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Transparent yttrium aluminium garnet (YAG) polycrystal can be used as a host material for a solid state laser. In the present study, the authors prepared completely transparent YAG ceramics from active powder. The optical and mechanical properties of YAG ceramics are very sensitive to point defects. In order to examine the relationship between these properties and point defects, it is first necessary to characterise the defects. The authors report the effect of doping on oxygen diffusivity in several YAG ceramics, doped with various elements. Although Nd doping slightly increases the oxygen diffusion coefficient and the number of oxygen vacancies increases with increasing Nd concentration in as sintered materials, the variation of the oxygen diffusion coefficient in well annealed samples is small. These results suggest that the oxygen vacancies exist in non-equilibrium. However, grain boundary diffusivity was not influenced by preannealing before the oxygen diffusion experiments. The oxygen defec...

(+/-)-7beta,8alpha-Dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (DE-1) undergoes reaction with anhydrous HCl in dioxane to yield predominantly ( approximately 94%) a single chlorohydrin. This chlorohydrin was assigned structure 9, in which the chloro goup at C-10 is located cis to the C-9 hydroxyl group, on the basis of its (1)H NMR spectrum. This result is in contrast to the reaction of a diastereomeric benzo[a]pyrene 7,8-diol 9,10-epoxide (DE-2) with HCl, which yields only trans-chlorohydrin 8. The hydrolysis of cis-chlorohydrin 9 in 10:90 dioxane-water solutions yields the same ratio of tetrols ( approximately 89% cis/11% trans) as that formed by acid-catalyzed hydrolysis of DE-1. This result again contrasts with the hydrolysis of trans-chlorohydrin 8, which undergoes hydrolysis to give tetrols in a ratio different from that from acid-catalyzed hydrolysis of DE-2. A marked common ion rate depression in the hydrolysis of cis-chlorohydrin 9 is observed, which shows that hydrolysis proceeds via an intermediate carbocation that has a sufficient lifetime to be trapped by external chloride ion. The observation that DE-1 reacts with HCl to give mainly the cis-chlorohydrin is rationalized by quantum chemical calculations that suggest that the cis-chlorohydrin is more stable than the epimeric trans-chlorohydrin.

Novel benzazepine oxazolidinone antibacterials were synthesized and evaluated against clinically relevant susceptible and resistant organisms. The effect of ring nitrogen position and N-substitution on antibacterial activity is examined.

A new and promising group of antibacterial agents, collectively known as the oxazolidinones and exemplified by linezolid (PNU-100766, marketed as Zyvox), have recently emerged as important new therapeutic agents for the treatment of infections caused by Gram-positive bacteria. Because of their significance, extensive synthetic investigations into the structure-activity relationships of the oxazolidinones have been conducted at Pharmacia. One facet of this research effort has focused on the identification of bioisosteric replacements for the usual oxazolidinone A-ring. In this paper we describe studies leading to the identification of antibacterial agents incorporating a novel isoxazoline A-ring surrogate. In a gratifying result, the initial isoxazoline analogue prepared was found to exhibit in vitro antibacterial activity approaching that of the corresponding oxazolidinone progenitor. The synthesis and antibacterial activity profile of a preliminary series of isoxazoline analogues incorporating either a C-C or N-C linkage between their B- and C-rings will be presented. Many of the analogues exhibited interesting levels of antibacterial activity. The piperazine derivative 54 displayed especially promising in vitro activity and in vivo efficacy comparable to the activity and efficacy of linezolid.

The electrode properties of manganese dioxides prepared by the reduction with various reagents were examined. The particle size and morphology depended on reducing agents. Some samples obtained were aggregated round particles of submicron order and the others were fine needle-like shape of a few nanometers in width and several tens of nanometers in length. The former showed around 200 mA h/g, while the later showed high capacity of 500 mA h/g in the open circuit voltage (OCV) measurements until 1 V (vs. Li). The cell assembled with Li anode showed a good cycle performance in the range of 3.9–2.0 V with a capacity of 150 mA h/g.

Important resistance patterns in Gram-negative pathogens include active efflux of antibiotics out of the cell via a cellular pump and decreased membrane permeability. A 3-arylpiperidine derivative (1) has been identified by high-throughput assay as a potentiator with an IC(50) approximately 90 microM. This report details the evaluation of the tether length, aryl substitution and the importance of the fluorine on antibiotic accumulation. Evaluation of various tether lengths demonstrated that the two-carbon tethered analogues are optimal. Removal of the fluorine has a modest effect on antibiotic accumulation and the defluorinated analogue 17 is equally potent to the original lead 1.

