Stereo (C7)-dependent topoisomerase II inhibition and tumor growth suppression by a new quinolone, BO-2367.

Abstract

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.

• Authors: T Yoshinari, E Mano, H Arakawa, M Kurama, T Iguchi, S Nakagawa, N Tanaka, A Okura
• Journal: Japanese journal of cancer research : Gann (Jpn J Cancer Res) Vol. 84 Issue 7 Pg. 800-6 (Jul 1993) ISSN: 0910-5050 [Print] Japan
• PMID: 8396568 (Publication Type: Journal Article)

Chemical References

• Anti-Infective Agents
• DNA, Neoplasm
• DNA, Superhelical
• Fluoroquinolones
• Quinolones
• Topoisomerase II Inhibitors
• BO 2367
• Etoposide
• DNA Topoisomerases, Type II

Topics

• Animals
• Anti-Infective Agents (chemistry, pharmacology)
• Carcinoma (prevention & control)
• Colonic Neoplasms (prevention & control)
• DNA Topoisomerases, Type II (biosynthesis, chemistry, drug effects)
• DNA, Neoplasm (drug effects)
• DNA, Superhelical (drug effects)
• Drug Screening Assays, Antitumor
• Enzyme Induction
• Etoposide (pharmacology)
• Female
• Fluoroquinolones
• Leukemia L1210 (drug therapy, enzymology, genetics)
• Leukemia P388 (drug therapy)
• Mice
• Mice, Inbred Strains
• Quinolones (chemistry, pharmacology)
• Stereoisomerism
• Topoisomerase II Inhibitors