[Sanitary-toxicologic features of the joint action of a mixture of benzene and acetophenone vapors in the atmosphere].
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Acetaminophen↗
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Pharmacokinetics of 3-[bis(2-hydroxyethyl)amino]acetophenone [4,5-diphenyloxazolyl-(2)]hydrazone (ZIMET 98/69) in rats.
The pharmacokinetics of 3H-ZIMET 98/69 after i.v. and oral administration to rats was studied. After i.v. administration of 2.5 and 10 mg/kg a biphasic exponential decay of total serum radioactivity was found, so that a two compartment open model could be assumed. Oral administration of 10 mg/kg results only a moderate bioavailability (25%), which further decreased after administration of higher doses. The distribution steady state between serum and tissue is reached rapidly. Elimination proceeds slowly, the serum half-life being 64-84 h.
Administration, Oral↗
Pharmacokinetics of 3-[Bis(2-hydroxyethyl)amino]acetophenone-(4,5- diphenyloxazol-2-yl)hydrazone (ZIMET 98/69) in mice.
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Animals↗
Anaerobic degradation of ethylbenzene and toluene in denitrifying strain EbN1 proceeds via independent substrate-induced pathways.
Denitrifying strain EbN1 utilizes either ethylbenzene or toluene as the sole source of organic carbon under strictly anoxic conditions. When cells were grown on ethylbenzene, 1-phenylethanol and acetophenone were detected in the culture supernatant. However, these two compounds were not observed when cells were grown on benzoate. Growth on ethylbenzene, 1-phenylethanol, or acetophenone strictly depended on the presence of CO2, whereas growth on benzoate did not. These results suggest that strain EbN1 degrades ethylbenzene via 1-phenylethanol and acetophenone as intermediates, and that acetophenone is subsequently carboxylated. In suspensions of benzoate-grown cells, induction was required for degradation of ethylbenzene, 1-phenylethanol, and acetophenone. Induction was also required for toluene-grown cells to gain activity to degrade ethylbenzene, and, conversely, for ethylbenzene-grown cells to degrade toluene. In accordance with our findings from these studies, two-dimensional gel electrophoretic analysis of extracts of cells grown on benzoate, acetophenone, ethylbenzene, or toluene showed that a number of substrate-specific proteins were induced in strain EbN1. Growth on toluene or ethylbenzene induced a distinct set of proteins. However, some of the induced proteins in ethylbenzene or acetophenone grown cells were identical. This agrees with the finding that acetophenone is an intermediate in the degradation of ethylbenzene.
Acetophenones↗
Synthesis of compounds with antiproliferative activity as analogues of prenylated natural products existing in Brazilian propolis.
This work describes the syntheses and antitumoral properties of five prenyl compounds from which antiproliferative activities were predicted by using the TOPS-MODE approach, a computational method for drug design. The syntheses of 2-(3-methylbut-2-enyloxy)acetophenone (2), 2-hydroxy-5-(3-methylbut-2-enyl)acetophenone (3), 2-hydroxy-3-(1,1-dimethylallyl)acetophenone (4), and 5-(3-methylbut-2-enyl)-2-(3-methylbut-2-enyloxy)acetophenone (5) were realized by O-prenylation of phenolic compounds with prenyl bromide and by Claisen rearrangement, respectively. Reaction of 2-hydroxy-5-(3-methylbut-2-enyl)acetophenone 3 under Vilsmeier-Haack conditions with phosphoryl chloride and N,N-dimethylformamide yielded 6-(3-methylbut-2-enyl)chromone-3-carbaldehyde (6). The compounds were tested for their cytotoxicity toward a diverse panel of cultured human tumor cell lines. Compound 3 showed significant selective cytotoxic activity (IC(50) < 9 microg/ml).
Acetophenones↗
A new dual inhibitor of arachidonate metabolism isolated from Helichrysum italicum.
