- Exploiting structure-activity relationships of QS-21 in the design and synthesis of streamlined saponin vaccine adjuvants
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We report the design, synthesis, immunological evaluation, and conformational analysis of new saponin variants as promising vaccine adjuvants. These studies have provided expedient synthetic access to streamlined adjuvant-active saponins and yielded molecular-level insights into saponin conformation that correlated with their in vivo adjuvant activities.
- Anguita, Juan,Barriales, Diego,Corzana, Francisco,Fernández-Tejada, Alberto,Ghirardello, Mattia,Jiménez-Barbero, Jesús,Poveda, Ana,Ruiz-De-Angulo, Ane,Sacristan, Nagore
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Read Online
- Simultaneous Detection of Glutathione and Hydrogen Polysulfides from Different Emission Channels
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Glutathione (GSH) and hydrogen polysulfides (H2Sn) play crucial roles in many physiological processes. To unravel the complicated interrelationship and cellular cross-talk between GSH and H2Sn, the development of single-molecule fluorescent probes that can selectively sense GSH and H2Sn simultaneously from different emission channels is highly desirable. In this report, we have developed the first dual-detection fluorescent probe, ACC-SePh, which responded to GSH with green fluorescence emission, whereas it reacted with H2Sn and emitted blue fluorescence. The probe exhibited excellent selectivity and sensitivity toward GSH and H2Sn over other common reactive sulfur species, such as Cys, Hcy and H2S. Importantly, we also demonstrated that ACC-SePh can be used for dual-channel imaging of endogenous GSH and H2Sn in living RAW264.7 cells.
- Chen, Wenqiang,Yue, Xiuxiu,Zhang, Hui,Li, Wenxiu,Zhang, Liangliang,Xiao, Qi,Huang, Chusheng,Sheng, Jiarong,Song, Xiangzhi
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Read Online
- Click Reaction of Selenols with Isocyanates: Rapid Access to Selenocarbamates as Peroxide-Switchable Reservoir of Thiol-Peroxidase-Like Catalysts
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Selenols react with isocyanates under mild catalyst-free conditions to generate selenocarbamates in good yield and with high selectivity over potentially competing nucleophilic additions. The methodology enables the incorporation of a wide variety of functional groups providing access to a broad array of densely functionalised selenocarbamates. In the presence of competing heteroatom-centered nucleophiles, isocyanates selectively couple with selenols. Selenocarbamates exhibited thiol-peroxidase-like properties, enabling the reduction of hydrogen peroxide at the expense of thiols, which are converted into the corresponding disulfides. A series of control experiments suggested that the catalytic mechanism proceeds through a pathway, involving a H2O2-promoted transcarbamoylation reaction leading to a thiocarbamate with concomitant releasing of catalytically active selenolate anions. By undergoing peroxide-driven thiol-selenol exchange, selenocarbamates behave as equivalents of selenolate anions with thiol-peroxidase-like activity. (Figure presented.).
- Capperucci, Antonella,Petrucci, Alessandra,Faggi, Cristina,Tanini, Damiano
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supporting information
p. 4256 - 4263
(2021/07/17)
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- Synthesis of Seleno Oxindoles via Electrochemical Cyclization of N-arylacrylamides with Diorganyl Diselenides
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The tandem cyclization of acrylamide with diselenides facilitated by electrochemical oxidation was successfully developed. This strategy provided an environmentally friendly method for the construction of C?Se bond. A series of seleno oxindoles with pharmacological activity were obtained by using this well-designed tandem cyclization strategy. The in vitro antitumor activity of the compounds was also screened through MTT assay. Results showed that the seleno oxindoles exhibited better antitumor activity than other oxindole derivatives. (Figure presented.).
- Wang, Xin-Yu,Zhong, Yuan-Fang,Mo, Zu-Yu,Wu, Shi-Hong,Xu, Yan-Li,Tang, Hai-Tao,Pan, Ying-Ming
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supporting information
p. 208 - 214
(2020/12/04)
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- O-(tert-butyl) Se-phenyl selenocarbonate: A convenient, bench-stable and metal-free precursor of benzeneselenol
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A study by our laboratory shows that air, light and moisture stable O-(tert-butyl) Se-phenyl selenocarbonate could be employed as a safer, practical and efficient alternative to generate “in situ” benzeneselenol or benzeneselenolate anion under different and transition metal-free conditions. This procedure seems to be of general application since the nucleophilic selenium species obtained can be trapped by electrophiles such as alkyl halides, epoxides and electron-deficient alkenes and alkynes under different reaction conditions.