The rates and products of the reactions of (+/-)-7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (1) and (+/-)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (2) in water and dioxane-water mixtures have been determined over a pH range wider than that of earlier studies. This study provides additional insight on the mechanisms of the pH-independent reactions of 1 and 2. The rate profile for reaction of 1 shows acid-catalyzed hydrolysis at pH5, a rate plateau at pH 5-9.5, a negative inflection at pH 10-11.5, and a rate increase at pH11.5. The rate decrease between pH 10 and pH 11.5 is accompanied by a decrease in the yield of tetrols from 60% (pH 8) to 29% (pH 11.2) and is interpreted to be the result of a partial change in mechanism brought about by attack of hydroxide ion acting as a base to deprotonate a carbocation intermediate and regenerate 1 at pH10, thus reducing the contribution of the pathway for tetrol formation in which water attacks the carbocation. The rate profile for the reaction of 2 exhibits only a single rate plateau at intermediate pH, along with increases in rate at low and high pH because of second-order reactions of 2 with H+ and HO-, respectively. The lack of a rate depression at pH10 and the product studies for the reaction of 2 in dilute sodium azide solutions suggest that the tetrol-forming reactions of the pH-independent reaction of 2 are concerted or near-concerted.

A series of new nitrogen-carbon-linked (azolylphenyl)oxazolidinone antibacterial agents has been prepared in an effort to expand the spectrum of activity of this class of antibiotics to include Gram-negative organisms. Pyrrole, pyrazole, imidazole, triazole, and tetrazole moieties have been used to replace the morpholine ring of linezolid (2). These changes resulted in the preparation of compounds with good activity against the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. The unsubstituted pyrrolyl analogue 3 and the 1H-1,2,3-triazolyl analogue 6 have MICs against H. influenzae = 4 microgram/mL and M. catarrhalis = 2 microgram/mL. Various substituents were also placed on the azole moieties in order to study their effects on antibacterial activity in vitro and in vivo. Interesting differences in activity were observed for many analogues that cannot be rationalized solely on the basis of sterics and position/number of nitrogen atoms in the azole ring. Differences in activity rely strongly on subtle changes in the electronic character of the overall azole systems. Aldehyde, aldoxime, and cyano azoles generally led to dramatic improvements in activity against both Gram-positive and Gram-negative bacteria relative to unsubstituted counterparts. However, amide, ester, amino, hydroxy, alkoxy, and alkyl substituents resulted in no improvement or a loss in antibacterial activity. The placement of a cyano moiety on the azole often generates analogues with interesting antibacterial activity in vitro and in vivo. In particular, the 3-cyanopyrrole, 4-cyanopyrazole, and 4-cyano-1H-1,2,3-triazole congeners 28, 50, and 90 had S. aureus MICs

Rates of reaction of (+/-)-7beta,8alpha-dihydroxy-9alpha, 10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (DE-2) have been determined in 1:9 dioxane-water solutions containing 1.0 M KCl, 0.5 M KBr, and 0.1 M NaI over the pH range 4-13. These pH-rate profiles are more complicated than those for reaction of DE-2 in 0.2 M NaClO4 solutions and are interpreted in part by mechanisms in which halide ion attacks the diol epoxide as a nucleophile at intermediate pH, resulting in the formation of a trans-halohydrin. Reaction of DE-2 in these halide solutions at pH 12, the rate of reaction of DE-2 increases due to a second-order reaction of HO- with DE-2.

The rates of reaction of (±)-7β,8α-Dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (1) in 1:9 dioxane−water buffer solutions containing primary amines whose pKa values span the range of 5.4−10.7 have been determined. For those amines with pKa values ca. 8, both acid and base forms of the buffer react with 1. The magnitude of the kinetic term in the base form of the amine (RNH2) increases with amine pKa and is attributed to nucleophilic addition of the amine to the epoxide group. Curvatures in plots of the kinetic term due to buffer (kbuff)...