Six acetophenones (1-6) and one gamma-pyrone (7), previously isolated from Helichrysum italicum, were tested for their ability to inhibit enzymatic and non-enzymatic lipid peroxidation, the stable 1,1-diphenyl-2-pycryl-hydrazyl free radical, superoxide scavenging and arachidonic acid metabolism. In addition, they were studied in different experimental models such as the chronic inflammation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA), the phospholipase A(2)-induced mouse paw oedema test, the carrageenan-induced mouse paw oedema test, and the writhing induced by acetic acid in the mouse. Of the assayed compounds, only 1 inhibited enzymatic lipid peroxidation but had no effect on non-enzymatic lipid peroxidation. None of them scavenged the superoxide radical. Study of the inhibition of arachidonic acid metabolism demonstrated that 1 was an inhibitor of both cyclooxygenase and 5-lipoxygenase, whereas 2 was a selective inhibitor of 5-lipoxygenase. In the assay of phospholipase A(2)-induced mouse paw oedema, the gamma-pyrone derivative inhibited oedema formation, showing a similar profile to that obtained with cyproheptadine. The acetophenones were effective at 30 and 60 min. In the carrageenan test, acetophenone 1 gave the best results and had analgesic effects in the acetic acid writhing test. In conclusion acetophenone 1 (4-hydroxy-3-(3-methyl-2-butenyl)acetophenone) is a new dual inhibitor of arachidonate metabolism, and could be a useful tool for obtaining anti-inflammatory and analgesic drugs.
Acetophenones↗
Mechanism of the hydrogenation of ketones catalyzed by trans-dihydrido(diamine)ruthenium II complexes.
The complexes trans-RuH(Cl)(tmen)(R-binap) (1) and (OC-6-43)-RuH(Cl)(tmen)(PPh(3))(2) (2) are prepared by the reaction of the diamine NH(2)CMe(2)CMe(2)NH(2) (tmen) with RuH(Cl)(PPh(3))(R-binap) and RuH(Cl)(PPh(3))(3), respectively. Reaction of KHB(sec)Bu(3) with 1 yields trans-Ru(H)(2)(R-binap)(tmen) (5) while reaction of KHB(sec)Bu(3) or KO(t)Bu with 2 under Ar yields the new hydridoamido complex RuH(PPh(3))(2)(NH(2)CMe(2)CMe(2)NH) (4). Complex 4 has a distorted trigonal bipyramidal geometry with the amido nitrogen in the equatorial plane. Loss of H(2) from 5 results in the related complex RuH(R-binap)(NH(2)CMe(2)CMe(2)NH) (3). Reaction of H(2) with 4 yields the trans-dihydride (OC-6-22)-Ru(H)(2)(PPh(3))(2)(tmen)(6). Calculations support the assignment of the structures. The hydrogenation of acetophenone is catalyzed by 5 or 4 in benzene or 2-propanol without the need for added base. For 5 in benzene at 293 K over the ranges of concentrations [5] = 10(-)(4) to 10(-)(3) M, [ketone] = 0.1 to 0.5 M, and of pressures of H(2) = 8 to 23 atm, the rate law is rate = k[5][H(2)] with k = 3.3 M(-1) s(1), DeltaH++ = 8.5 +/- 0.5 kcal mol(-1), DeltaS++ = -28 +/- 2 cal mol(-1) K(-1). For 4 in benzene at 293 K over the ranges of concentrations [4] = 10(-4) to 10(-3) M, [ketone] 0.1 to 0.7 M, and of pressures of H(2) = 1 to 6 atm, the preliminary rate law is rate = k[4][H(2)] with k = 1.1 x 10(2) M(-1) s(-1), DeltaH++ = 7.6 +/- 0.3 kcal mol(-1), DeltaS++ = -23 +/- 1 cal mol(-1) K(-1). Both theory and experiment suggest that the intramolecular heterolytic splitting of dihydrogen across the polar Ru=N bond of the amido complexes 3 and 4 is the turn-over limiting step. A transition state structure and reaction energy profile is calculated. The transfer of H(delta+)/H(delta-) to the ketone from the RuH and NH groups of 5 in a Noyori metal-ligand bifunctional mechanism is a fast process and it sets the chirality as (R)-1-phenylethanol (62-68% ee) in the hydrogenation of acetophenone. The rate of hydrogenation of acetophenone catalyzed by 5 is slower and the