Design,synthesis, and in vitro evaluation of BP-1-102 analogs with modified hydrophobic fragments for STAT3 inhibition

Twelve novel analogs of STAT3 inhibitor BP-1-102 were designed and synthesised with the aim to modify hydrophobic fragments of the molecules that are important for interaction with the STAT3 SH2 domain. The cytotoxic activity of the reference and novel compounds was evaluated using several human and two mouse cancer cell lines. BP-1-102 and its two analogs emerged as effective cytotoxic agents and were further tested in additional six human and two murine cancer cell lines, in all of which they manifested the cytotoxic effect in a micromolar range. Reference compound S3I-201.1066 was found ineffective in all tested cell lines, in contrast to formerly published data. The ability of selected BP-1-102 analogs to induce apoptosis and inhibition of STAT3 receptor-mediated phosphorylation was confirmed. The structure–activity relationship confirmed a demand for two hydrophobic substituents, i.e. the pentafluorophenyl moiety and another spatially bulky moiety, for effective cytotoxic activity and STAT3 inhibition.     

Physiological comparison of cells with high and low alcohol dehydrogenase activities in bacterial populations consuming ethanol

Measuring the physiological heterogeneity of natural and industrial microbial populations is essential to studying, modelling and monitoring of microbial populations. It was discovered that populations of Escherichia coli and Bacillus megaterium growing in medium with ethanol as an external source of energy have two actively respiring but physiologically different subpopulations. Cells of one subpopulation have negligibly low alcohol dehydrogenase (ADH) activity (ADH-L cells) and cells of the other have high ADH activity (ADH-H cells). The subpopulation of ADH-H bacterial cells was measured using 10 min incubations of cells in a 1% solution of allyl alcohol for fast selective killing of cells with high activity of ADH and flow cytometry detection of dead cells after this incubation. The content of ADH-H cells during exponential phase of batch culture varied from 9 % to 90 % and lowered to zero for a few hours during starvation of the population. ADH-L cells are actively respiring cells and not depolarized cells. The simultaneous presence of ADH-L and ADH-H cells growing in the medium with ethanol can be explained by the fact that ADH-H cells oxidize actively external ethanol whereas ADH-L cells oxidize only intracellular storage carbohydrates. The method for enumeration of cells with high ADH activity can be used to monitor the heterogeneity of bacterial populations consuming ethanol as a sole source of carbon and energy.     

Isolation and characterization of mutated alcohol oxidases from the yeast <Emphasis Type="Italic">Hansenula polymorpha</Emphasis> with decreased affinity toward substrates and their use as selective elements of an amperometric biosensor

Background  

Accurate, rapid, and economic on-line analysis of ethanol is very desirable. However, available biosensors achieve saturation at very low ethanol concentrations and thus demand the time and labour consuming procedure of sample dilution.     

c-Fos and bone loss: A proto-oncogene regulates osteoclast lineage determination

Development of gene transfer systems provides a key tool for understanding gene function. Exciting and often unexpected consequences from embryo manipulations are yielding insights into molecular mechanisms underlying development under normal and pathogenic states, and are providing animal models for diseases. Contributing to this progress is the elegant work on c-fos⁽¹⁾, where Wagner and coworkers identify this proto-oncogene as a primary factor which directs cell differentiation along the osteoclast/macrophage lineages, and thus regulates bone remodeling. Their studies support a link between skeletogenesis, marrow formation and hematopoiesis, and may help to delineate mechanisms underlying the oncogenic transformation of skeletal and hematopoietic cells.