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

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DNA Topoisomerase II-Mediated Interaction of Doxorubicin and Daunorubicin Congeners with DNA1 (CANCER RESEARCH 49, 5969-5978, November 1, 1989] DNA Topoisomerase II-mediated Interaction of Doxorubicin and Daunorubicin Congeners with DNA1 Annette Bodley, Leroy F. Liu, Mervyn Israel, Ramakrishnan Seshadri, Yoshihiro Koseki, Fernando C. Giuliani, Stanley Kirschenbaum, Robert Silber, and Milan Potmesil2 Department of Biological Chemistry [A. B., L. F. L.J, The Johns Hopkins University School of Medicine, Baltimore, Maiyland 21205; Departments of Pharmacology and Medicinal Chemistry, and Cancer Center [M. I., R. S., Y. K.j, University of Tennessee-Memphis, Memphis, Tennessee 38163; Farmitalia Carlo Erba, Centro Ricerche [F. C. G.], Ñerviano, Italy; and Departments of Radiology fS. K., M. P.] and Medicine [R. SJ, New York University School of Medicine, New York, New York 10016 ABSTRACT This interaction appears to play a substantial role in the cyto toxicity exerted by anthracyclines. The precise nature of the Three groups of doxorubicin and daunorubicin analogues, differing by process, however, remains obscure. their substituents on the chromophore and sugar moieties, were used in this study. The 3'-A'-unsubstituted (Group I), 3'-/V-acyl (Group 2), and It has been proposed that the formation of a ternary complex drug-topoisomerase II-DNA could be a prerequisite for the .V-,V-alkyl (Group 3) analogues were tested for: (a) in vivo antitumor stabilization of DNA cleavable complexes (7). It is unclear activity and in vitro cytotoxicity; (b) cellular or tissue uptake and meta whether the intercalative mode of drug-DNA binding or just an bolic conversion; (c) strength of DNA intercalation; and (</)interaction with DNA topoisomerase II (topo-II). Compounds of Group 1 were increased concentration of drug molecules around topoisomer cytotoxic, were strongly intercalative, and, except for those with C-14 ase II-DNA adducts is essential for this step. Our previous side chain substitution, induced the formation of topo-II-DNA cleavable studies (7) have shown that DXR3 analogues with undetectable complexes. As shown previously, esterolysis of C-14-acyl substituents or low DNA binding stabilize the cleavable complex between was required to yield a metabolite which can interact with topo-II in the the enzyme and DNA; these results thus favor the former purified system. The C-14-substituted compounds of Group 2 and their possibility. Understandably, even weak DNA binding, not de C-14-unsubstituted metabolites were cytotoxic. These drugs were weak tectable with the methods applied previously, could be impor intercalators, and the C-14-unsubstituted congeners induced cleavable tant for the formation of drug-topoisomerase II-DNA ternary complex formation in the purified system, but with reduced potency relative to doxorubicin. The type of the 3'-^Y-position substituent deter complexes. mined whether Group 3 analogues were cytotoxic and strong intercala In the present study, we have analyzed three groups of DXR tors, or less active and nonintercalating. Although C-14-unsubstituted and daunorubicin analogues, which differ by the substitution intercalators of Group 3 did not form cleavable complexes in the purified pattern on the chromophore as well as on the sugar moiety. system, they were cytotoxic. The drugs show a range of intercalative strengths from strong The study shows that DNA intercalation is required but not sufficient to undetectable. The study has identified some of the structural for the activity by topo-II-targeted anthracyclines. In addition to the properties of the analogues which are connected with DNA planar chromophore which is involved in intercalation, two other domains intercalation and/or topoisomerase II inhibition. It also shows of the anthracycline molecule are important for the interaction with topo- that several biologically active intercalating agents apparently II: (a) substitution of the ( -14 position totally inhibits drug activity in do not interact with this enzyme. the purified system, but enhances cytotoxicity by aiding drug uptake and presumably acting on other cellular targets; and (b) substitutions on the 3'-.