Cyanopyrazoles as analogs of purine precursors--II. Effects on macromolecular synthesis and cell cycle progression.
The cytotoxic and cytokinetic effects, and in vitro inhibition of macromolecular synthesis by cyanopyrazoles were studied using Friend leukemia and Ehrlich ascites tumor cells. At concentrations in the range of 2.5 mM to 50 microM analog 3(5)-amino-4-cyano-5(3)-trichloromethylpyrazole (I) was highly cytotoxic and completely inhibited thymidine, uridine and leucine incorporation into macromolecular material. 24 hr incubation of FL cells with cytostatic concentrations of compound I (in the range of 2 to 0.5 microM) resulted in an accumulation of cells in the G2 + M phase. Analogs N-hydroxyethyl-3(5)-amino-4-cyano-5(3)-trichloromethylpyrazole (II) and 3(5)-amino-4-cyanopyrazole (III) were not cytotoxic at concentrations up to 5 mM and did not substantially inhibit precursor incorporation into macromolecules but exhibited a cytostatic activity. These compounds caused a decrease of FL cells in the G2 + M phase and an accumulation in the S phase. Analogs I and II displayed a similar in vivo inhibitory effect on thymidine incorporation into DNA in EAT cells. The results indicate that the cytotoxicity of cyanopyrazoles correlates with their ability to inhibit precursor incorporation into macromolecular material. On the other hand, the cytostatic action of compound I is not coupled to a block of nucleic acid synthesis.
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005622:Friend murine leukemia virus; D007700:Kinetics; D007942:Leukemia, Experimental / Q000378:metabolism; D046911:Macromolecular Substances; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D011687:Purines / Q000096:biosynthesis*; D011720:Pyrazoles / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013936:Thymidine / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D011687:Purines; D011720:Pyrazoles; D012334:RNA, Neoplasm; D013936:Thymidine