ee of the product is low (14% S) when 2-propanol is used as the solvent, but both the rate and ee (up to 55% R) increase when excess KO(t)Bu is added. The formation of ruthenium alkoxide complexes in 2-propanol might explain these observations. Alkoxide complexes [RuP(2)]H(OR)(tmen), [RuP(2)] = Ru(R-binap) or Ru(PPh(3))(2), R= (i) Pr, CHPhMe, (t)Bu, are observed by reacting the alcohols (i)PrOH, phenylethanol, and (t)BuOH with the dihydrides 5 and 6, respectively, under Ar. In the absence of H(2), the amido complexes 3 and 4 react with acetophenone to give the ketone adducts [RuP(2)]H(O=CPhMe)(NH(2)CMe(2)CMe(2)NH) in equilibrium with the enolate complexes trans- [RuP(2)](H)(OCPh=CH(2))(tmen) and eventually the decomposition products [RuP(2)]H(eta(5)-CH(2)CPhCHCPhO), with the binap complex characterized crystallographically. In general, proton transfer from the weakly acidic molecules dihydrogen, alcohol, or acetophenone to the amido nitrogen of complexes 3 and 4 is favored in two ways when the molecule coordinates to ruthenium: (1) an increase in acidity of the molecule by the Lewis acidic metal and (2) an increase in the basicity of the amido nitrogen caused by its pyramidalization. The formato complexes trans-[RuP(2)]H(OCHO)(tmen) were prepared by reacting the respective complex 4 or 5 with formic acid. The crystal structure of RuH(OCHO)(PPh(3))(2)(tmen) displays similar features to the calculated transition state for H(delta+)/H(delta-) transfer to the ketone in the catalytic cycle.
Journal Article↗
Kinetic modeling of omega-transamination for enzymatic kinetic resolution of alpha-methylbenzylamine.
A kinetic model for omega-transaminase from Bacillus thuringiensis JS64 was developed by using the King-Altman method to simulate the kinetic resolution of alpha-methylbenzylamine (alpha-MBA). Starting from a ping-pong bi-bi mechanism, a complete kinetic model including substrate inhibition only in the reverse reaction (i.e., transamination between acetophenone and L-alanine) was developed. The asymmetric synthesis of (S)-alpha-MBA proved to be difficult due to a much lower maximum reverse reaction rate than the maximum forward reaction rate, thermodynamically exergonic forward reaction (i.e., transamination between (S)-alpha-MBA and pyruvate), and the severe product and substrate inhibition of the reverse reaction. Experimental values for kinetic parameters show that the product inhibition constant of (S)-alpha-MBA is the most important parameter on determining the resolution reaction rate, suggesting that the resolution reaction rate will be very low unless (S)-alpha-MBA strongly inhibits the reverse reaction. Using the kinetic model, the kinetic resolution of alpha-MBA in aqueous buffer was simulated, and the simulation results showed a high degree of consistency with experimental data over a range of reaction conditions. Various simulation results suggest that the crucial bottleneck in the kinetic resolution of alpha-MBA lies mainly in the accumulation of acetophenone in reaction media as the reaction proceeds, whereas L-alanine exerts a little inhibitory effect on the reaction. The model predicts that removing acetophenone produced during the reaction can enhance the reaction rate dramatically. Indeed, the biphasic reaction system is capable of extracting acetophenone from the aqueous phase, showing a much higher reaction rate compared to a monophasic reaction system. The kinetic model was also useful in predicting the properties of other, better enzymes as well as the optimal concentrations of amino acceptor and enzyme in the resolution reaction.
Acetophenones↗
Phenolic and terpenoid compounds from Chione venosa (sw.) urban var. venosa (Bois Bandé).
