Rhomboids are intramembrane serine proteases with diverse physiological functions in organisms ranging from archaea to humans. Crystal structure analysis has provided a detailed understanding of the catalytic mechanism, and rhomboids have been implicated in various disease contexts. Unfortunately, the design of specific rhomboid inhibitors has lagged behind, and previously described small molecule inhibitors displayed insufficient potency and/or selectivity. Using a computer-aided approach, we focused on the discovery of novel scaffolds with reduced liabilities and the possibility for broad structural variations. Docking studies with the E. coli rhomboid GlpG indicated that 2-styryl substituted benzoxazinones might comprise novel rhomboid inhibitors. Protease in vitro assays confirmed activity of 2-styryl substituted benzoxazinones against GlpG but not against the soluble serine protease α-chymotrypsin. Furthermore, mass spectrometry analysis demonstrated covalent modification of the catalytic residue Ser201, corroborating the predicted mechanism of inhibition and the formation of an acyl enzyme intermediate. In conclusion, 2-styryl substituted benzoxazinones are a novel rhomboid inhibitor scaffold with ample opportunity for optimization.
- MeSH
- benzoxaziny chemická syntéza chemie MeSH
- chymotrypsin chemie MeSH
- DNA vazebné proteiny antagonisté a inhibitory chemie genetika MeSH
- Drosophila chemie MeSH
- endopeptidasy chemie genetika MeSH
- enzymatické testy MeSH
- Escherichia coli enzymologie MeSH
- inhibitory serinových proteinas chemická syntéza chemie MeSH
- katalytická doména MeSH
- lidé MeSH
- membránové proteiny antagonisté a inhibitory chemie genetika MeSH
- mutace MeSH
- objevování léků MeSH
- proteiny Drosophily metabolismus MeSH
- proteiny z Escherichia coli antagonisté a inhibitory chemie genetika MeSH
- serin chemie MeSH
- simulace molekulového dockingu MeSH
- skot MeSH
- styreny chemická syntéza chemie MeSH
- transformující růstový faktor alfa metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- skot MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The kinetics of the ozonation reaction of 1,1-diphenylethylene (DPE) on the surface of ice grains (also called "artificial snow"), produced by shock-freezing of DPE aqueous solutions or DPE vapor-deposition on pure ice grains, was studied in the temperature range of 268 to 188 K. A remarkable and unexpected increase in the apparent ozonation rates with decreasing temperature was evaluated using the Langmuir-Hinshelwood and Eley-Rideal kinetic models, and by estimating the apparent specific surface area of the ice grains. We suggest that an increase of the number of surface reactive sites, and possibly higher ozone uptake coefficients are responsible for the apparent rate acceleration of DPE ozonation at the air-ice interface at lower temperatures. The increasing number of reactive sites is probably related to the fact that organic molecules are displaced more to the top of a disordered interface (or quasi-liquid) layer on the ice surface, which makes them more accessible to the gas-phase reactants. The effect of NaCl as a cocontaminant on ozonation rates was also investigated. The environmental implications of this phenomenon for natural ice/snow are discussed. DPE was selected as an example of environmentally relevant species which can react with ozone. For typical atmospheric ozone concentrations in polar areas (20 ppbv), we estimated that its half-life on the ice surface would decrease from ∼5 days at 258 K to ∼13 h at 188 K at submonolayer DPE loadings.
We measured the kinetics of ozonation reaction of 1,1-diphenylethylene (DPE) in artificial snow, produced by shock freezing of DPE aqueous solutions sprayed into liquid nitrogen. It was demonstrated that most of the reactant molecules are in direct (productive) contact with gaseous ozone, thus the technique produces snow with organic molecules largely ejected to the surface of snow grains. The kinetic data were used to evaluate the snow specific surface area (∼70 cm(2) g(-1)). This number is a measure of the availability of the molecules on the surface for chemical reaction with gaseous species. The experimental results were consistent with the Langmuir-Hinshelwood type reaction mechanism. DPE represents environmentally relevant compounds such as alkenes which can react with atmospheric ozone, and are relatively abundant in natural snow. For typical atmospheric ozone concentrations in polar areas (20 ppbv), we estimated that half-life of DPE on the surface of snow grains is ∼5 days at submonolayer coverages and -15 °C.
