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

Research output: Contribution to journalArticlepeer-review

231 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
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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