The Caribbean island of Grenada furnishes the popular aphrodisiac drug Bois Bandé, which consists of the stem bark and the roots of Chione venosa (sw.) URBAN var. venosa (Rubiaceae), a native tree growing in the islands' rain forest. The phytochemical investigation of dichloromethane and methanolic-aqueous extracts of the bark and the roots yielded three acetophenone derivatives described for the first time in plants - ortho-hydroxy-acetophenone-azine (1), acetophenone-2-O-[beta-D-apiofuranosyl-(1''-->6')-O-beta-D-glucopyranoside] (2) and acetophenone-2-O-beta-D-glucopyranoside (3) - along with five known compounds, alpha-morroniside (4), sweroside (5), diderroside (6), daucosterol (7) and beta-sitosterol (8). Their structures were elucidated by 1D and 2D NMR analysis, UV-Vis and ESI-MS.
Acetophenones↗
A succession of isomers of ruthenium dihydride complexes. Which one is the ketone hydrogenation catalyst?
Reaction of RuHCl(PPh(3))(2)(diamine) (1a, diamine = (R,R)-1,2-diaminocyclohexane, (R,R)-dach; 1b, diamine = ethylenediamine, en) with KO(t)Bu in benzene quickly generates solutions of the amido-amine complexes RuH(PPh(3))(2)(NHC(6)H(10)NH(2)), (2a'), and RuH(PPh(3))(2)(NHCH(2)CH(2)NH(2)), (2b'), respectively. These solutions react with dihydrogen to first produce the trans-dihydrides (OC-6-22)-Ru(H)(2)(PPh(3))(2)(diamine) (t,c-3a, t,c-3b). Cold solutions (-20 degrees C) containing trans-dihydride t,c-3a react with acetophenone under Ar to give (S)-1-phenylethanol (63% ee). Complexes t,c-3 have lifetimes of less than 10 min at 20 degrees and then isomerize to the cis-dihydride, cis-bisphosphine isomers (OC-6-32)-Ru(H)(2)(PPh(3))(2)(diamine) (Delta/Lambda-c,c-3a, c,c-3b). A solution containing mainly Delta/Lambda-c,c-3a reacts with acetophenone under Ar to give (S)-1-phenylethanol in 20% ee, whereas it is an active precatalyst for its hydrogenation under 5 atm H(2) to give 1-phenylethanol with an ee of 50-60%. Complexes c,c-3 isomerize to the cis-dihydride, trans-bisphosphine complexes (OC-6-13)-Ru(H)(2)(PPh(3))(2)(diamine) (c,t-3a, c,t-3b) with half-lives of 40 min and 1 h, respectively. A mixture of Delta/Lambda-c,c-3a and c,t-3a can also be obtained by reaction of 1a with KBH(Bu(sec))(3). A solution of complex c,t-3a in benzene under Ar reacts very slowly with acetophenone. These results indicate that the trans-dihydrides t,c-3a or t,c-3b along with the corresponding amido-amine complexes 2a' or 2b' are the active hydrogenation catalysts in benzene, while the cis-dihydrides c,c-3a or c,c-3b serve as precatalysts. The complexes RuCl(2)(PPh(3))(2)((R,R)-dach) or 1a, when activated by KO(t)Bu, are also sources of the active catalysts. A study of the kinetics of the hydrogenation of acetophenone in benzene catalyzed by 3a indicates a rate law: rate = k[c,c-3a](initial)[H(2)] with k = 7.5 M(-1) s(-1). The turnover-limiting step appears to be the reaction of 2a' with dihydrogen as it is for RuH(NHCMe(2)CMe(2)NH(2))(PPh(3))(2) (2c'). The catalysts are more active in 2-propanol, even without added base, and the kinetic behavior is complicated. The basic cis-dihydride c,t-3a reacts with [NEt(3)H]BPh(4) to produce the dihydrogen complex (OC-14)-[Ru(eta(2)-H(2))(H)(PPh(3))(2)((R,R)-dach)]BPh(4) (4) and with diphenylphosphinic acid to give the complex RuH(O(2)PPh(2))(PPh(3))(2)((R,R)-dach) (5). The structure of 5 models aspects of the transition state structure for the ketone hydrogenation step. Complex 2b' decomposes rapidly under Ar to give dihydrides 3b along with a dinuclear complex (PPh(3))(2)HRu(mu-eta(2);eta(4)-NHCHCHNH)RuH(PPh(3))(2) (6) containing a rare, bridging 1,4-diazabutadiene group. The formation of an imine by beta-hydride elimination from the amido-amine ligand of 2a' under Ar might explain some loss of enantioselectivity of the catalyst. The structures of complexes 1a, 5, and 6 have been determined by single-crystal X-ray diffraction.
