Abstract
2-(1-Aryl-1-hydroxymethyl)- and 2-aroyl-DHAQ derivatives (DHAQ, 1,4-dihydroxy-9,10-anthraquinone), and 2-(1-aryl-1-hydroxymethyl)-ATO derivatives (ATO, anthracene-1,4,9,10-tetraone) were synthesized and their antitumor activities were determined. 2-(1-Aryl-1-hydroxymethyl)-DHAQ derivatives showed a stronger cytotoxicity compared to the series of 2-(1-hydroxyalkyl)-1,4-dihydroxy-9,10-anthraquinone derivatives. It was suggested that the presence of aryl group at the side chain accelerated the bioreductive activation leading to cell death. 2-Aroyl-DHAQ derivatives, despite their higher electrophilicity, revealed smaller cytotoxicity and antitumor activity (expressed by T/C value) than 2-(1-aryl-1-hydroxymethyl)-DHAQ derivatives. Thus, no consistent relationship between the electronic effect on aromatic side chain and the cytotoxicity was observed. ATO series exhibited a higher antitumor activity (T/C, 125–218%), though their cytotoxicity was not further improved compared to that of 2-(1-aryl-1-hydroxymethyl)-1,4-dihydroxy-9,10-anthraquinones. They manifested no correlation between the cytotoxicity and the antitumor activity. In case of 2-[1-hydroxy-1-(4-propylphenyl)-methyl]-ATO, the most bioactive onein vivo among the same series, it showed an ED50 value of 10.2 mg/mL and a T/C value of 218%. It is assumed that the anthracene-1,4,9,10-tetraones after uptake into cellular tissues might be transformed to a cytotoxic metabolite(s).
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References Cited
Baik, K. U., Jung, S. H. and Ahn, B. Z. Recognition of Phar-macophore of ar-Turmerone for its anticancer Activity.Arch. Pharm. Res. 16, 254–256 (1993a).
Baik, K. U., Jung, S. H. and Ahn, B. Z Structure-Activity Relationship of ar-Turmerone Analogues.Arch. Pharm. Res. 16, 219 (1993b)
Blanz, J., Mewes, K., Ehninger, G., Gebhardt, R., Zeller, K. P.,Drug. Metab. Dispos., 19, 871–880 (1991).
Ehninger, G., Chuler, U., Proksch, B., Zeller, K. P., Blanz, J., Pharmacokinetics and metabolism of mitoxantrone. A review.Clin. Pharmacokinet., 18 365–38 (1990).
Jin, G. Z., Kim, Y., Ho, C. J., Sok, D. E., and Ahn, B. Z., 1,4,9,10-Anthraquinone Derivatives: Synthesis and Antitumor Activity.Arch. Pharm. Pharm. Med. Chem., 331, 380–384 (1998a).
Jin, G. Z., Song, G. Y., Zheng, S. G., Kim, Y., Sok, D. E., and Ahn, B. Z., 2-(1-Oxyalkyl)-1,4-dioxy-9,10-anthraquinones: Synthesis and Evaluation of antitumor Activity.Arch. Pharm. Res., 21(2), 208–206 (1998b).
Mewes, K., Blanz, J., Ehninger, G., Gebhardt, R., and Zeller, K. P., Cytochrome p-450-induced Cytotoxicity of Mitoxantrone by Formation of Electrophilic Intermediates.Cancer Res., 2093, 1, 5135–5142 (1993).
National Cancer Institute Protocol, U. S. A. (1972)
Song, G. Y., Zheng, X. G., Kim, Y., You, Y. J., Sok, D. E., and Ahn, B. Z., Naphthazarin derivatives (II): Formation of glutathione conjugate inhibition of DNA topoisomerase-I and cytotoxicity.Bioorg. Chem. Med. Chem. Letter 9, 2407–2412 (1999).
Song, G. Y., Kim, Y., Zheng, X, G., You, Y. J., Cho, H., Chung, J. H., Sok, D. E. and Ahn, B. Z. Naphthazarin Derivatives (IV). Synthesis, Inhibition of DNA topoisomerase-I and Cytotoxicity of 2- or 6-Acyl-5,8-dimethoxy-1,4-naphthoquinones.European J. Med. Chem. (1999) in press.
Thayer, P. S., Himnelfarb, L. A., Watt, G. L.,Cancer Chemotherapy 2, 1–25 (1971).
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Nam, NH., Jin, GZ., Tam, M.N. et al. Effect of the aryl substituent on antitumor activity of 2-substituted-1,4-dihydroxy-9,10-anthraquinones and 2-substitutedanthracene-1,4,9,10-tetraones. Arch Pharm Res 22, 592–607 (1999). https://doi.org/10.1007/BF02975332
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DOI: https://doi.org/10.1007/BF02975332