Abstract
Fourty eight derivatives of 2-(1-oxyalkyl)-1,4-dioxy-9,10-anthraquinone were synthesized, and their antitumor activity was evaluated. On the whole, 2-(1-hydroxyalkyl)-1,4-dihydroxy-9,10-anthraquinones (DHAQ=1,4-dihydroxy-9,10-anthraquinone) showed stronger cytotoxic activity againnst L1210 cells than 2-(1-hydroxyalkyl)-1,4-dimethoxy.-9,10-anthraquinones(DMAQ=1,4-dimethoxy-9,10-anthraquinone), implying that free hydroxy groups at C-1 and C-4 of the anthraquinone structure are necessary for the cytotoxic activity. The bioactivity of 2-(1-hydroxyalkyl)-DHAQ derivatives differed according to the size of alkyl group at C-1, while the elongation of alkyl group over 7 carbon atoms failed to enhance, the bioactivity, the derivatives possessing alkyl moiety of 1–6 carbon atoms showed an increase in the cytotoxicity and the antitumor activity in Sarcoma-180; 2-hydroxymethyl-DHAQ (ED50, 15 μg/ml; T/C, 125%), 2-(1-hydroxyethyl)-DHAQ(1.9 μg/ml; 139.2%), 2-(1-hydroxypropyl)-DHAQ (7.2 μg/ml; 135.1%), 2-(1-hydroxybutyl)-DHAQ (10.2 μg/ml; 125.3%), 2-(1-hydroxypentyl)-DHAQ (23.7 μg/ml; 110.1%) and 2-(1-hydroxyhexyl)-DHAQ (58 μg/ml; 108%). Next, 2-(1-Hydroxyalkyl)-DHAQ derivatives were acetylated to produce 2-(1-acetoxyalkyl)-DHAQ analogues. Although the acetylation somewhat enhanced the cytotoxicity, but not the antitumor action. In addition, the presence of phenyl group at C-1' enhanced the cytotoxicity and the T/C value, compared to alkyl groups of same size; 2-(1-hydroxy-1-phenyl)-DHAQ (ED50, 5.6 μg/ml; T/C., 137%).
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References Cited
Abramson, H. N., Banning, J. W., Nachtman, J. P., Roginski, E. T., Sardessai, M., Wormser, H. C., Wu, J., Nagia, Z., Schroeder, R. R., Bernardo, M. M., Synthesis of Anthraquinoyl Glucosaminosides and Studies on the Influence of Aglycone Hydroxyl Substitution on Superoxide Generation, DNA Binding, and Antimicrobial Propertiee.J. Med. Chem, 29(9), 1709–1714 (1986).
Andreani, A., Rambaldi, M., Bonazzi, D., Lelli, G., Greci, L., Potential antitumor agents, XIV., 8-Disubstituted anthraquinones.Arch. Pharm., 318, 842–848 (1985).
Baek, K. U., Song, G. Y., Kim, Y., Sok, D. E., and Ahn, B. Z., 2-(1-oxyalkyl)-1,4-dioxynaphthoquinone derivatives: Synthesis and evaluation of their antitumor activity.Arch. d. Pharmazie (Weinheim) 1997, in press.
Blanz, J., Mewes, K., Ehninger, G., Proksch, B., Waidelich, D., Greger, B., Zeller, K. P., Evidence for oxidative activation of mitoxantrone in human.Durg. Metab. Dispos., 19, 871–880 (1991).
Bodley, A., Liu, L. F., Israel, M., Seshadri, R., Koseki, Y., Giuliani, F. C., Kschenbaum, S., Silber, R., Potmesil, M., DNA topoisomerase II-mediated interaction of doxorubicin and daunorubicin congeners with DNA.Cancer. Res., 49, 5969–5978 (1989).
Brunmark, A. and Cadenas, E., Redox ans inhibition chemistry of quinoid compounds and its biological implications.Free Red. Biol. Med., 7, 435–477 (1988).
Charcosset, J. Y., Soues, S., Laval, F., Poisons of DNA topoisomerases I and II.Bull. Cancer (Paris), 80(11), 923–954 (1993).
Chen, K. X., Gresh, N., Pullman, B., A theoretical investigation on the sequence selective binding of mitoxantrone to double-stranded tetranucleotides.Nucleic. Acids. Res., 14, 3799–3812 (1986).
