MAMMALIAN TOPOISOMERASE II INHIBITORY ACTIVITY OF -DIMETHYL-4-PYRIDINYL)-4-OXO-3-QUINOLINECARBOXYLIC ACID AND RELATED DERIVATIVES

-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid (1), a previou sly reported potent inhibitor of bacterial DNA gyrase, was found to be interactive with mammalian topoisomerase II (topo II). In a DNA-cleav age assay using topo II isolated from HeLa cells, 1 exhibited an EC50 value of 7.6 muM (VP-16; EC50 = 0.81 muM). A series of analogues modif ied 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) an alogue had potency comparable to that of 1; when both these compounds were substituted at the 2-position with methyl or phenyl, an interesti ng relationship between activity and the conformation of the carboxyl group emerged. Upon replacement of the 5-H of 1 with NH2 or F, sustain ed potency was seen. No enhancement of activity was evident upon repla cing the 7-substituent of 1 with other pyridinyl groups, 4-methyl-1-pi perazinyl, or pyrrolidinyl groups; however, the 7-(4-hydroxyphenyl) an alogue (CP-115,953) was 6-fold more potent than 1. The topo II inhibit ory properties of 1 translated to modest in vitro cytotoxicity and in vivo activity versus P388.