Cytostatic activity of pyridazinee derivatives. Part III. Cytotoxic studies on some pyridazine-3,6-diones and pyridazin-6-ones using a particle counter and a proliferation inhibition test.
The cytoxicity of 10 pyridazine-3,6-dione and 11 pyridazine-6-one derivatives was studied on L-1210 cells using the proliferation inhibition (PI) test and particle counter (PC) test. Eight compounds with ED50 value below 1 microgram/ml in the PI system and with minimal effective concentration (MEC) below 0.2 mg/ml in the PC system, were qualified for further in vivo investigation. A good solubility-activity relationship depending on bromine substituents at C-4 and C-5 in the pyridazine-3, 6-dione group was observed. The activity of soluble, pyridazine-3,6-diones depended proportionally on the number of bromine substituents at C-4 and C-5 -contrary to solubility inversely proportional to the number of bromine atoms. The moderately soluble and moderately active compounds appear to have the highest efficiency. Activity of pyridazine-6-ones seems also to be related to the number of chlorine atoms substituted at those positions. The preliminary information about the cellular mechanism and quantitative differences in the action of model analogues in correlation to structure-solubility was obtained. A new cytotoxic particle counter index (CPCI) was helpful for differentiation of activity of pyridazine analogues.
D000818:Animals; D000970:Antineoplastic Agents; D002455:Cell Division / Q000187:drug effects; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D051379:Mice; D011724:Pyridazines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D011724:Pyridazines