- MeSH
- molekulární struktura MeSH
- ozon chemie MeSH
- sníh chemie MeSH
- styreny chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A new and diastereoselective method for the synthesis of the estrone skeleton from a substituted styrene based on sequential 3-fold use of Cp 2ZrBu 2 (oxidative addition-alkylation and two cyclization-alkylation sequences) and a ruthenium complex catalyzed RC-metathesis of a sterically hindered diene was developed. The prepared estratetraene was obtained in 7 steps from a commercially available starting material and thus the overall synthesis of estrone could be accomplished in 9 steps. Moreover, we have also found that the course of the reaction of substrates bearing the 2-halo-1,7-diene moiety with Cp 2ZrBu 2, i.e., cyclization or oxidative addition to the C-X bond, could be controlled by the nature of the halogen leaving group.
Cíl práce: Posouzení adsorpčních schopností přírodního aluminosilikátu vůči organickým látkám obsaženým v cigaretovém kouři s důrazem na toxické složky (formaldehyd a další aldehydy a ketony nikotin, aromatické sloučeniny a další škodliviny). Metodika: Cigaretový' kouř z hořící cigarety byl prosáván adsorpční trubicí naplněnou vzorkem testovaného aluminosilikátu a následně další adsorpční trubicí naplněnou speciálním adsorbentem ' n Tenax používaným ke kvantitativní adsorpci organických látek v analytice ovzduší. Organické látky zachycené v obou adsorpčních trubicích byly následně analyzovány na tandemu GC-MS. Porovnáním výsledků obou analýz byly stanoveny adsorpční schopnosti aluminosilikátu vůči jednodivým identifikovaným složkám cigaretového kouře. Adsorpce formaldehydu byla posouzena separátním pokusem. Ke kvantitativnímu záchytu formaldehydu byl místo Tenaxu použit silikagel impregnovaný roztokem 2,4-dinitrofenylhydrazinu. Výsledky: Bylo zjištěno, že aluminosilikát přírodního původu přednostně sorbuje z cigaretového kouře především organické látky polární povahy, nepolární látky se bud nesorbují vůbec, anebo jen částečně. Z technického hlediska je zajímavá především dobrá adsorpce formaldehydu, styrénu (karcinogenní látky) a nikotinu (didežitá součást cigaretového kouře). Závěr: Aluminosilikát přírodního původu může účinně sloužit v místnostech s vysokou koncentrací cigaretového kouře či jiných jedovatých látek (např. formaldehyd) ke snižování koncentrací těchto škodlivin.
Objective: The tests of adsorption properties of a natural alumosilicate lo the compounds contained in cigarette smoke with respect to toxic substances (formaldehyde and other aldehydes and ketones, nicotine, aromatic compounds, etc.). Methods: The cigarette smoke was flowed through an adsorption tube filled with the tested alumosilicate followed by an adsorption tube filled with a special adsorbent Tenax used for quantitative adsorption of organic compounds in analyzed atmosphere. The organic substances adsorbed in both adsorption lubes were consequendy analysed by GC-MS. The adsorption capability of the alumosilicate was estimated on the basis of the comparison of the obtained results. The adsorption of formaldehyde was estimated in the second test carried out separately. For the quantitative adst)rption of formaldehyde silicagel impregnated with 2,4-dinitrohydrazine was used. Results: The investigated natural alumosilicate adsorbs preferentially the polar organic compounds from the cigarette smoke, the nonpolar compounds being adsorbed only partially or not at all. From the technical point of wiew the good adsorption of formaldehyde and styrene (carcinogenic substances) as well as that of nicotine (singnificant component of the cigarette smoke) is interesting. Conclusion: The natural alumosilicate can be used in room with high concentration of cigarette smoke or other poisonous substances (e.g. formaldehyde) to reduce their concentrations.