Journal Article↗
Infrared spectroscopy of gas-phase Cr+ coordination complexes: determination of binding sites and electronic states.
Infrared spectra were recorded for a series of gas-phase Cr+ complexes using infrared multiphoton dissociation (IRMPD) in a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. The functionalized aromatic ligands (acetophenone, anisole, aniline, and dimethyl aniline) offer a choice of either aromatic ring-pi or n-donor-base binding sites. Use of the FELIX free electron laser light source allowed convenient, rapid scanning of the chemically informative wavelength range from approximately 500 to 1800 cm(-1), which in many cases characterized the preferred site of metal binding, as well as the electronic spin state of the complex. Mono-complex ions, Cr+(ligand), for anisole, aniline, and dimethyl aniline and bis-complex ions, Cr+(ligand)(2), for anisole, aniline, and acetophenone were produced by ligand attachment to laser-desorbed Cr+ ions in the FT-ICR cell. The photodissociation yields plotted as a function of wavelength were interpreted as approximations to the infrared absorption spectra and were compared with computed spectra of different possible geometries and spin states. Clear-cut diagnostic features in the spectra of the acetophenone, anisole, and aniline complexes showed the sites of Cr+ attachment to be the carbonyl oxygen site for acetophenone (bis-complex) and the ring-pi site for anisole and aniline (both mono- and bis-complexes). The bis-complexes of aniline and anisole are low-spin (probably doublet) states, while the mono-complexes of these same ligands are high-spin (sextet) states. The dimethyl aniline complex gave a cluttered spectrum in poor agreement with calculations, which may reflect a mixture of binding-site isomers in this case.
Journal Article↗
Synthesis of functional aromatic multisulfonyl chlorides and their masked precursors.
The synthesis of functional aromatic bis(sulfonyl chlorides) containing an acetophenone and two sulfonyl chloride groups, i.e., 3,5-bis[4-(chlorosulfonyl)phenyl]-1-acetophenone (16), 3,5-bis(chlorosulfonyl)-1-acetophenone (17), and 3,5-bis(4-(chlorosulfonyl)phenyloxy)-1-acetophenone (18) via a sequence of reactions, involving in the last step the quantitative oxidative chlorination of S-(aryl)- N,N'-diethylthiocarbamate, alkyl- or benzyl thiophenyl groups as masked nonreactive precursors to sulfonyl chlorides is described. A related sequence of reactions was used for the synthesis of the aromatic trisulfonyl chloride 1,1,1-tris(4-chlorosulfonylphenyl)ethane (24). 4-(Chlorosulfonyl)phenoxyacetic acid, 2,2-bis[[[4-(chlorosulfonyl)phenoxyacetyl]oxy]methyl]-1,3-propanediyl ester (27), 5,11,17,23-tetrakis(chlorosulfonyl)-25,26,27,28-tetrakis(ethoxycarbonylmethoxy)calix[4]arene (38), 5,11,17,23,29,35-hexakis(chlorosulfonyl)-37,38,39,40,41,42-hexakis(ethoxycarbonylmethoxy)calix[6]arene (39), 5,11,17,23,29,35,41,47-octakis(chlorosulfonyl)-49,50,51,52,53,54,55,56-octakis(ethoxycarbonylmethoxy)calix[8]arene (40), 5,11,17,23-tetrakis(tert-butyl)-25,26,27,28-tetrakis(chlorosulfonyl phenoxyacetoxy)calix[4]arene (44), 5,11,17,23,29,35-hexakis(tert-butyl)-37,38,39,40,41,42-hexakis(chlorosulfonylphenoxyacetoxy)calix[6]arene (45), and 5,11,17,23,29,35,41,47-octakis(tert-butyl)-49,40,51,52,53,54,55,56-octakis(chlorosulfonylphenoxyacetoxy)calix[8]arene (46) were synthesized by two different multistep reaction procedures, the last step of both methods consisting of the chlorosulfonation of compounds containing suitable activated aromatic positions. 