title: DNA topoisomerase II-mediated interaction of doxorubicin and daunorubicin congeners with DNA.
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 cogeners 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.
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: A
authors.initials: A
authors.lastname: Bodley
authors.forename: L F
authors.initials: LF
authors.lastname: Liu
authors.forename: M
authors.initials: M
authors.lastname: Israel
authors.forename: R
authors.initials: R
authors.lastname: Seshadri
authors.forename: Y
authors.initials: Y
authors.lastname: Koseki
authors.forename: F C
authors.initials: FC
authors.lastname: Giuliani
authors.forename: S
authors.initials: S
authors.lastname: Kirschenbaum
authors.forename: R
authors.initials: R
authors.lastname: Silber
authors.forename: M
authors.initials: M
authors.lastname: Potmesil
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism*; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy*; D007942:Leukemia, Experimental; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects*; D014410:Tumor Stem Cell Assay
chemical_list: D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II; D003630:Daunorubicin