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Antitumor Quinolones with Mammalian Topoisomerase II Mediated DNA Cleavage Activity

Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., 3-6-6 Asahimachi, Machida, Tokyo 194 [Y. Y., H. N.]; Pharmaceutical Research Laboratories, Kyowa Hakko Co., Ltd., Shizuoka [T. A., M. M.]; and Central Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Tochigi [J. H.], Japan

Ninety quinolones were evaluated to determine whether their ability to induce mammalian topoisomerase II mediated DNA cleavage in vitro correlated with their antitumor activity in vivo. Ten quinolones generated linear DNA at a yield of more than 10% of substrate supercoiled DNA in the mammalian topoisomerase II mediated DNA cleavage assay. All of these compounds showed a significant increase in life span (>20%) in the murine leukemia P388 model. These antitumor quinolones have closely related structures: two halogens at C-6 and C-8; and cyclopropyl at N-1 of quinolone skeleton. In contrast, many analogues of the above quinolones, as well as new quinolones used clinically as an antibacterial drug, did not induce the cleavable complex in vitro or show antitumor activity in vivo. These findings indicate that quinolone derivatives can be a promising new class of antitumor agent targeting mammalian topoisomerase II.

¹ To whom requests for reprints should be addressed.

Received 9/21/91. Accepted 3/10/92.

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