2,4,6-Tris(chlorosulfonyl)aniline (47) was obtained by the chlorosulfonation of aniline. The conformation of two series of multisulfonyl chlorides i.e., 38, 39, 40 and 44, 45, 46, was investigated by (1)H NMR spectroscopy. The masked nonreactive precursor states of the functional aromatic multisulfonyl chlorides and the aromatic multisulfonyl chlorides reported here represent the main starting building blocks required in a new synthetic strategy elaborated for the preparation of dendritic and other complex organic molecules.
Journal Article↗
Electrophysiological and behavioral responses of Dendroctonus frontalis (Coleoptera: Curculionidae) to volatiles isolated from conspecifics.
Olfactory sensitivity of the southern pine beetle, Dendroctonus frontalis Zimmermann, to compounds isolated from the mid/hindguts of newly emerged conspecific adults was assayed with coupled gas chromatography-electroantennographic detection. All previously reported pheromones for D. frontalis plus eight additional compounds (fenchyl alcohol, myrtenal, cis-verbenol, trans-pinocarveol, acetophenone, trans-myrtanol, cis-myrtanol, and 2-phenylethanol) consistently elicited antennal responses from at least one sex. The eight additional compounds were assayed individually at three release rates (0.4-0.8, 3-9, and 25-100 mg/d) for the ability to alter D. frontalis responses to traps baited with D. frontalis attractant (4 mg/d frontalin and 17 mg/d alpha-pinene). At the high release rate, cis-verbenol enhanced attraction of D. frontalis females, whereas the other seven compounds significantly reduced attraction of one or both sexes. Acetophenone significantly reduced attraction of male D. frontalis at the low release rate, and five compounds (fenchyl alcohol, trans-pinocarveol, acetophenone, cis-myrtanol, and 2-phenylethanol) reduced attraction of one or both sexes at the intermediate rate. Only acetophenone significantly altered the sex ratio of beetles trapped, decreasing the proportion of males. Attraction of predatory checkered beetles (Cleridae) was enhanced by cis-verbenol released at the high rate but was not altered by any compound inhibitory to D. frontalis. Analyses of volatiles from individual D. frontalis indicated that the majority of the eight compounds were produced in greater quantities by newly emerged beetles than ones attacking pine bolts. Five of the compounds were associated predominantly with one sex. Possible ecological roles of these compounds in the biology of D. frontalis are discussed.
Animals↗
Synthetic and biological activity evaluation studies on novel 1,3-diarylpropenones.
Fourteen novel C-prenylated and O-allylated 1,3-diarylpropenones (chalcones) were synthesized by Claisen-Schmidt condensation reaction of C-prenylated/O-allylated acetophenones with appropriate aldehydes; twelve of these model chalcones were screened in an assay based on the confrontation of invasive human MCF-7/6 mammary carcinoma cells with fragments of normal embryonic chick heart in vitro. Out of the twelve chalcones tested, three were found to exhibit potent anti-invasive activity. Some of these chalcones and their precursor acetophenones were also tested for inhibition of initiation of lipid peroxidation in rat liver microsomes; a prenylated acetophenone carrying two methoxy groups and two free phenolic hydroxy functions was found to be a potential antioxidant.
