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DNA Topoisomerase II-mediated Interaction of Doxorubicin and Daunorubicin Congeners with DNA¹

Department of Biological Chemistry [A. B., L. F. L.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Departments of Pharmacology and Medicinal Chemistry, and Cancer Center [M. I., R. S., Y. K.], University of Tennessee-Memphis, Memphis, Tennessee 38163; Farmitalia Carlo Erba, Centro Ricerche [F. C. G.], Nerviano, Italy; and Departments of Radiology [S. K., M. P.] and Medicine [R. S.], New York University School of Medicine, New York, New York 10016

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.

¹ Supported in part by USPHS Grants CA-37082, CA-37209, CA-11655, and CA-39662 from the National Cancer Institute, NIH, Department of Health and Human Services; by Grant CH-348A from the American Cancer Society; and grants from Farmitalia Carlo Erba and the Marcia Slater Society for Research in Leukemia.

² To whom requests for reprints should be addressed, at Department of Radiology, Laboratory of Experimental Therapy, New York University School of Medicine, 550 First Avenue, New York, NY 10016.

Received 2/ 1/89. Revised 6/29/89. Accepted 8/ 3/89.

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