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
- 56 Downloads
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).
Key words1,4-dihydroxy-9,10-anthraquinone anthracene-1,4,9,10-tetraones antitumor activity structure-activity relationship
Unable to display preview. Download preview PDF.
- Baik, K. U., Jung, S. H. and Ahn, B. Z Structure-Activity Relationship of ar-Turmerone Analogues.Arch. Pharm. Res. 16, 219 (1993b)Google Scholar
- 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).Google Scholar
- National Cancer Institute Protocol, U. S. A. (1972)Google Scholar
- 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.Google Scholar
- Thayer, P. S., Himnelfarb, L. A., Watt, G. L.,Cancer Chemotherapy 2, 1–25 (1971).Google Scholar