Linezolid (formerly U-100766) and eperezolid (formerly U-100592) are novel oxazolidinone antimicrobial agents that are active against multi-drug-resistant staphylococci, streptococci, enterococci, corynebacteria, and mycobacteria. Preliminary studies also demonstrated that the compounds inhibited some test strains of anaerobic bacteria. Therefore, we extended the in vitro evaluation of these agents to include a total of 54 different anaerobic species. Minimal inhibitory concentration (MIC) values were determined using a standard agar dilution method for 143 anaerobic bacterial isolates. Eperezolid and linezolid demonstrated potent activity against the anaerobic Gram-positive organisms with most MIC values in the range of 0.25-4 microg/mL. Viridans streptococci demonstrated MICs of 1-2 microg/mL; Peptostreptococcus species and Propionibacterium species were inhibited by

Various electron-withdrawing groups were incorporated into the meta position of tropone-substituted 3-phenyl-2-oxazolidinones and their influence on antibacterial activity examined. Consideration of in vitro and in vivo test results indicated that one or two fluorine atoms flanking the para tropone appendage is the optimum arrangement for these compounds. Synthetic routes to enantiomerically enriched analogues are reported.

The compatibility of NiSi in the self-aligned suicide (SALICIDE) process has been investigated for deep submicrometer device applications. In the SALICIDE process, the suicide formation should be laterally confined to the Si regions as source drain and gate regions of a metaloxide semiconductor field effect transistor. It has been found that the NiSi produced by a one-step thermal annealing is confined laterally to the Si regions. The thin NiSi layer having a thickness of 26.7 nm has the sheet resistance of 6.2 Ω/ω The minimum value 6.2 Ω/ω is achieved by the silicidation in the temperature range of 400–500 °C. A thickness dependence of electrical resistivity has been observed on NiSi layers thinner than 53.3 nm thick. The resistivity increases gradually with decreasing thickness. The NiSi layers thicker than 53.3 nm thick have a resistivity of 13.7 μΩ cm comparable with that of bulk NiSi. No linewidth dependence of sheet resistance was observed. The 42.0 nm thick silicide on poly-Si having line widths from 0.2 to 16.0 μm have a sheet resistance of 3.2 Ω/ω The thin suicides must be thermally stable through subsequent device processing. Silicide agglomeration has been observed after heat treatments of 600 °C. The silicide agglomeration results in an increase of the sheet resistance. However, the device processing after the formation of NiSi can be performed with temperatures lower than 600 °C. A few of the junctions silicided by using NiSi have a leakage current larger than that of the non-silicided junctions. This problem can be solved if a thermal annealing is done at 450 °C in H 2 -N 2 before the Ni deposition. This result suggests that the annealing in H 2 -N 2 acts effectively in order to prevent extra generation centers created in the depletion layer during the silicidation.

High-average-power laser is widely used for material processing, development of lithography source and many scientific researches and so on. As there are so many applications of high power lasers, the demands for more powerful laser are growing rapidly. A Faraday element is one of the indispensable optical elements for isolation of laser amplifiers and birefringence compensation of laser materials in such two-pass high-power laser systems. The single crystal TGG(terbium gallium garnet) grown by the Czochralski method takes a long time to grow, and is difficult to make large-size crystals. Ceramic TGG [1, 2] are attractive for actual applications because of low fabrication cost in mass production and short fabrication time. The mechanical properties of ceramic are generally better than those of single crystal because the polycrystalline ceramics are aggregates of crystalline grains. External force is dissipated in ceramics because of random orientation of the grains. Therefore, the fracture toughness of ceramics TGG is larger than that of single crystal TGG. It is also expected that the thermal fracture limit of ceramic TGG is larger than that of single crystal.

Important resistance patterns in Gram-negative pathogens include active efflux of antibiotics out of the cell via a cellular pump and decreased membrane permeability. A 3-arylpiperidine derivative (1) has been identified by high-throughput assay as a potentiator with an IC50 ∼90 μM. This report details the evaluation of the tether length, aryl substitution and the importance of the fluorine on antibiotic accumulation. Evaluation of various tether lengths demonstrated that the two-carbon tethered analogues are optimal. Removal of the fluorine has a modest effect on antibiotic accumulation and the defluorinated analogue 17 is equally potent to the original lead 1.

