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

研究成果: 雜誌貢獻文章

203 引文 斯高帕斯(Scopus)

摘要

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.

原文英語
頁(從 - 到)5969-5978
頁數10
期刊Cancer Research
49
發行號21
出版狀態已發佈 - 1989
對外發佈Yes

    指紋

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

引用此

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