Crespi, M. D., Ivanier, S. E., Genovese, J., Baldi, A., Mitoxantrone affects topoisomerase activities in human breast cancer cells.Biochem. Biophys. Res. Commun., 136, 521–528 (1986).
Dodd, N. J., Mukherjee, T., Free radical formation from anthracycline antitumour agents and model systems-I. Model naphthoquinones and anthraquinones.Biochem. Pharmacol., 33, 379–385 (1984).
Ehninger, G., Schuler, U., Proksch, B., Zeller, K. P., Blanz, J., Pharmacokinetics and metabolism of mitoxantrone. A review.Clin. Pharmacokinet., 18, 365–380 (1990).
Finley, K. T., The addition and substitution chemistry of quinones. InThe chemistry of the Quinoid Compounds (Parai, s. ed.), Part II, pp. 878–1144, 1974, John wiley, London.
Fisher, G. R., Brown, J. R., Patterson, L. H., Involvement of hydroxyl radical formation and DNA strand breakage in the cytotoxicity of anthraquinone antitumour agents.Free. Radic. Res. Commun., 11, 117–125 (1990).
Fisher, G. R., Gutierrez, P. L., Oldcorne, M. A., Patterson, L. H., NAD(P)H(quinoneacceptor) oxidoreductase(DT-diaphorese)-mediated two electron reduction of anthraquinone-based antitumour agents and generation of hydroxyl radicals.Biochem. Pharmacol., 43, 575–585 (1992).
Frederick, C. A., Williams, L. D., Ughetto, G., Van Der Marel, G. A., Van Boom, J. H., Wang, A. H., Structural comparison of anticancer drug-DNA complexes: adriamycin and daunomycin.Biochemistry., 29, 2538–2549 (1990).
Gant, T. W., and Cohen, G. M., Reaction of glutathione or amino acids with quinones forming semiquinone radicals. InFree Radicals, Oxidants stress and Drug Action (C. Rice-Evans, ed.), pp. 377–397 (1987).
Gaudiano, G. and Koch, T. H., Redox cjemistry of anthracycline antitumor drugs and use of captodative radicals as tools for its elucidation and control.Chem. Res. Toxicol., 4, 2–16 (1991).
Isabella, P. D., Capranico, G., Palumbo, M., Sissi, C., Krapcho, A. R., Zunino, F., Sequence selectivity of topoisomerase II DNA cleavage stimulated by mitoxantrone derivatives: relationships to drug DNA binding anf cellular effects.Mol. Pharmacol., 43, 715–721 (1993).
Islam, S. A., Neidle, S., Gandecha, B. M., Partridge, M., Patterson, L. H., Brown, J. R., Comparative Computer Graphics and Solution Studies of the DNA Interaction of Substituted Anthraquinones Based on Doxorubicin and Mitoxantrone.J. Med. Chem., 28, 857–864 (1985).
Itokawa, H., Ibraheim, Z. Z., Qiao, Y. F., Anthraquinones, naphthohydroquinones and naphtho hydroquinone dimers from Rubia cordifolia and their cytotoxic activity.Chem. Pharm. Bull., 41, 1869–1872 (1993).
Jeziorek, D., Dyl, D., A theoretical study of the mechanism of oxygen binding by model anthraquinone. I: Quantum mechanical evaluation the oxygen-binding sites of 1, 4-hydroquinone.Anticancer. Drug. Des., 8, 223–235 (1993).
Kapuscinski, J., Darzynkiewicz, Z., Interactions of atitumor agents Ametantrone and Mitoxantrone with double-stranded DNA.Biochem. Pharmacol. 34(24), 4203–4213 (1985).
Kong, X. B., Rubin, L., Chen, L. I., Ciszewska, G., Watanabe, K. A., Tong, W. P., Sirotnak, F. M., and Chou, T. C., Topoisomerase II-mediated DNA cleavage activity and irreversibility of cleavable complex formation induced by DNA intercalation with alkylating capability.Mol. Pharmacol., 41, 237–244 (1992).
Koyama, M., Takahashi, K., Chou, T. C., Darzynkiewicz, Z., Kapuscinski, J., Rosskelly, T., and Watanabe, K. A., Intercalating Agents with Covalent Bond Forming Capability. A Novel Type of Potential Anticancer Agents. Dirivatives of Chrysophanol and Emodin.J. Med. Chem., 32, 1594–1599 (1989).