Acetophenones↗
Mechanistic study of beta-substituent effects on the mechanism of ketone reduction by SmI(2).
The rate constants for the reduction of 2-butanone, methylacetoacetate, N, N-dimethylacetoacetamide, and a series of 4'- and 2'-substituted acetophenone derivatives by SmI(2) were determined in dry THF using stopped-flow absorption decay experiments. Activation parameters for the electron-transfer processes in each series of compounds were determined by a temperature-dependence study over a range of 30 to 50 degrees C. Two types of reaction pathways are possible for these electron-transfer processes. One proceeds through coordination (Scheme 1) while the other involves chelation (Scheme 2). The results described herein unequivocally show that both coordination and chelation provide highly ordered transition states for the electron-transfer process but the presence of a chelation pathway dramatically increases the rate of the reduction of these substrates by SmI(2). The ability of various functional groups to promote a chelated reaction pathway plays a crucial role in determining the rate of the reaction. Among the 2'-substituted acetophenone series, the presence of a fluoro, amino, or methoxy substituent enhances the rate of reduction compared to the 4'-analogues. In particular, the presence of a 2'-fluoro substituent on acetophenone provides a highly ordered transition state and considerably enhances the rate of ketone reduction.
Acetophenones↗
Combinatorial synthesis and antibacterial evaluation of an indexed chalcone library.
A 120-membered chalcone library has been designed and prepared from six differently substituted acetophenones (A1-A6) and 20 benzaldehydes (B1-B20). The library was subjected to biological studies targeted against six bacterial strains. For the identification of the most-active member(s) of the library, the so-called indexed or positional-scanning method was applied. Six out of 26 sub-libraries, i.e., AL1-AL6, were synthesized by keeping the acetophenone moiety A fixed and using equimolar quantities of the 20 different benzaldehydes. The remaining 20 sub-libraries BL1-BL20 were prepared by keeping the benzaldehyde B component fixed and varying the six acetophenones (Table 1). The bactericidal activities of the resulting sub-libraries were tested and used as indices to the rows or columns of a two-dimensional matrix. Finally, parallel synthesis of 24 specific members with the highest-expected antibacterial activities, present in two sub-libraries, was carried out. These chalcones were screened again, and the results were exploited for establishing the structure-activity relationship (SAR) and the identification of the lead compound, which turned out to be 1,3-bis(2-hydroxyphenyl)prop-2-en-1-one (A2B2) in terms of activity towards Staphylococcus aureus and Bacillus subtilis (Tables 5-7).
Anti-Bacterial Agents↗
Designing the "search pathway" in the development of a new class of highly efficient stereoselective hydrosilylation catalysts.
The direct coupling of oxazolines and N-heterocyclic carbenes leads to chelating C,N ancillary ligands for asymmetric catalysis that combine both an "anchor" unit and a stereodirecting element. Reacting various N-substituted imidazoles with 2-bromo-4(S)-tert-butyl- and 2-bromo-4(S)-isopropyloxazoline gave the imidazolium precursors of the stereodirecting ancillary ligands. A library of ten different ligand precursors was obtained by using this simple procedure (65-97 % yield). These protioligands were metalated in a subsequent step by reaction with [{Rh(mu-OtBu)(nbd)}2] (nbd=norbornadiene), generated in situ from KOtBu and [{RhCl(nbd)}2] giving the corresponding N-heterocyclic carbene complexes [RhBr(nbd)(oxazolinyl-carbene)] 4 a-j in good yields. X-ray diffraction studies of two of the rhodium complexes, 4 d and 4 j, established a distorted square-pyramidal coordination geometry with the bromo ligand occupying the apical position. The rhodium-carbene bond length was found to be 2.070(4) A (4 d) and 2.012(3) A (4 j). Complexes 4 a-j were treated with AgBF4 in dichloromethane, giving the active cationic square-planar catalysts for the hydrosilylation of ketones. As a reference reaction for the catalyst optimisation, the