New benzoxanthone derivatives as topoisomerase inhibitors and DNA cross-linkers

• Published in: Bioorganic & medicinal chemistry 2010-02, Vol.18 (3), p.1010-1017
• Main Authors: Cho, Hee-Ju, Jung, Mi-Ja, Woo, Sangwook, Kim, Jungsook, Lee, Eung-Seok, Kwon, Youngjoo, Na, Younghwa
• Format: Article
• Language: English
• Subjects: Anticancer activities; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzene Derivatives - chemistry; Benzene Derivatives - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; DNA - antagonists & inhibitors; DNA - metabolism; DNA cross-linking; DNA Topoisomerases - metabolism; DNA Topoisomerases, Type I - metabolism; DNA Topoisomerases, Type II - metabolism; Drug Screening Assays, Antitumor; General aspects; Humans; Medical sciences; Molecular Structure; Neoplasms - drug therapy; Oxiranylmethoxybenzoxanthones; Pharmacology. Drug treatments; Thiiranylmethoxybenzoxanthones; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors; Topoisomerase inhibition; Topoisomerase Inhibitors; Xanthones - chemistry; Xanthones - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.12.069

We synthesized 12 benzoxanthone derivatives classified as three different groups based on the tetracyclic ring shapes and evaluated their pharmacological activities to find potential anticancer agents. In the cytotoxicity test, most compounds showed effective cancer cell growth inhibition against the HT29 and DU145 cell lines. Among the compounds tested, compound 19 was the most effective in the cancer cell lines tested. Compound 9 showed dual inhibitory activities against DNA relaxation by topoisomerases I and II. The% inhibition of compound 9 on topoisomerase I was comparable to that of camptothecin. Compound 9 efficiently blocked topoisomerase II function by almost threefold than etoposide at 20 μM. Compound 19 had selective topoisomerase II inhibitory activity at 100 μM. The DNA cross-linking test revealed that only compounds 8 and 19, which possess epoxy groups, cross-linked DNA duplex, while 14 did not. From the combined pharmacological results, we proposed that the target through which compound 19 inhibits cancer cell growth may be the DNA duplex itself and/or DNA–topoisomerase II complex.