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61.
[reaction: see text] The synthesis of allocyathin B(3) from an advanced intermediate possessing the ring system and relative stereochemistry but lacking the isopropyl and hydroxymethyl groups is reported. The isopropyl group was introduced by radical cyclization of a methyl propargyl acetal of an alpha-bromo ketone, and the hydroxymethyl group was generated by Pd-catalyzed carbonylation of a vinyl triflate. The route provides functionalized intermediates that could allow access to more complex members of the cyathin family of diterpenes. 相似文献
62.
Marchand C Nguyen CH Ward B Sun JS Bisagni E Garestier T Hélène C 《Chemistry (Weinheim an der Bergstrasse, Germany)》2000,6(9):1559-1563
Sequence-specific DNA recognition can be achieved by oligonucleotides that bind to the major groove of oligopyrimidine x oligopurine sequences. These intermolecular structures could be used to modulate gene expression and to create new tools for molecular biology. Here we report the synthesis and biochemical characterization of triple helix-specific DNA cleaving reagents. It is based on the previously reported triplex-specific ligands, benzo[e]pyridoindole (BePI) and benzo[g]pyridoindole (BgPI), covalently attached to ethylenediaminotetraacetic acid (EDTA). In the presence of iron, a reducing agent and molecular oxygen, BgPI-EDTA x FeII but not BePI-EDTA x FeII induced a double-stranded cut in a plasmid DNA at the single site where a triplex-forming oligonucleotide binds. At single nucleotide resolution, it was found that upon triplex formation BePI-EDTA x FeII led to cleavage of the pyrimidine strand and protection of the purine strand. BgPI-EDTA x FeII cleaved both strands with similar efficiency. The difference in cleavage efficiency between the two conjugates was rationalized by the location of the EDTA x FeII moiety with respect to the grooves of DNA (major groove: BePI-EDTA x FeII, minor groove: BgPI-EDTA x FeII). This work paves the way to the development of a new class of triple helix directed DNA cleaving reagents. Such molecules will be of interest for sequence-specific DNA cleavage and for investigating triple-helical structures, such as H-DNA, which could play an important role in the control of gene expression in vivo. 相似文献
63.
At least one Holy Grail for many academic researchers and pharmaceutical research divisions alike has been to identify therapeutically useful selective PI3K inhibitors. There are several different but closely related PI3Ks which are thought to have distinct biological roles. Until now, however, researchers have been frustrated by poor selectivity of the available pharmacological inhibitors, which are unable to distinguish the different isoforms of PI3K adequately. Fortunately, recently published work gives cause for optimism; there are now several patent specifications published that describe new PI3K inhibitors, including some that are more selective for the delta isoform of PI3K. Given the involvement of PI3Ks in a plethora of biological settings, such isoform-selective inhibitors may have immense potential use for the treatment of patients with inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. 相似文献
64.
Ward Whitt 《Queueing Systems》1991,9(3):235-268
A fundamental principle of queueing theory isL=W (Little's law), which states that the time-average or expected time-stationary number of customers in a system is equal to the product of the arrival rate and the customer-average or expected customer-stationary time each customer spends in the system. This principle is now well known and frequently applied. However, in recent years there have been extensions, such as H=G and the continuous, distributional, ordinal and central-limit-theorem versions, which show that theL=W relation, when viewed properly, has much more power than was previously realized. Moreover, connections have been established between H=G and other fundamental relations, such as the rate conservation law and PASTA (Poisson arrivals see time averages), which show that there is a much greater unity in the overall theory than was previously realized. This paper provides a review.This paper is dedicated to the memory of our colleague Professor Peter Franken (1937–1989), who contributed greatly to the subject of this paper and to queueing theory more generally. 相似文献
65.
66.
67.