- Temperini, Andrea,Siciliano, Carlo
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- Lysosomal Reacidification Ameliorates Vinyl Carbamate-Induced Toxicity and Disruption on Lysosomal pH
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Ethyl carbamate (EC) is a carcinogen toxicant, commonly found in fermented foods and beverages. The carcinogenic and toxic possibility of EC is thought to be related to its metabolite vinyl carbamate (VC). However, we found interesting mechanisms underlying VC-induced toxicity in this study, which were greatly different from EC. We first conducted a simple synthesis procedure for VC and found that VC possessed higher toxicity but failed to regulate levels of reactive oxygen species, glutathione, and autophagy. Notably, VC treatment resulted in upregulation of lysosomal pH, which was responsible for its cytotoxicity. Cyclic adenosine monophosphate (cAMP) pretreatment could enhance restoration of lysosomal acidity and ameliorate VC-induced damage. Inhibition of protein kinase A and cystic fibrosis transmembrane conductance regulator can block cAMP-induced cytoprotection. Together, our results provided the evidence for novel mechanisms of toxicity and possible protection method under VC exposure, which might give new perspectives on the study of EC-induced toxicity.
- Chen, Wei,Cui, Sunliang,Hu, Dongwen,Li, Yuting,Qi, Jifeng
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p. 8951 - 8961
(2020/09/16)
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- Fluorescent probe for differentially detecting GSH and H2Sn (n is more than) through single-wavelength excitation
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The invention discloses a fluorescent probe for distinguishing and detecting GSH and H2Sn (n is more than 1) by single excitation, and belongs to the technical field of chemical analysis and detection, wherein the molecular structural formula is defined in the specification. According to the invention, the probe emits green fluorescence after reacting with GSH, and emits red fluorescence after reacting with H2Sn; the probe can realize simultaneous distinguishing detection of GSH and H2Sn (n is more than 1) under single-wavelength excitation, and has the characteristics of good selectivity, high sensitivity, wider pH working range and the like; and the probe can emit red fluorescence in the detection process, so that the excellent properties show that the fluorescent probe has important application value in the fields of environment, biology and the like.
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Paragraph 0007; 0037
(2020/09/16)
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- Fluorescent probe for differentially detecting GSH and H2Sn (n >1) through two channels
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The invention discloses a fluorescent probe for differentially detecting GSH and H2Sn (n > 1) through two channels, and belongs to the technical field of chemical analysis and detection. The probe hasa molecular structural formula shown in the description. The probe emits green fluorescence after reacting with GSH and emits red fluorescence after reacting with H2Sn. The probe not only can realizesimultaneous distinguishing detection of GSH and H2Sn (n > 1), but also has the characteristics of good selectivity, high sensitivity, relatively wide pH working range and the like. Meanwhile, in thedetection process, the probe can emit red fluorescence, and large Stokes shift is shown. The excellent properties show that the fluorescent probe has important application value in the fields of environment, biology and the like.
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Paragraph 0006; 0036
(2020/12/15)
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- Visible-Light-Promoted Selenylative Spirocyclization of Indolyl-ynones toward the Formation of 3-Selenospiroindolenine Anticancer Agents
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A metal-free and efficient visible-light-induced spirocyclization of indolyl-ynones with diselenides at room temperature under air atmosphere to prepare 3-selenospiroindolenines in moderate to good yields has been developed. The resulting products were tested for in vitro anticancer activity by MTT assay, and compounds 3 c and 3 e showed potent cancer cell-growth inhibition activities.
- Zhou, Xiu-Jie,Liu, Hao-Yang,Mo, Zu-Yu,Ma, Xian-Li,Chen, Yan-Yan,Tang, Hai-Tao,Pan, Ying-Ming,Xu, Yan-Li
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supporting information
p. 1536 - 1539
(2020/04/20)
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- Selenols: a new class of carbonic anhydrase inhibitors
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Stable aryl selenols were obtained through a convenient procedure. Selenols represent a new chemotype acting as carbonic anhydrase inhibitors (CAIs), inhibiting four human isoforms, CAs I, II, VII and the tumor-associated CA IX. X-ray crystallographic, physical and computational studies provided insights into the binding mode of this conceptually new class of CAIs.
- Angeli, Andrea,Tanini, Damiano,Nocentini, Alessio,Capperucci, Antonella,Ferraroni, Marta,Gratteri, Paola,Supuran, Claudiu T.
