Stereo (C7)-dependent topoisomerase II inhibition and tumor growth suppression by a new quinolone, BO-2367.
A new antimicrobial quinolone (-)BO-2367, (-)-7-[(1R*, 2R*, 6R*)-2-amino-8-azabicyclo[4.3.0.]-non-3-en-8-yl]-1- cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, strongly inhibited both mammalian and bacterial topoisomerase II. The IC50 values of (-)BO-2367 against the DNA relaxation activity of L1210 topoisomerase II and the supercoiling activities of Escherichia coli gyrase and Micrococcus luteus gyrase were 3.8, 0.5, and 1 microM, respectively. This compound enhanced double-stranded DNA cleavage mediated by topoisomerase II not only with purified enzyme, but also with intact L1210 cells. All these activities of (-)BO-2367 were more than 2-fold stronger than those of VP-16. Intriguingly, (+)BO-2367, which has an enantiomeric substituent at the C7 position of (-)BO-2367, did not affect the activity of the mammalian topoisomerase II, while it inhibited E. coli gyrase. Intraperitoneal injection of (-)BO-2367 at 0.08 mg/kg increased the lifespan of CDF1 female mice bearing ascitic L1210 leukemia by 2.4 times, and subcutaneous injection at 1.25 mg/kg completely inhibited the growth of colon 26 carcinoma implanted subcutaneously. These results suggest that (-)BO-2367 is a potent antitumor agent which targets topoisomerase II. These enantiomers should be a useful tool for studying drug-topoisomerase II interactions.
Banyu Tsukuba Research Institute in Collaboration with Merck Research Laboratories, Tsukuba.
T
T
Yoshinari
E
E
Mano
H
H
Arakawa
M
M
Kurama
T
T
Iguchi
S
S
Nakagawa
N
N
Tanaka
A
A
Okura
D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D002277:Carcinoma / Q000517:prevention & control; D003110:Colonic Neoplasms / Q000517:prevention & control; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis / Q000737:chemistry / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects*; D004278:DNA, Superhelical / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004790:Enzyme Induction; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D024841:Fluoroquinolones; D007939:Leukemia L1210 / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008815:Mice, Inbred Strains; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D059005:Topoisomerase II Inhibitors
D000890:Anti-Infective Agents; D004273:DNA, Neoplasm; D004278:DNA, Superhelical; D024841:Fluoroquinolones; D015363:Quinolones; D059005:Topoisomerase II Inhibitors; C083091:BO 2367; D005047:Etoposide; D004250:DNA Topoisomerases, Type II