Potent antitumor activity of quinolone compounds with an unsaturated aminoazabicyclo group at the C-7 position of the quinolone ring.
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.
Arakawa
H
H
Banyu Tsukuba Research Institute, Merck Research Laboratories, Japan.
Mano
E
E
Hakoda
N
N
Yoshinari
T
T
Nakagawa
S
S
Okura
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D001943:Breast Neoplasms; D004247:DNA / Q000378:metabolism; D005260:Female; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D015363:Quinolones / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C099906:1-cyclopropyl-6,8-difluoro-4-oxo-7-(2-amino-8-azabicyclo(4.3.0)non-3-en-8-yl)quinoline-3-carboxylic acid; C099907:1-cyclopropyl-6-fluoro-8-methoxy-7-(2-amino-8-azabicyclo(4.3.0)non-3-en-8-yl)quinoline-3-carboxylic acid; C099905:5-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; D000970:Antineoplastic Agents; D015363:Quinolones; D004247:DNA