Therapeutic potential of new Pt(II) and Ru(III) triazole-pyrimidine complexes against Leishmania donovani.

We have already established an in vitro culture system using murine macrophages infected with Leishmania donovani in which the time course of parasite growth is determined quantitatively. We adopted this system for the screening of three triazole-pyrimidine derivatives that would ideally prove to be effective against L. donovani with no toxicity to the host cell. Amphotericin B deoxycholate was used as the standard drug and gave a IC50 value of 3.89 microg/ml. The three triazole-pyrimidine compounds assayed have been reported to be potent growth inhibitors of L. donovani promastigote and amastigote stages. Compounds SPIV and SPVI exhibited the highest toxicity for extracellular forms of parasites, with IC50 values of 19.95 and 21.61 microg/ml, respectively. The triazole-pyrimidine SPV, although to a lower degree, also showed pronounced effects against promastigote forms with IC50 of 33.14 microg/ml. Drug activity was higher against amastigote than against promastigote stages. The compounds SPIV and SPVI interfered with the synthesis of macromolecules, affecting primarily DNA at the lower concentration tested (5 microg/ml), while SPV also showed interference, though to a lesser extent, and at a higher concentration (15 microg/ml) the percentage of inhibition rose considerably. The synthesis or RNA and proteins was also depressed significantly by these compounds at administration rates of 15 microg/ml. Ultrastructural alterations were evident in the main organelles of L. donovani (nucleus, kinetoplast, mitochondria), after the addition of the three compounds at a concentration of 5 microg/ml, to the in vitro culture. The in vitro promastigote forms of L. donovani can degrade glucose to carbon dioxide, and part of the carbon skeleton of the glucose is excreted as end metabolites. The excretion of these metabolites, mainly acetate, was also inhibited by the three compounds assayed, suggesting that this could be due to a direct effect on some of the enzymes related to this fermentation pathway or to the inhibition exerted by the compounds on enzyme synthesis.

Cytotoxicity of three new triazolo-pyrimidine derivatives against the plant trypanosomatid: Phytomonas sp. isolated from Euphorbia characias.

There is no effective chemotherapy against diseases caused by Phytomonas sp., a plant trypanosomatid responsible for economic losses in major crops. We tested three triazolo-pyrimidine complexes [two with Pt(II), and another with Ru(III)] against promastigotes of Phytomonas sp. isolated from Euphorbia characias. The incorporation of radiolabelled precursors, ultrastructural alterations and changes in the pattern of metabolite excretion were examined. Different degrees of toxicity were found for each complex: the platinum compound showed an inhibition effect on nucleic acid synthesis, provoking alterations on the levels of mitochondria, nucleus and glycosomes. These results, together with others reported previously in our laboratory about the activity of pyrimidine derivatives, reflect the potential of these compounds as agents in the treatment of Phytomonas sp.

Cytotoxicity of three new triazolo-pyrimidine derivatives against the plant trypanosomatid: Phytomonas sp. isolated from Euphorbia characias

There is no effective chemotherapy against diseases caused by Phytomonas sp., a plant trypanosomatid responsible for economic losses in major crops. We tested three triazolo-pyrimidine complexes [two with Pt(II), and another with Ru(III)] against promastigotes of Phytomonas sp. isolated from Euphorbia characias. The incorporation of radiolabelled precursors, ultrastructural alterations and changes in the pattern of metabolite excretion were examined. Different degrees of toxicity were found for each complex: the platinun compound showed an inhibition effect on nucleic acid synthesis, provoking alterations on the levels of mitochondria, nucleus and glycosomes. These results, together with others reported previously in our laboratory about the activity of pyrimidine derivatives, reflect the potential of these compounds as agents in the treatment of Phytomonas sp.

Activities of Pt(II) and Ru(III) triazole-pyrimidine complexes against Trypanosoma cruzi and T. brucei brucei.

We studied the biological activity of three newly synthesized metal complexes of triazole-pyrimidine derivatives that were previously observed to inhibit in vitro growth of epimastigotes of Trypanosoma cruzi and procyclic forms of Trypanosoma brucei brucei. We analyzed the possible inhibitory effect of these compounds on the synthesis of DNA, RNA and protein, ultrastructure and excretion of metabolites by these parasites. RNA synthesis was inhibited by all three complexes assayed. These complexes also led to anomalies of the main organelles (e.g. nucleus, kinetoplast and mitochondria). In addition, these complexes may be capable of altering the excretion of metabolites by the parasites.

Expression of transcription factors in endometrium during natural cycles.

PURPOSE: The sex steroid control of the endometrial cycle is mediated by transcription factors, four of which are the estrogen and progesterone receptors, c-jun and c-fos, all expressed by the endometrium. The aim of this study was to analyze the distribution of the transcription factors in the different endometrial compartments during natural cycles. METHODS: We studied 53 reproductively-normal women, of whom 26 were in the proliferative phase and 27 in the secretory phase. An endometrial biopsy was performed and serum values of LH, FSH, estradiol, and progesterone were determined. We studied the expression of transcription factors using monoclonal antibodies. RESULTS: A correlation between estrogen receptor and c-jun and c-fos expression was observed in stroma and epithelia, and progesterone receptor expression correlated with c-jun expression in epithelia. C-jun and c-fos presented greater expression in the proliferative phase than in the secretory phase, in the stroma and in both epithelia. No relation was found between estradiol serum levels and any transcription factor, but progesterone serum levels correlated significantly with most such factors. CONCLUSION: The two proto-oncogenes could play a decisive role in regulating the endometrial cycle; they could mediate the effects induced by sex steroid, and could be related to other transcription factors.