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supporting information
p. 648 - 651
(2019/01/25)
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- Metal-free visible-light induced cyclization/substitution cascade reaction of alkyne-tethered cyclohexadienones and diselenides: Access to 5-hydroxy-3-selenyl-4a,8a-dihydro-2: H -chromen-6(5 H)-ones
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A simple and efficient Se-radical triggered cyclization/substitution cascade reaction of alkyne-tethered cyclohexadienones to afford 5-hydroxy-3-selenyl-4a,8a-dihydro-2H-chromen-6(5H)-ones has been developed. This transformation via the 3,5-diselenyl-4a,8a-dihydro-2H-chromen-6(5H)-one intermediate followed by hydrolysis in the presence of CsOAc affords the desired product 3. The resulting products were tested for their in vitro anticancer activity using MTT assay, and compounds 3e and 3q showed potent cancer cell-growth inhibition activities.
- Ma, Xian-Li,Wang, Qian,Feng, Xi-Yuan,Mo, Zu-Yu,Pan, Ying-Ming,Chen, Yan-Yan,Xin, Mao,Xu, Yan-Li
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supporting information
p. 3547 - 3551
(2019/07/09)
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- Total Synthesis of Bis-anthraquinone Antibiotic BE-43472B
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This is a full account of our synthetic endeavor on the total synthesis of bis-anthraquinone antibiotic BE-43472B, an unusual octacyclic aromatic polyketide with a bis-anthraquinone scaffold. Three key steps enabled a facile access to the anthraquinone unit corresponding to the ABCF rings; (1) cyclo-condensation or -addition of benzonitrile oxides with cyclic enone derivatives, (2) benzoin cyclization for the stereoselective ring fusion with an angular hydroxy group, and (3) pinacol rearrangement for stereoselective installation of the angular aryl group. Other keys for the success include, (4) diastereoselective methylation of a lactol derivative, and (5) late-stage installation of the C3 hydroxy group through stereoselective oxirane ring formation via halohydrin derivatives. Whereas oxidation of the double bond in the enone with an adjacent 1,3-diketone moiety failed, the projected oxidation was achieved with the alkene keeping the isoxazole moiety intact as a 1,3-diketone equivalent. In the racemic total synthesis, X-ray crystal structure analysis of the target was achieved, proving the three-dimensional architecture for the first time. The asymmetric total synthesis was also achieved by exploiting a cycloadduct of the nitrile oxide and the enantiomerically pure cyclohexenone, which was convertible to the common intermediate via dehydrogenation followed by alkoxycarbonylation.
- Yamashita, Yu,Hirano, Yoichi,Takada, Akiomi,Takikawa, Hiroshi,Suzuki, Keisuke
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p. 2490 - 2515
(2018/05/25)
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- Chiral alpha-selenofluorophenyl acetate compound as well as preparation and application thereof
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The invention discloses a novel chiral compound with an alpha-selenofluorophenyl acetate structure, and a preparation method and application thereof. The structure of the novel chiral compound is shown in the attached figure. The preparation method of the novel chiral compound is characterized in that the optical pure alpha-fluorophenylacetate is split and synthesized at high efficiency by using optical pure chloramphenicol amine as a splitting agent, and then is esterified with diphenyl diselenide. The novel chiral compound is used as a chiral derivative reagent to detect the absolute configuration of multiple chiral compounds of chiral amine, alkamine, amino-acid ester and the like, and is characterized in that the nuclear-magnetic fluorine spectrum of the derivative reacted by a chiralprimer and (R)-alpha-selenofluorophenyl acetate and (S)-alpha-selenofluorophenyl acetate is tested, and the absolute configuration of the chiral primer is judged by contrasting the chemical displacement of alpha-F of the chiral primer under two conditions. The preparation method has the advantages that the reagent synthesis is simple, the operation is convenient, the chemical displacement difference is large, and the method is a simple and efficient method for judging the absolute configuration.
