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.

4′‐demethylepipodophyllotoxin‐9‐(4,6‐O‐ethylidene‐β‐D‐glucopyranoside)

4′‐(9‐acridinyl‐amino) methanesulfon‐m‐anisidide

Tris[hydroxymethyl]‐aminomethane

adenosine 5′‐triphosphate

ethylenediaminetetraacetic acid

sodium dodecyl sulfate

Dulbecco's phosphate‐buffered saline (Ca2+, Mg2+free)

90 mM Tris, 90 mM boric acid, and 4 mM EDTA