Maria K. Spassova

Some pyrazoles as inhibitors of purine biosynthesis de novo

Abstract The inhibitory effect of some pyrazole derivatives on purine biosynthesis was studied in a pigeon liver cell-free system. It was demonstrated that 3-amino-4-carbethoxypyrazole, 3-amino-4-carboxypyrazole and 3-(3′3′-bis-β-chloroethyltriazenyl-1′)-4-carbethoxypyrazole were inhibitors, while N - β -hydroxyethyl-3-amino-4-carbethoxypyrazole was almost inactive. A possible mechanism of action is discussed.

Pharmacobiochemistry of arylalkyltriazenes and their application in cancer chemotherapy

As a class of organic compounds tr iazenes were characterized and described a very long time ago (Griess, 1862), however, data about their biological action did not appear until considerably later. About 28 years ago Stock et al. (Clarke et al., 1955; Burchenal et al., 1956) were the first to establish the antitumor activity of certain aryldimethyltriazenes, but their therapeutic use did not become possible until the synthesis of DTIC [5(4)-(3,3-dimethyl-l-triazeno)imidazole-4(5)-carboxamide]. This compound has been the most extensively studied agent in the treatment of malignant melanoma and the subject of detailed research in the pharmacobiochemistry of this class of compounds. In the present review, data on the synthesis and mechanism of action (molecular and cellular) of arvlalkyl tr iazenes in the last 20 years have been systematized, and a summary of the activity and therapeutic use of DTIC is given.

Cyanopyrazoles as analogs of purine precursors—1. 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.

Mechanism of inhibitory effect of some pyrazole derivatives on purine biosynthesis de novo

Abstract The inhibitory effect of some pyrazole derivatives on GAR synthesis was studied. It was found that nonalkylating analogues and chloroethyltriazeno analogues inhibited GAR synthesis. A possible mechanism of action of triazeno derivatives on purine biosynthesis de novo was shown.

Lysine-orotate potentiates the toxicity of an extract of the mushroom Amanita phalloides

Upon simultaneous administration lysine-orotate increases (about 40-fold) the toxicity in mice of a crude Amanita phalloides extract. This effect, though less prominent, is also observed if these two compounds are injected 1 hr apart. The potentiating effect of lysine-orotate is dose dependent and neither L-lysine nor orotic acid exert any effect on the toxicity of the crude A. phalloides extract. Lysine-orotate increases the toxicity of amatoxins (alpha-amanitin) only, not affecting the toxicity of phalloidins. Thin layer chromatography on silica gel plates and column chromatography on Sephadex LH-20 has proven the formation of a relatively stable complex of amanitin and lysine-orotate. The results demonstrate that lysine-orotate should not be used as a hepatoprotective agent in cases of Amanita intoxication.

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.