-V position of the sugar ring can, depending on the nature of the MATERIALS AND METHODS substituent, inhibit intercalation and/or topo-II-targeting activity. These findings may provide guidance for the synthesis and development of new Drugs and Drug Treatments. Table 1 lists the 24 DXR or daunorub active analogues. icin analogues included in this study. Of the .V-A'-unsubstituted anthra cyclines, all except ADI21 and AD268 were prepared in the laboratories of Farmitalia Carlo Erba as previously described (8-12). AD268 and INTRODUCTION S'-A'-acyl- or 3'-jV-alkylanthracyclines were synthesized as reported earlier (13-17). The preparation of ADI 20 and ADI 21 will be described Mammalian DNA topoisomerase II, a nuclear enzyme that elsewhere. All products were purified to homogeneity, the purity was alters the topologica! state of DNA and is essential for cell tested by thin-layer and high-performance liquid chromatography, and replication and viability (reviewed in Refs. 1-3), appears to be each compound was fully characterized by microchemical analysis as the principal target for several groups of anticancer agents (3- well as by the IR, UV, and nuclear magnetic resonance spectral prop 6). A covalent complex between topoisomerase II and DNA is erties. an obligatory intermediate in the catalysis of DNA topoisomer- 3The abbreviations used are: DXR. doxorubicin (Adriamycin); AD32. N- ization. Stabilization of this complex by natural products of trifluoroacetyladriamycin-14-valerate; AD38. A'-acetyladriamycin: AD41. A'-tri- microbial or plant origin and their analogues presents an initial fluoroacetyladriamycin: AD92, A'-trifluoroadriamycinol; ADI 15. A'-pentafluo- ropropionyladriamycin; AD 120. iV-trifluoroacetyl-14-mcthoxydaunorubicin: event which leads to cell death. The stabilization of the complex AD121, 14-methoxydaunorubicin; AD133, A'-acetyladriamycin-14-valerate; can interfere with vital functions involving DNA replication. AD143, A'-trifluoroacetyladriamycin-l4-0-hemiadipatc; AD194, /V-(n-bu- tyl)adriamycin-14-\alerate; ADI98. iV-benzyladriamycin-14-valerate; AD199, Received 2/1/89; revised 6/29/89; accepted 8/3/89. /V.jV-dimethyladriamycin-14-valerate: AD202. A',A'-di(n-butyl)adriamycin-14-val- The costs of publication of this article were defrayed in part by the payment erate: AD206, A;tiV-dibenzyladriamycin-14-valerate; AD268, adriamycin-14- of page charges. This article must therefore be hereby marked advertisement in thiovalerate: AD280. A'.A'-dimethyladriamycin: AD284. A'-(n-butyl)adriamycin: AD285. A',A'-di(fl-butyl)adriamycin: AD288. A'-benzyladriamycin; AD289, N,N- accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1Supported in part by USPHS Grants CA-37082, CA-37209, CA-11655, and dibenzyladriamycin; CE. cloning efficiency; DMSO, dimethyl sulfoxide: CA-39662 from the National Cancer Institute, NIH, Department of Health and 4'deoDXR. 4'-deoxydoxorubicin: 4'd4'IDXR. 4'-deoxy-4'-iododoxorubicin: 4- Human Services; by Grant CH-348A from the American Cancer Society; and dmxDNR. 4-demethoxydaunorubicin; DTT. dithiothreitol: 4'epiDXR. 4'-epi- grants from Farmitalia Carlo Erba and the Marcia Slater Society for Research in doxorubicin: HPLC, high-performance liquid chromatography; ¡.a.,intraarteri- Leukemia. ally. ID50. median inhibition dose; ILS, increase in life span; IR, infrared; LDgo. 2To whom requests for reprints should be addressed, at Department of lethal dose at the 90°Vcellkill level: PAB. protein-associated DNA single-strand Radiology, Laboratory of Experimental Therapy, New York University School breaks; SDS. sodium dodecyl sulfate: 14-thia DXR, 14-thiadoxorubicin; UV, of Medicine, 550 First Avenue, New York, NY 10016. ultraviolet. 5969 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1989 American Association for Cancer Research. ANTHRACYCLINES AND TOPOISOMERASE II-DNA INTERACTION For in vitro study, the compounds were dissolved in saline (0.16 M macological studies on Day 7 after the tumor transfer. NaCl), DMSO, or Diluent 12 (polyethoxylated castor oil:ethanol; Phar Tissue Culture Lines. P388 cells were obtained from inoculated DBA/ maceutical Resources Branch, Division of Cancer Treatment, National 2 mice and maintained for two passages of transfer in 25-cm3 plastic Cancer Institute) diluted with saline (1:5). Saline or Diluent 12 was tissue culture flasks (Corning Glass Works, Corning, NY) in RPMI also used for the formulation of drugs for in vivo application. 1964 medium (Grand Island Biological Co., Grand Island, NY), sup Murine Tumors. P388 lymphocytic leukemia cells were maintained plemented with 10% heat-inactivated fetal calf serum (Flow Laborato by serial i.p. passage in DBA/2 mice. For experimental purposes, IO6 ries, Inc., Rockville, MD), 20 ¿tM2-mercaptoethanol (Sigma Chemical cells were injected i.p. into each male BALB/c x DBA/2 F! (hereafter Co., St. Louis, MO), and antibiotics (100 Mg/ml of streptomycin and called CD2F,) or C57BL/6 x DBA/2 F, (hereafter called B6D2F,) kanamycin, and 100 lU/ml of penicillin). The cultures were grown at mouse. The assay procedures were similar with the standard National 37°Cina humidified atmosphere of 95% air:5% CO2 (20-22). Cancer Institute protocols (18). Drug treatments began on Day 1 after Exponentially growing P388 or CCRF-CEM cells (human lympho- leukemia inoculation and, in some experiments, continued for 4 con blastic leukemia line) were grown in multiwell tissue culture plates
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