Mutations in the coding region of the hypoxanthine (guanine) phosphoribosyltransferase (HPRT) gene of Chinese hamster V-79 cells were examined after exposure of the cells to a high cytotoxic dose (0.48 microM; 35% survival) and a low noncytotoxic dose (0.04 microM; 100% survival) of the ultimate carcinogen (+)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-BPDE]. Independent 8-azaguanine-resistant colonies were isolated and cDNAs were prepared by reverse transcription. The coding region of the cDNA of the HPRT gene was amplified by the polymerase chain reaction and sequenced. An examination of the DNA base sequence changes induced by different doses of (+)-BPDE demonstrated that the high dose of (+)-BPDE caused base substitution mutations almost exclusively at G.C base pairs whereas the low dose of (+)-BPDE caused mutations at both G.C and A.T base pairs. Thus, use of a low dose of (+)-BPDE allowed the detection of mutations (at A.T base pairs) that were not readily observed with a high dose of (+)-BPDE. The data also suggest that the low dose of (+)-BPDE may have caused a different profile of base substitutions at G.C base pairs and exon deletions than the high dose. The results indicate dose-dependent differences in the profile of mutations for an ultimate carcinogen.

The conformation of the 1 R,2 S,3 R,4 S-benzo[ c]phenanthrene- N (2)-dG adduct, arising from trans opening of the (+)-1 S,2 R,3 R,4 S- anti-benzo[ c]phenanthrene diol epoxide, was examined in 5'- d(ATCGC XCGGCATG)-3'.5'-d(CATGCCG CGCGAT)-3', where X = 1 R,2 S,3 R,4 S-B[ c]P- N (2)-dG. This duplex, derived from the hisD3052 frameshift tester strain of Salmonella typhimurium, contains a (CG) 3 iterated repeat, a hotspot for frameshift mutagenesis. NMR experiments showed a disconnection in sequential NOE connectivity between X (4) and C (5), and in the complementary strand, they showed another disconnection between G (18) and C (19). In the imino region of the (1)H NMR spectrum, a resonance was observed at the adducted base pair X (4) x C (19). The X (4) N1H and G (18) N1H resonances shifted upfield as compared to the other guanine imino proton resonances. NOEs were observed between X (4) N1H and C (19) N (4)H and between C (5) N (4)H and G (18) N1H, indicating that base pairs X (4) x C (19) and C (5) x G (18) maintained Watson-Crick hydrogen bonding. No NOE connectivity was observed between X (4) and G (18) in the imino region of the spectrum. Chemical shift perturbations of greater than 0.1 ppm were localized at nucleotides X (4) and C (5) in the modified strand and G (18) and C (19) in the complementary strand. A total of 13 NOEs between the protons of the 1 R-B[ c]Ph moiety and the DNA were observed between B[ c]Ph and major groove aromatic or amine protons at base pairs X (4) x C (19) and 3'-neighbor C (5) x G (18). Structural refinement was achieved using molecular dynamics calculations restrained by interproton distances and torsion angle restraints obtained from NMR data. The B[ c]Ph moiety intercalated on the 3'-face of the X (4) x C (19) base pair such that the terminal ring of 1 R-B[ c]Ph threaded the duplex and faced into the major groove. The torsion angle alpha' [X (4)]-N3-C2-N2-B[ c]Ph]-C1 was calculated to be -177 degrees, maintaining an orientation in which the X (4) exocyclic amine remained in plane with the purine. The torsion angle beta' [X (4)]-C2-N2-[B[ c]Ph]-C1-C2 was calculated to be 75 degrees. This value governed the 3'-orientation of the B[ c]Ph moiety with respect to X (4). The helical rise between base pairs X (4) x C (19) and C (5) x G (18) increased and resulted in unwinding of the right-handed helix. The aromatic rings of the B[ c]Ph moiety were below the Watson-Crick hydrogen-bonding face of the modified base pair X (4) x C (19). The B[c]Ph moiety was stacked above nucleotide G (18), in the complementary strand.

L'hydrolyse est catalysee par une serie d'acides: Cl 2 CHPO 3 H − , ClCH 2 PO 3 H − , H 2 PO 4 − , et C 2 H 5 PO 3 H −

On propose un mecanisme dicationique pour la solvolyse de l'epoxyde derive de la dibenzo [a,j] acridine

Replacement of the morpholine C-ring of linezolid 1 with a 1,3,4-thiadiazolyl ring leads to oxazolidinone analogues 5 having potent antibacterial activity against both gram-positive and gram-negative organisms. Conversion of the C5 acetamide group to a thioacetamide further increases the potency of these compounds.

