Mammalian topoisomerase II inhibitory activity of 1-cyclopropyl-6,8- difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarb oxylic acid and related derivatives.
1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-ox o-3-quinolinecarboxylic acid (1), a previously reported potent inhibitor of bacterial DNA gyrase, was found to be interactive with mammalian topoisomerase II (topo II). In a DNA-cleavage assay using topo II isolated from HeLa cells, 1 exhibited an EC50 value of 7.6 microM (VP-16; EC50 = 0.81 microM). A series of analogues modified at the 1-, 2-, 3-, 5-, and 7-positions of 1 were subsequently made and assessed for topo II inhibition. Compound 1 was considerably more potent than derivatives where the 1-substituent was alkyl, aryl, or H, or when N-c-C3H5 was replaced with S. The descarboxyl (i.e., 3-H) analogue had potency comparable to that of 1; when both these compounds were substituted at the 2-position with methyl or phenyl, an interesting relationship between activity and the conformation of the carboxyl group emerged. Upon replacement of the 5-H of 1 with NH2 or F, sustained potency was seen. No enhancement of activity was evident upon replacing the 7-substituent of 1 with other pyridinyl groups, 4-methyl-1-piperazinyl, or pyrrolidinyl groups; however, the 7-(4-hydroxyphenyl) analogue (CP-115,953) was 6-fold more potent than 1. The topo II inhibitory properties of 1 translated to modest in vitro cytotoxicity and in vivo activity versus P388.
Wentland
M P
MP
Department of Medicinal Chemistry, Sterling Winthrop Pharmaceuticals Research Division, Sterling Winthrop Inc., Collegeville, Pennsylvania 19426-0900.
Lesher
G Y
GY
Reuman
M
M
Gruett
M D
MD
Singh
B
B
Aldous
S C
SC
Dorff
P H
PH
Rake
J B
JB
Coughlin
S A
SA
D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D024841:Fluoroquinolones; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D015363:Quinolones; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D015363:Quinolones; D059005:Topoisomerase II Inhibitors; C083398:1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxyic acid