New Heterocyclic Compounds from Oxazol-5(4H)-one and 1,2,4-Triazin-6(5H)-one Classes: Synthesis, Characterization and Toxicity Evaluation.

This paper describes the synthesis of new heterocycles from oxazol-5(4H)-one and 1,2,4-triazin-6(5H)-one classes containing a phenyl-/4-bromophenylsulfonylphenyl moiety. The oxazol-5(4H)-ones were obtained via condensation of 2-(4-(4-X-phenylsulfonyl)benzamido)acetic acids with benzaldehyde/4-fluorobenzaldehyde in acetic anhydride and in the presence of sodium acetate. The reaction of oxazolones with phenylhydrazine, in acetic acid and sodium acetate, yielded the corresponding 1,2,4-triazin-6(5H)-ones. The structures of the compounds were confirmed using spectral (FT-IR, 1H-NMR, 13C-NMR, MS) and elemental analysis. The toxicity of the compounds was evaluated on Daphnia magna Straus crustaceans and on the budding yeast Saccharomyces cerevisiae. The results indicate that both the heterocyclic nucleus and halogen atoms significantly influenced the toxicity against D. magna, with the oxazolones being less toxic than triazinones. The halogen-free oxazolone had the lowest toxicity, and the fluorine-containing triazinone exhibited the highest toxicity. The compounds showed low toxicity against yeast cells, apparently due to the activity of plasma membrane multidrug transporters Pdr5 and Snq2. The predictive analyses indicated an antiproliferative effect as the most probable biological action. The PASS prediction and CHEMBL similarity studies show evidence that the compounds could inhibit certain relevant oncological protein kinases. These results correlated with toxicity assays suggest that halogen-free oxazolone could be a good candidate for future anticancer investigations.

Interaction between Polyphenolic Antioxidants and Saccharomyces cerevisiae Cells Defective in Heavy Metal Transport across the Plasma Membrane.

Natural polyphenols are compounds with important biological implications which include antioxidant and metal-chelating characteristics relevant for their antimicrobial, antitumor, or antiaging potential. The mechanisms linking polyphenols and heavy metals in their concerted actions on cells are not completely elucidated. In this study, we used the model eukaryotic microorganism Saccharomyces cerevisiae to detect the action of widely prevalent natural polyphenols on yeast cells defective in the main components involved in essential heavy metal transport across the plasma membrane. We found that caffeic and gallic acids interfered with Zn accumulation, causing delays in cell growth that were alleviated by Zn supplementation. The flavones morin and quercetin interfered with both Mn and Zn accumulation, which resulted in growth improvement, but supplemental Mn and especially Zn turned the initially benefic action of morin and quercetin into potential toxicity. Our results imply that caution is needed when administering food supplements or nutraceuticals which contain both natural polyphenols and essential elements, especially zinc.

Saccharomyces cerevisiae and Caffeine Implications on the Eukaryotic Cell.

Caffeine-a methylxanthine analogue of the purine bases adenine and guanine-is by far the most consumed neuro-stimulant, being the active principle of widely consumed beverages such as coffee, tea, hot chocolate, and cola. While the best-known action of caffeine is to prevent sleepiness by blocking the adenosine receptors, caffeine exerts a pleiotropic effect on cells, which lead to the activation or inhibition of various cell integrity pathways. The aim of this review is to present the main studies set to investigate the effects of caffeine on cells using the model eukaryotic microorganism Saccharomyces cerevisiae, highlighting the caffeine synergy with external cell stressors, such as irradiation or exposure to various chemical hazards, including cigarette smoke or chemical carcinogens. The review also focuses on the importance of caffeine-related yeast phenotypes used to resolve molecular mechanisms involved in cell signaling through conserved pathways, such as target of rapamycin (TOR) signaling, Pkc1-Mpk1 mitogen activated protein kinase (MAPK) cascade, or Ras/cAMP protein kinase A (PKA) pathway.

Anchoring plant metallothioneins to the inner face of the plasma membrane of Saccharomyces cerevisiae cells leads to heavy metal accumulation.

In this study we engineered yeast cells armed for heavy metal accumulation by targeting plant metallothioneins to the inner face of the yeast plasma membrane. Metallothioneins (MTs) are cysteine-rich proteins involved in the buffering of excess metal ions, especially Cu(I), Zn(II) or Cd(II). The cDNAs of seven Arabidopsis thaliana MTs (AtMT1a, AtMT1c, AtMT2a, AtMT2b, AtMT3, AtMT4a and AtMT4b) and four Noccaea caerulescens MTs (NcMT1, NcMT2a, NcMT2b and NcMT3) were each translationally fused to the C-terminus of a myristoylation green fluorescent protein variant (myrGFP) and expressed in Saccharomyces cerevisiae cells. The myrGFP cassette introduced a yeast myristoylation sequence which allowed directional targeting to the cytosolic face of the plasma membrane along with direct monitoring of the intracellular localization of the recombinant protein by fluorescence microscopy. The yeast strains expressing plant MTs were investigated against an array of heavy metals in order to identify strains which exhibit the (hyper)accumulation phenotype without developing toxicity symptoms. Among the transgenic strains which could accumulate Cu(II), Zn(II) or Cd(II), but also non-canonical metal ions, such as Co(II), Mn(II) or Ni(II), myrGFP-NcMT3 qualified as the best candidate for bioremediation applications, thanks to the robust growth accompanied by significant accumulative capacity.

The antioxidant response induced by Lonicera caerulaea berry extracts in animals bearing experimental solid tumors.

Lonicera caerulea is a species of bush native to the Kamchatka Peninsula (Russian Far East) whose berries have been extensively studied due to their potential high antioxidant activity. The aim of our work was to investigate the in vivo effects of the antioxidant action of Lonicera caerulea berry extracts on the dynamics of experimentally-induced tumors. Our data showed that aqueous Lonicera caerulaea extracts reduced the tumor volume when administered continuously during the tumor growth and development stages, but augmented the tumor growth when the administration of extracts started three weeks before tumor grafting. Prolonged administration of Lonicera caerulaea berry extracts induced the antioxidant defense mechanism in the tumor tissues, while surprisingly amplifying the peripheral oxidative stress.

Chemical and biological studies of Ribes nigrum L. buds essential oil.

Ribes nigrum buds are used in medicine for the diuretic and antiseptic properties of their volatile compounds. We present in this paper comparative data concerning the chemical composition of Ribes nigrum buds essential oils obtained from three blackcurrant varieties. Essential oils were isolated by steam distillation and were analyzed by gas chromatography coupled with mass spectrometry. The Ribes nigrum essential oils (extracted from all three varieties) exhibited similar and large antibacterial spectrum, acting against Acinetobacter (A.) baumanii, Escherichia (E.) coli, Pseudomonas (P.) aeruginoasa and Staphylococcus (S.) aureus, as proved by the very low MIC values observed for the respective strains. The subinhibitory concentrations of the essential oils induced a decrease in the bacterial ability to colonize the inert substratum for A. baumanii, E. coli and S. aureus, demonstrating that besides the bactericidal activity, the Ribes nigrum essential oils also exhibit anti-pathogenic potential.