Micronucleus-inducing and antitumor activity of three newly synthesized bridged nitrogen atom-containing pyrimidines.

PURPOSE: To study micronucleus (MN)-inducing and antitumor activity of 3 newly synthesized compounds having condensed nitrogen-containing heterocyclic structures with a bridged nitrogen atom (code numbers - DGB-216, DGS-618 and DGS-623). MATERIALS AND METHODS: The compounds were tested for MN-inducing activity in SH-SY5Y and HeLa tumor cell lines at doses close to IC50 (assessed by means of trypan blue dye exclusion technique ) and 1/2 of IC50 after 24 h incubation without recovery time. In parallel, apoptotic cells were also registered after 24 h incubation of cells with the compounds, staining with Hoechst 33258 and investigation under fluorescent microscope. The compounds were also studied in albino mice bone marrow cells at doses of 1/2, 1/5 and 1/10 of LD50 injected intraperitoneally (i.p.) twice at 0 and 24 h and preparing bone marrow smears 24 h after the last injection. The antitumor activity of the compounds was studied on mouse Ehrlich ascites carcinoma assay by measuring the mean survival time. RESULTS: Only DGS-618 showed cytotoxity at concentrations close to 75.0-80.0 microg/ml; the others were not cytoxic at concentration about 250.0 microg/ml. No one substance induced significant number of cells with MN and apoptosis compared with the negative control. Only DGS-618 was slightly mutagenic in MN-assay at dose of 1/2 of LD50. In contrast, this compound was absolutely inactive in Ehrlich tumor assay. Only DGS-623 was active and induced significant increase in the mean lifespan of mice by 31.0-24.0% in 2 experiments. CONCLUSION: The compound DGS-618 which does not induce MN both in vivo and in vitro and shows antitumor activity in vivo is worth testing in other tumor models. Recent publications show that the search of antitumor agents among pyrazolyl-pyrimidine-containing compounds could be successful because some of them synthesized in the USA and Japan possess expressed antitumor activity.

Relationship between the chemical structures and biological activities (toxicity, mutagenic and antitumor) in newly synthesized derivatives of pyrazolo pyrimidines.

The relationship between chemical structure, micronucleus-inducing and antitumor activities was studied in four newly synthesized pyrazolo pyrymidine compounds (DGB-216, DGB-227, DGB-228 and DGB-331). In bone marrow erythrocytes of mice no one of compounds was active. Only DGB-216 has slight antitumor activity and increases the mean life span of mice with Ehrlich ascite carcinoma by 11%, while others were practically non-active. Changes in the chemical structures of the compounds lead to substantial changes in the acute toxicity only. The search of antitumor compounds among the derivatives of -6-etoxycarbonyl-pyrazolo[1,5a]-pyrymidine and -2-methyl-pyrazolo[1,5a]-pyrymidine is useless, as it has been shown in the present investigation. But the search of compounds with antitumor properties among derivatives of pyrazolo pyrymidines is a perspective idea because recently some very active antitumor compounds based on mentioned strusture were synthesized in Italy and the USA.

Isomerization/Recyclization of some 5-Ethoxycarbonyl-pyrimidines.

This communication reports on the investigation of a new recyclization conversion of a pyrimidine ring, which can be referred to as C-C recyclization. In this reaction the nucleophile cleaves the pyrimidine ring at the N(3)-C(4) bond, and following rotation around the single C(5)-C(6) bond the new cyclization takes place. This type of recyclization has general applicability, and takes place upon alkali treatment of substituted 4-methyl-5-ethoxycarbonyl- and 4-amino-5-ethoxycarbonyl-pyrimidines (1) which are transformed respectively to 4-hydroxy-5-acetyl- and 4-hydroxy-5-carbamoylpyrimidines (2). The obtained pyrimidyl-ketones can be readily converted to their hydrazones 7-12.