hydrosilylation of acetophenone with diphenylsilane was studied and the system optimised with respect to the counterion (BF(4) (-)), solvent (THF) and the silane reducing agent (diphenylsilane). The reaction product (1-phenylethanol) was obtained with the highest enantiomeric excess (ee) by carrying out the reaction at -60 degrees C, whilst the enantioselectivity drops upon going both to lower and higher temperatures. The observation that the temperature dependence of the ee values goes through a maximum indicated a change in the rate-determining step as the temperature is varied. The determination of the initial reaction rate in the hydrosilylation of acetophenone upon varying the catalyst (4 d) and substrate concentrations at -55 degrees C established a rate law for the initial conversion which is first-order in both substrates as well as the catalyst (Vi = k[4][PhCOMe][Ph2SiH2]). The catalytic system derived from complex 4 d was found to afford high yields and good enantioselectivities in the reduction of various aryl alkyl ketones (acetophenone: 92 % isolated yield and 90 % ee, 2-naphtyl methyl ketone: 99 % yield, 91 % ee). The selectivity for the reduction of prochiral dialkyl ketones is comparable or even superior to the best previously reported for prochiral nonaromatic ketones; whereas cyclopropyl methyl ketone is hydrosilylated with an enantioselectivity of 81 % ee, the increase of the steric demand of one of the alkyl groups leads to improved ee's, reaching 95 % ee in the case of tert-butyl methyl ketone. Linear chain n-alkyl methyl ketones, which are particularly challenging substrates, are reduced in good asymmetric induction, such as 2-octanone (79 % ee) and even 2-butanone (65 % ee).
Journal Article↗
Genes involved in the anaerobic degradation of ethylbenzene in a denitrifying bacterium, strain EbN1.
Genes involved in anaerobic degradation of the petroleum hydrocarbon ethylbenzene in the denitrifying Azoarcus-like strain EbN1 were identified on a 56-kb DNA contig obtained from shotgun sequencing. Ethylbenzene is first oxidized via ethylbenzene dehydrogenase to (S)-1-phenylethanol; this is converted by (S)-1-phenylethanol dehydrogenase to acetophenone. Further degradation probably involves acetophenone carboxylase forming benzoylacetate, a ligase forming benzoylacetyl-CoA, and a thiolase forming acetyl-CoA and benzoyl-CoA. Genes of this pathway were identified via N-terminal sequences of proteins isolated from strain EbN1 and by sequence similarities to proteins from other bacteria. Ethylbenzene dehydrogenase is encoded by three genes (ebdABC), in accordance with the heterotrimeric enzyme structure. Binding domains for a molybdenum cofactor (in subunit EbdA) and iron/sulfur-clusters (in subunits EbdA and EbdB) were identified. The previously observed periplasmic location of the enzyme was corroborated by the presence of a twin-arginine leader peptide characteristic of the Tat system for protein export. A fourth gene (ebdD) was identified, the product of which may act as an enzyme-specific chaperone in the maturation of the molybdenum-containing subunit. A distinct gene (ped) coding for (S)-1-phenylethanol dehydrogenase apparently forms an operon with the ebdABCD genes. The ped gene product with its characteristic NAD(P)-binding motif in the N-terminal domain belongs to the short-chain dehydrogenase/reductase (SDR) superfamily. A further operon apparently contains five genes (apc1-5) suggested to code for subunits of acetophenone carboxylase. Four of the five gene products are similar to subunits of acetone carboxylase from Xanthobacter autotrophicus. Upstream of the apc genes, a single gene (bal) was identified which possibly codes for a benzoylacetate CoA-ligase and which is co-transcribed with the apc genes. In addition, an apparent operon containing almost all genes required for beta-oxidation of fatty acids was detected; one of the gene products may be involved in thiolytic cleavage of benzoylacetyl-CoA. The DNA fragment also included genes for regulatory systems; these were two sets of two-component systems, two LysR homologs, and a TetR homolog. Some of these proteins may be involved in ethylbenzene-dependent gene expression.
Amino Acid Sequence↗