Krapcho, A. P., Getahun, Z., Avery, Jr K. L., Vargas, K. J., and Hacker, M. P., Spinelli, S., Pezzoni, G., Manzotti, C., Synthesis and antitumor evaluations of symmetrically and unsymmetrically substituted 1, 4-bis[(aminoalky)amino]anthracene-9, 10-diones and 1,4-bis[(aminoalky)amino]-5,8-dihydroxyan thracene-9, 10-diones.J. Med. Chem., 34, 2373–2380 (1991).
Kuzuya, M., Noguchi, A., Kaeai, K., Quantum chemical study for genotoxic and antitumor activities of hydroxyanthraquinonesRegul. Toxicol. Pharmacol., 13, 185–194 (1991).
Lin, A. J., Cosby, L. A., Shansky, C. W. and Sartorelli, A. C., Potential bioreductive alkylating agents. I. Benzoquinone derivatives.J. Med. Chem., 15, 1247–1252 (1972).
Lin, T. S., Teicher, B. A. and Sartorelli, A. C., 2-Methylanthraquinone Derivatives as Potential Bioreductive alkylating Agents.J. Med. Chem., 23, 1237–1242 (1980).
Mewes, K., Blanz, J., Ehninger, G., Gebhardt, R., Zeller, K. P., Cytochrome P-450-induced cytotoxicity of mitoxantrone by formation of electrophilic intermediate.Cancer. Research., 53, 5135–5142 (1993).
Monks, T. J., Hanzlik, R. P., Cohen, G. M., Ross, D., and Graham, D. G., Contemporary Issuse in Toxicology. Quinone Chemistry and Toxicity.Toxicol. Appl. Pharmacol., 112, 2–16 (1992).
Morier-Teissier, E., Boitte, N., Helbecque, N., Berier, J. L., Pomery, N., Synthesis and antitumor properties of an anthraquinone bisubtituted by the copper chelating peptide Gly-Gly-His.J. Med. Chem., 36, 2084–2090 (1993).
Mukherjee, T., Land, E. J., Swallow, A. J., and Bruce, M., One electron reduction of adriamycin and daunomycin: Short-term stability of the semiquinones.Arch. Biochem. Biophys. 272, 450–458 (1989).
Palmer, B. D., Rewcastle, G. W., Atwell, G. J., Potential antitumor agents. Chromophore requirement forin vivo antitumor activity among the general class of linear tricyclic carboxamide.J. Med. Chem., 31, 707–712 (1988).
Patterson, L. H., Rationale for the use of aliphatic N-oxides of cytotoxic anthraquinones as prodrug DNA binding agents: a new class of bioreductive agent.Cancer. Metastasis. Rev., 12, 119–134 (1993).
Rosenberg, L. S., Carvlin, M. J., Krugh, T. R., The antitumor agent mitoxantrone binds cooperatively to DNA; evidence for heterogeneity in DNA conformation.Biochemistry., 25, 1002–1008 (1986).
Terada, A., Tanoue, Y., Hatada, A. and Sakamoto, H., Synthesis of shikhikin and related compounds.Bull. Chem. Soc. JPN., 60, 205–213 (1987).
Tewey, K. M., Rowe, T. C., Yang, L., Halligan, B. D. and Lin, L. F., Adriamycin induced DNA damage mediated by mammalian DNA topoisomerase II.Science (Washington DC)., 226. 466–468 (1984).
Traganos, F., Dihydroxyanthraquinon and related bis (substituted) aminoanthrquinons: a novel class of antitumor agents.Pharmacol. Ther., 22, 199–214 (1983).
Yoshio, H., Makoto, K., Chemical studies on the natural anthrquinone I. Synthesis of Munjkstin Emodin and 3-hydroxy-2-methylanthraquinone.Chem. Pharm Bull., 21, 2790–2795 (1973).
Zunino, F., Capranico, G., DNA topoisomerase II as the primary target of anti-tumor anthracyclins.Anticancer. Drug. des., 5, 307–317 (1990).
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Jin, GZ., Song, GY., Zheng, XG. et al. 2-(1-Oxyalkyl)-1,4-dioxy-9,10-anthraquinones: Synthesis and evaluation of antitumor activity. Arch. Pharm. Res. 21, 198–206 (1998). https://doi.org/10.1007/BF02974028
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DOI: https://doi.org/10.1007/BF02974028