Linezolid is a novel oxazolidinone antibacterial agent active against staphylococci (including methicillin-resistant strains), enterococci (including vancomycin-resistant strains), streptococci (including penicillin-intermediate and -resistant Streptococcus pneumoniae), and other aerobic and facultative bacteria. The agent has also demonstrated activity against a broad spectrum of Gram-positive and Gram-negative anaerobic bacteria. Previous time-kill assessments have shown linezolid to be generally bacteriostatic against staphylococci and enterococci, and bactericidal against streptococci. In this study, an anaerobic glovebox technique was employed to conduct time-kill assessments for four strains of anaerobic Gram-positive, and seven strains of anaerobic Gram-negative bacteria. The time-kill experiment was performed using Anaerobe Broth medium. The drugs were tested at four-fold the minimum inhibitory concentration (MIC), or at the higher concentration of 8mg/L for linezolid, 2mg/L for clindamycin, and 8mg/L for metronidazole. Samples for viable count were taken at 0, 6, and 24h, and plated using the Bioscience International Autospiral DW. Exposure of samples to the aerobic environment during plating was held to less than 30min. Plates were counted after a 48h anaerobic incubation (37 degrees C). The species tested included Bacteroides fragilis (2), B. distasonis, B. thetaiotaomicron, Fusobacterium nucleatum, F. varium, Prevotella melaninogenica, Clostridium perfringens, Eubacterium lentum and Peptostreptococcus anaerobius (2). The activity of linezolid was compared to that of metronidazole and clindamycin, two standard anti-anaerobe agents. As expected, the control agents were very active in these assays. Metronidazole yielded log(10)CFU/mL reductions of 3.0 or greater for nine of ten strains; clindamycin yielded log(10)CFU/mL reductions of 2.0 or greater for six of 11 strains, and 3.0 or greater for three strains. Linezolid also produced significant in vitro killing in this model achieving log(10)CFU/mL reductions of 2.0 or greater for six of 11 strains, and 3.0 or greater for four strains. The profile of activity was similar to that of clindamycin indicating that additional developmental studies of linezolid with anaerobic bacteria are warranted.

Oxazolidinones make up a relatively new class of antimicrobial agents which possess a unique mechanism of bacterial protein synthesis inhibition. U-100592 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]- phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide and U-100766 (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]- 2-oxo-5-oxazolidinyl]methyl]-acetamide are novel oxazolidinone analogs from a directed chemical modification program. MICs were determined for a variety of bacterial clinical isolates; the respective MICs of U-100592 and U-100766 at which 90% of isolates are inhibited were as follows: methicillin-susceptible Staphylococcus aureus, 4 and 4 micrograms/ml; methicillin-resistant S. aureus, 4 and 4 micrograms/ml; methicillin-susceptible Staphylococcus epidermidis, 2 and 2 micrograms/ml; methicillin-resistant S. epidermidis, 1 and 2 micrograms/ml; Enterococcus faecalis, 2 and 4 micrograms/ml; Enterococcus faecium, 2 and 4 micrograms/ml; Streptococcus pyogenes, 1 and 2 micrograms/ml; Streptococcus pneumoniae, 0.50 and 1 microgram/ml; Corynebacterium spp., 0.50 and 0.50 micrograms/ml; Moraxella catarrhalis, 4 and 4 micrograms/ml; Listeria monocytogenes, 8 and 2 micrograms/ml; and Bacteroides fragilis, 16 and 4 micrograms/ml. Most strains of Mycobacterium tuberculosis and the gram-positive anaerobes were inhibited in the range of 0.50 to 2 micrograms/ml. Enterococcal strains resistant to vancomycin (VanA, VanB, and VanC resistance phenotypes), pneumococcal strains resistant to penicillin, and M. tuberculosis strains resistant to common antitubercular agents (isoniazid, streptomycin, rifampin, ethionamide, and ethambutol) were not cross-resistant to the oxazolidinones. The presence of 10, 20, and 40% pooled human serum did not affect the antibacterial activities of the oxazolidinones. Time-kill studies demonstrated a bacteriostatic effect of the analogs against staphylococci and enterococci but a bactericidal effect against streptococci. The spontaneous mutation frequencies of S. aureus ATCC 29213 were

Amyloid fibrils form through nucleation and growth. To clarify the mechanism involved, direct observations of both processes are important (1, 2). First, we developed a new technique for the direct observation of amyloid fibrils using total internal reflection fluorescence microscopy (TIRFM) combined with thioflavin T (ThT) fluorescence. Fibril growth of b2-microglobulin (b2-m) and amyloid b peptide was visualized in real-time at the single fibril level revealing various dramatic images. With amyloid b peptide, we succeeded in observing the formation of the senile plaque-like spherulitic structures with diameters of around 15 m m on the chemically modified quartz surface, suggesting the underlying physicochemical mechanism of senile plaque formation. Second, using atomic force microscopy, ultrasonication-induced formation of b 2-m fibrils was shown, indicating that ultrasonication is useful to accelerate the nucleation process. Third, with the proteolytic fragment of b 2-m, propagation and a transformation of fibril morphology was demonstrated. These direct observations indicate that templatedependent growth and structural diversity are key factors determining the structure and function of amyloid fibrils. The idea can be represented by a cubic puzzle consisting of 27 small cubes, whose folding and misfolding mimic protein folding and amyloid fibril formation, respectively.

