, Ramakrishnan Seshadri, Yoshihiro Koseki, Fernando C. Giuliani, Stanley Kirschenbaum, Robert Silber, Milan Potmesil

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209 Citations (Scopus)

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′WV-acyl (Group 2), and 3′-JV-alkyl (Group 3) analogues were tested for: (a) in vivo antitumor activity and im vitro cytotoxicity; (b) cellular or tissue uptake and metabolic conversion; (c) strength of DNA intercalation; and 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-acyI 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′WV-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′-W 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 - Nov 1 1989

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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