Antitumor quinolones with mammalian topoisomerase II mediated DNA cleavage activity.
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 (greater than 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.
Yamashita
Y
Y
Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Japan.
Ashizawa
T
T
Morimoto
M
M
Hosomi
J
J
Nakano
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism*; D004278:DNA, Superhelical / Q000187:drug effects / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D007941:Leukemia P388 / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D015363:Quinolones / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004278:DNA, Superhelical; D015363:Quinolones; D004250:DNA Topoisomerases, Type II