On propose un mecanisme dicationique pour la solvolyse de l'epoxyde derive de la dibenzo [a,j] acridine

U-78608, a new monocarbam antibiotic, was evaluated for in vitro activity against 312 clinical isolates of aerobic and anaerobic bacteria and subjected to several in vitro biochemical tests characterizing its interactions with beta-lactamases and penicillin-binding proteins (PBPs). The antibacterial activity of the compound was compared directly with those of SQ 83,360 (pirazmonam) and aztreonam. U-78608, SQ 83,360, and aztreonam had generally poor activity against gram-positive aerobic bacteria and anaerobic bacteria. U-78608 demonstrated activity primarily against gram-negative aerobic bacteria, with potency generally comparable to that of SQ 83,360. U-78608 and SQ 83,360 were less active than aztreonam for some gram-negative species; however, both compounds were 8- to 64-fold more active than aztreonam against Acinetobacter species, Pseudomonas aeruginosa, and Pseudomonas maltophilia. All three compounds resisted inactivation by several different beta-lactamases from gram-positive and gram-negative bacteria. Neither U-78608 nor SQ 83,360 exhibited significant inhibition of these enzymes, while aztreonam inhibited beta-lactamases from P. aeurginosa and Klebsiella oxytoca. All three compounds exhibited strong affinity to PBP 3 of Escherichia coli and moderate to negligible affinity to the other E. coli PBPs; quantitative measurements indicated that U-78608 had greater PBP 3 affinity than either SQ 83,360 or aztreonam.

Homoepitaxial silicon thick films have been produced by medium pressure plasma chemical vapor deposition at rates as fast as 60nm∕s and at a temperature of around 700°C, with a silane gas partial pressure of 4mTorr. The continuous transition of the film structures from agglomerated to faceted columnar and to epitaxial planar structure was observed with an increase in the plasma power. The calorimetric analysis during deposition has also confirmed that the thermal boundary layer thickness between the plasma and substrate reduced with the increasing power and became comparable to the mean free path of the vapors when epitaxy was achieved at high rates. In addition, the rate for epitaxial growth was observed to increase linearly with silane gas partial pressure. These potentially indicate that less coagulated silicon atom clusters formed in the reduced boundary thickness have contributed effectively to the high rate epitaxial growth.

The rates of reaction of (+/-)-7..beta..,8..cap alpha..-dihydroxy-9..beta..,10..beta..-epoxy-7,8,9,10-tetrahydrobenzo(..cap alpha..) pyrene (DE-1, in which the 7-hydroxyl group and epoxide oxygen are cis) in solutions of varied DNA, Poly(A), and Poly(G) concentrations were determined as a function of pH. The rate data were consistent with a mechanism in which DE-1 forms a physical complex with the polynucleotide, and this physical complex than reacts both by a pathway whose rate is first-order in respect to hydronium ion concentration (k/sub cat//sup H/ route) and by a second pathway whose rate is independent of hydronium ion concentration (k/sub cat//sup H/ route) and by a second pathway whose rate is independent of hydronium ion concentration (k/sub cat//sup 0/ route). Product studies showed that > 95% of the products formed from both the k/sub cat//sup H/ and k/sub cat//sup 0/ reactions were tetraols resulting from cis and trans hydration of the epoxide, and 50 fold) than free diol epoxide by the acid-catalyzed routes (k/sub cat//sup H/ >> k/sub H+/) and moderatelymore » faster ( k/sub 0/). Poly(G) is a significantly better catalyst than either DNA or Poly(A) for both k/sub cat//sup H/ and k/sub cat//sup 0/ reactions. At pH ca. 7, however, the physical DE-1-DNA complex reacts mainly by the k/sub cat//sup 0/ reaction, whereas the physical DE-2-DNA complex reacts mostly by the k/sub cat//sup 0/ reaction.« less