Production of hybrid 16-membered macrolides by expressing combinations of polyketide synthase genes in engineered Streptomyces fradiae hosts 总被引:1,自引:0,他引:1
Reeves CD Ward SL Revill WP Suzuki H Marcus M Petrakovsky OV Marquez S Fu H Dong SD Katz L 《Chemistry & biology》2004,11(10):1465-1472
Combinations of the five polyketide synthase (PKS) genes for biosynthesis of tylosin in Streptomyces fradiae (tylG), spiramycin in Streptomyces ambofaciens (srmG), or chalcomycin in Streptomyces bikiniensis (chmG) were expressed in engineered hosts derived from a tylosin-producing strain of S. fradiae. Surprisingly efficient synthesis of compounds predicted from the expressed hybrid PKS was obtained. The post-PKS tailoring enzymes of tylosin biosynthesis acted efficiently on the hybrid intermediates with the exception of TylH-catalyzed hydroxylation of the methyl group at C14, which was efficient if C4 bore a methyl group, but inefficient if a methoxyl was present. Moreover, for some compounds, oxidation of the C6 ethyl side chain to an unprecedented carboxylic acid was observed. By also expressing chmH, a homolog of tylH from the chalcomycin gene cluster, efficient hydroxylation of the 14-methyl group was restored. 相似文献
68.
[reaction: see text] The reaction of alpha-alkoxy aldehydes with Et4NAg(CN)2 or Me3SiCN in the presence of MgBr2 x OEt2 in CH2Cl2 at 0 degrees C gives the corresponding syn cyanohydrins in good yield with high diastereoselectivity. Excess MgBr2 x OEt2 (typically 5 equiv) is required for high diastereoselectivity. Et4NAg(CN)2 (but not Me3SiCN) is sufficiently reactive to give cyanohydrins at -78 degrees C, and higher diastereoselectivity is obtained at this temperature. 相似文献
69.
William W. Ward Hugh J. Prentice Amy F. Roth Chris W. Cody Sue C. Reeves 《Photochemistry and photobiology》1982,35(6):803-808
Abstract— In the jellyfish Aequorea, the green-fluorescent protein (GFP) functions as the in vivo bio-luminescence emitter via energy transfer from the photoprotein aequorin. Accumulated evidence has indicated that the Aequorea GFP is a relatively inflexible protein. Present evidence, however, indicates that the chromophore environment is readily accessible to a variety of external perturbants. Native Aequorea GFP has an absorbance maximum at 395 nm and a shoulder at 470 nm. In low ionic strength buffer at neutral pH and room temperature the 395/470 nm absorbance ratio is about 2.0. We show that this ratio is highly variable depending upon temperature, ionic strength, protein concentration, and pH. A maximum ratio of 6.5 (at a protein concentration of 18.6 mg/m/) and minimum of 0.42 (at a pH of 12.2) have been measured. In the latter case, the resulting absorption and excitation spectra resemble those of Renilla GFP in spectral shape (but not wavelength maximum). In all cases as the perturbant is varied the resulting spectra pass through a sharp isosbestic point, suggesting a relatively simple two-state mechanism. These spectral perturbations are fully reversible. On the basis of these results, we suggest that the chromophore binding site is conformationally flexible. pH-Dependent changes in the near-UV and visible circular dichroism spectra plus spectrophotometric titration of tyrosine residues lend additional support to this hypothesis. 相似文献
70.
Collot J Gradinaru J Humbert N Skander M Zocchi A Ward TR 《Journal of the American Chemical Society》2003,125(30):9030-9031
Homogeneous and enzymatic catalysis offer complementary means to generate enantiomerically pure compounds. Incorporation of achiral biotinylated rhodium-diphosphine complexes into (strept)avidin yields artificial metalloenzymes for the hydrogenation of N-protected dehydroamino acids. A chemogenetic optimization procedure allows one to produce (R)-acetamidoalanine with 96% enantioselectivity. These hybrid catalysts display features reminiscent both of enzymatic and of homogeneous systems. 相似文献