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.

Synthesis and antitumor activity of alkyltriazenopyrazoles.

The chemical synthesis of certain mono- and bis-dialkyltriazenopyrazoles is described. In antitumor studies it was found that none of the compounds produced increase in life span (ILS) of L 1210 bearing mice or inhibition of adenocarcinoma 755 growth above the criteria established. The introduction of a second triazenogroup increases the toxicity of the compounds tested.

Cyanopyrazoles as analogs of purine precursors--I. Inhibitory effect on purine biosynthesis de novo.

The in vitro inhibition of purine biosynthesis de novo by a series of cyanopyrazoles was studied. At concentration 1 mM trichloromethyl analogs (3(5)-amino-4-cyano-5(3)-trichloromethylpyrazole and N-hydroxyethyl-3(5)-amino-4-cyano-5(3)-trichloromethylpyrazole) were found to inhibit IMP synthesis 80 and 30% respectively. GAR synthesis was inhibited at a lower degree at the same range of concentrations. The compounds demonstrated a similar pattern of inhibition of the last steps, e.g. AICAR formylation and cyclization as found on the whole pathway.

Synthesis, structure and antibacterial activity of some alkyltriazenopyrazoles.

A series of bis-beta-chlorethyl-, dimethyl- and diethyltriazenopyrazoles (I-IV) were synthesized. By the method of IR spectroscopy the most probable transformation form of I was shown. The compounds were tested as antibacterial agents on a series of bacterial species. It was established that only one of them (VI) possessed a low inhibitory effect. All the rest inhibited strongly the growth of Staphylococcus aureaus 209 and E. coli 387.