We have examined the selectivity of rat liver microsomal epoxide hydrolase (EC 3.3.2.3) toward all of the possible positional isomers of benzo-ring diol epoxides and tetrahydroepoxides of benz[a]anthracene, as well as the 1,2-diol 3,4-epoxides of triphenylene. This set includes compounds with no bay region in the vicinity of the benzo-ring, a bay-region diol group, a bay-region epoxide group, and (for the triphenylene derivatives) both a bay-region diol and a bay-region epoxide. In all cases where both the tetrahydroepoxides and the corresponding diol epoxides were examined, there is a large retarding effect of hydroxyl substitution on the rate of the enzyme-catalyzed hydration. When the tetrahydroepoxides are fair or poor substrates (epoxide group in the 1,2-, 8,9-, or 10,11-position), the additional retardation introduced by adjacent hydroxyl groups causes the enzyme-catalyzed hydrolysis of the corresponding diol epoxides to be insignificantly slow or nonexistent. In contrast, a benz[a]anthracene derivative with an epoxide group in the 3,4-position, (-)-tetrahydrobenz[a]anthracene (3R,4S)-epoxide, has been identified as the best substrate known for epoxide hydrolase, with a Vmax at 37 degrees C and pH 8.4 of 6800 nmol/min/mg of protein, and the two diastereomeric (+/-)-benz[a]anthracene 1,2-diol 3,4-epoxides, unlike all the other diol epoxides examined to date, are moderately good substrates for epoxide hydrolase. This novel observation is accounted for by the fact that the very high reactivity of the tetrahydrobenz[a]anthracene 3,4-epoxide system towards epoxide hydrolase is large enough to overcome a kinetically unfavorable effect of hydroxyl substitution. The enantioselectivity and positional selectivity of the enzyme have been determined for the tetrahydro-1,2- and -3,4-epoxides of benz[a]anthracene as well as the 1,2-diol 3,4-epoxides. When the epoxide is located in the 3,4-position, the benzylic carbon is the preferred site of attack, whereas for the enantiomers of the bay-region tetrahydro-1,2-epoxides, the chemically less reactive non-benzylic carbon is preferred. The regio- and enantioselectivity of epoxide hydrolase are discussed in terms of a possible model for the hydrophobic binding site of this enzyme.

Etude realisee sur des diol epoxydes des benzo [a] anthracene, triphenylene et benzo [e] pyrene dans lesquels les equilibres entre les conformations alignees et non alignees sont modifies par la localisation du groupe diol dans une region baie de la molecule

Metabolism of triphenylene by liver microsomes from control, phenobarbital(PB)-treated rats and 3-methylcholanthrene(MC)-treated rats as well as by a purified system reconstituted with cytochrome P-450c in the absence or presence of purified microsomal epoxide hydrolase was examined. Control microsomes metabolized triphenylene at a rate of 1.2 nmol/nmol of cytochrome P-450/min. Treatment of rats with PB or MC resulted in a 40% reduction and a 3-fold enhancement in the rate of metabolism, respectively. Metabolites consisted of the trans-1,2-dihydrodiol as well as 1-hydroxytriphenylene, and to a lesser extent 2-hydroxytriphenylene. The (-)-1R,2R-enantiomer of the dihydrodiol predominated (70 to 92%) under all incubation conditions. Incubation of racemic triphenylene 1,2-oxide with microsomal epoxide hydrolase produced dihydrodiol which was highly enriched (80%) in the (-)-1R,2R-enantiomer. Experiments with 18O-enriched water showed that attack of water was exclusively at the allylic 2-position of the arene oxide, indicating that the 1R,2S-enantiomer of the oxide was preferentially hydrated by epoxide hydrolase. Thiol trapping experiments indicated that liver microsomes from MC-treated rats produced almost exclusively (greater than 90%) the 1R,2S-enantiomer of triphenylene 1,2-oxide whereas liver microsomes from PB-treated rats formed racemic oxide. The optically active oxide has a half-life for racemization of only approximately 20 s under the incubation conditions. This study may represent the first attempt to address stereochemical consequences of a rapidly racemizing intermediary metabolite.

Oxidation of 2-bromo-5-hydroxy-N-(4-hydroxyphenethyl)-4-methoxy-N-methylbenzamide (VIII) with ferricyanide afforded the narwedine-type enone (X) in an excellent yield (40%). Reduction of (X) with lithium aluminium hydride gave (±)-galanthamine (II) and (±)-epigalanthamine (XXI) in yields of 50 and 40% respectively. Oxidation of (II) with manganese dioxide afforded (±)-narwedine (XIX) This work also constitutes a formal synthesis of (±)-lycoramine.

