Potent antitumor activity of quinolone compounds with an unsaturated aminoazabicyclo group at the C-7 position of the quinolone ring

Anticancer Drug Des. 1996 Apr;11(3):221-9.

Abstract

Relationships between the substituents on the quinolone nucleus of 2 and related compounds and their biological activities were studied. 2, 3 and 1 carrying a (1R, 2R, 6R)-2-amino-8-azabicyclo[4.3.0.]non-3-en-8-yl group at the C-7 position increased the rate of formation of DNA-protein complexes in cells, and inhibited the growth of tumor cells more strongly than the compounds with other substituents. The introduction of a fluorine atom or a methoxy group at the 8-position and an amino group at the 5-position increased the activity still further. The three compounds listed were all effective against P388 leukemia in mice. Subcutaneous injection of 2 at 2 mg/kg strongly suppressed the growth of human MX-1 breast cancer cells in nude mice. 1 has various functional groups that increase the cytotoxic potential of quinolone derivatives: a (1R, 2R, 6R)-2-amino-8-azabicyclo[4.3.0.]non-3-en-8-yl moiety at C-7, a cyclopropyl group at the 1-position, fluorine atoms at the 6- and 8-positions, and an amino group at the 5-position of the quinoline carboxylic acid. These data suggest that this series of compounds provide good models for the further design of potent antitumor quinolones.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / therapeutic use
  • Breast Neoplasms
  • DNA / metabolism
  • Female
  • Humans
  • Leukemia L1210 / drug therapy
  • Leukemia P388 / drug therapy
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Structure
  • Neoplasm Transplantation
  • Quinolones / chemistry*
  • Quinolones / metabolism
  • Quinolones / therapeutic use
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • 1-cyclopropyl-6,8-difluoro-4-oxo-7-(2-amino-8-azabicyclo(4.3.0)non-3-en-8-yl)quinoline-3-carboxylic acid
  • 1-cyclopropyl-6-fluoro-8-methoxy-7-(2-amino-8-azabicyclo(4.3.0)non-3-en-8-yl)quinoline-3-carboxylic acid
  • 5-amino-1-cyclopropyl-6,8-difluoro-4-oxo-7-(2-amino-8-azabicyclo(4.3.0)non-3-en-8-yl)quinoline-3-carboxylic acid
  • Antineoplastic Agents
  • Quinolones
  • DNA