Treatment of ethyl 4, 5-dimethoxy-2-nitrobenzylidenemalonate (III), ethyl 4-benzyloxy-5-methoxy-2-nitrobenzylidenemalonate (IV), and ethyl 4, 5-methylenedioxy-2-nitrobenzylidenemalonate (V) with triethyl phosphite at 160-170° for 20 hr afforded 2-ethoxy-3-ethoxycarbonyl-6, 7-dimethoxyquinoline (VI), 7-benzyloxy-2-ethoxy-3-ethoxycarbonyl-6-methoxyquinoline (VII), and 2-ethoxy-3-ethoxycarbonyl-6, 7-methylenedioxyquinoline (VIII), respectively, in 53-68% yield. On the other hand, the 6-benzyloxy-2-ethoxycarbonyl-5-methoxyindole (XIII) was obtained with the same treatment of ethyl 4-benzyloxy-3-methoxy-2-nitrocinnamate (XII).

Novel syntheses of 1-substituted isoquinoline and spiro[cycloalkane-1,1′-isoquinoline] derivatives were achieved by condensation of 3-hydroxyphenethylamine with carbonyl compounds, and application of this method led to the total synthesis of (±)-coreximine.

Phenolic oxidative coupling of (±)-N-methylcoclaurine with potassium ferricyanide afforded (±)-glaziovine (III), whose methylation with diazomethane gave (±)-pronuciferine (VI). A very interesting dimeric compound (VIII) was also obtained.

During the past decade substantial progress has been made in elucidating factors that determine the tumorigenic activity of bay-region diol epoxides, major ultimate carcinogenic metabolites derived from polycyclic aromatic hydrocarbons. Neither high nor low chemical reactivity of the diol epoxides (as measured by rates of uncatalyzed solvolysis) is required for high tumorigenic response. In contrast, aspects of molecular structure such as conformation and absolute configuration strongly influence tumorigenic activity. The role of conformation is illustrated by the observation that those diol epoxides whose hydroxyl groups are pseudoaxial are weak or inactive as tumorigens. Absolute configuration is an important determinant of biological activity of bay-region diol epoxides: in all cases studied to date, the predominantly formed (R,S)-diol-(S,R)-epoxides are generally the most tumorigenic of the four metabolically possible configurational isomers. In the course of investigating the effects of structural factors on tumorigenic activity, we identified the (4R,3S)-diol-(2S,1R)-epoxide of benzo(c)phenanthrene as the most potent tumorigen (in initiation-promotion experiments on mouse skin) of the diol epoxides studied to date. Studies of all four configurationally isomeric diol epoxides derived from benzo(c)phenanthrene led to the striking observation that these diol epoxides exhibit an exceptionally high efficiency of covalent binding, relative to hydrolysis, when allowed to react with calf thymus DNA in aqueous solution. Thus, these diol epoxides should provide an excellent tool for the detailed study of such binding. When the four isomeric benzo(c)phenanthrene diol epoxides are compared, there appears to be no simple correlation between tumorigenic response and either the extent of binding to DNA or the major types of deoxyribonucleoside adducts formed. Deoxyribonucleoside adducts of benzo(c)phenanthrene diol epoxide have also been identified from the DNA of cultured rodent embryo cells after treatment of the cells with tritium-labeled benzo(c)phenanthrene. The distribution of adducts is consistent with predominant metabolic formation of the (4R,3S)-diol-(2S,1R)-epoxide; deoxyadenosine is the major site in the cellular DNA attacked by this epoxide, just as it is in DNA in solution. Further experiments are in progress which we hope will identify more subtle aspects of the DNA binding of benzo(c)phenanthrene diol epoxides that may be uniquely correlated with their tumorigenic activity.

The bay-region theory proposes that diol epoxides will have high biological activity when they are on angular benzo-rings and the epoxide group forms part of a bay-region of a carcinogenic polycyclic aromatic hydrocarbon. In general, predicted chemical reactivity for positional isomers of benzo-ring diol epoxides of individual hydrocarbons has been paralleled by their respective mutagenicity and/or tumorigenicity. Although relative reactivity of bay-region diol epoxides from a series of different hydrocarbons provides a fairly respectable index of tumorigenicity for the series, metabolic and stereochemical factors are also critically important determinants of biological activity. Several hydrocarbons have now been tested, either directly or indirectly, and have been found to meet the predictions of the theory.