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Paragraph 0027; 0029
(2018/09/11)
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- A Methylidene Group in the Phosphonic Acid Analogue of Phenylalanine Reverses the Enantiopreference of Binding to Phenylalanine Ammonia-Lyases
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Aromatic amino acid ammonia-lyases and aromatic amino acid 2,3-aminomutases contain the post-translationally formed prosthetic 3,5-dihydro-4-methylidene-5H-imidazol-5-one (MIO) group. MIO enzymes catalyze the stereoselective synthesis of α- or β-amino acid enantiomers, making these chemical processes environmentally friendly and affordable. Characterization of novel inhibitors enables structural understanding of enzyme mechanism and recognizes promising herbicide candidates as well. The present study found that both enantiomers of the aminophosphonic acid analogue of the natural substrate phenylalanine and a novel derivative bearing a methylidene at the β-position inhibited phenylalanine ammonia-lyases (PAL), representing MIO enzymes. X-ray methods unambiguously determined the absolute configuration of all tested enantiomers during their synthesis. Enzyme kinetic measurements revealed the enantiomer of the methylidene-substituted substrate analogue as being a mirror image relation to the natural l-phenylalanine as the strongest inhibitor. Isothermal titration calorimetry (ITC) confirmed the binding constants and provided a detailed analysis of the thermodynamic driving forces of ligand binding. Molecular docking suggested that binding of the (R)- and (S)-enantiomers is possible by a mirror image packing. (Figure presented.).
- Bata, Zsófia,Qian, Renzhe,Roller, Alexander,Horak, Jeannie,Bencze, László Csaba,Paizs, Csaba,Hammerschmidt, Friedrich,Vértessy, Beáta G.,Poppe, László
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supporting information
p. 2109 - 2120
(2017/06/23)
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- 2-(Phenylseleno)ethanesulfon-amide as a novel protecting group for aniline that can be deprotected by a radical reaction
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Anilines were protected as 2-(phenylseleno)ethanesulfonanilide (SeES anilide) via sulfonylation by 2-chlorosulfonyl chloride followed by the conjugate addition of benzeneselenol. The SeES anilide was deprotected by radical reduction using tributyltin hydride in the presence of AIBN. The corresponding anilines were obtained in high yields when the hydride and AIBN were added to the system slowly. Since the radical reaction proceeds under neutral conditions, chemoselective deprotection of the SeES group was accomplished. The SeES anilide was stable under various conditions, including some severe conditions.
- Kihara, Nobuhiro,Mitsuhashi, Yuji,Sato, Makoto,Hirose, Shun-Ichi,Goudo, Erika,Uzawa, Yoshinori,Shirai, Natsumi,Hamamoto, Sari,Iwasaki, Ryo,Fujioka, Akane
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supporting information
p. 2563 - 2566
(2016/06/06)
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- Selenols are resistant to irreversible modification by HNO
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The discovery of nitric oxide (NO) as an endogenously generated signaling species in mammalian cells has spawned a vast interest in the study of the chemical biology of nitrogen oxides. Of these, nitroxyl (azanone, HNO) has gained much attention for its potential role as a therapeutic for cardiovascular disease. Known targets of HNO include hemes/heme proteins and thiols/thiol-containing proteins. Recently, due to their roles in redox signaling and cellular defense, selenols and selenoproteins have also been speculated to be additional potential targets of HNO. Indeed, as determined in the current work, selenols are targeted by HNO. Such reactions appear to result only in formation of diselenide products, which can be easily reverted back to the free selenol. This characteristic is distinct from the reaction of HNO with thiols/thiolproteins. These findings suggest that, unlike thiolproteins, selenoproteins are resistant to irreversible oxidative modification, support that Nature may have chosen to use selenium instead of sulfur in certain biological systems for its enhanced resistance to electrophilic and oxidative modification.
- Bianco, Christopher L.,Moore, Cathy D.,Fukuto, Jon M.,Toscano, John P.
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- METHOD FOR PRODUCING SELENOL
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The main purpose of the present invention is to provide a method for producing a selenol with high yield without causing the fluctuations in yield among production lots. The purpose can be achieved by a method for producing a selenol, which comprises steps (1) and (2): (1) a step of reacting a Grignard reagent represented by general formula (1) with selenium to produce a reaction solution containing a selenomagnesium halide represented by general formula (2); and (2) a step of adding the reaction solution produced in step (1) mentioned above to an acidic solution dropwisely to produce a selenol represented by general formula (3).
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Paragraph 0081-0085
(2016/12/22)
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- Simple and catalyst-free method for the synthesis of diaryl selenides by reactions of arylselenols and arenediazonium salts
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We describe here a simple and catalyst-free method to synthesize diaryl selenides by reaction of arenediazonium tetrafluoroborate salts with arylselenols, generated in situ by using diaryl diselenides and hypophosphorous acid (H3PO2), using THF as solvent. This is a direct nucleophilic aromatic substitution (SNAr) reaction performed with diaryl diselenides and arenediazonium salts bearing electron-withdrawing and electron-donating groups affording the corresponding diaryl selenides in moderated to good yields.
- Balaguez, Renata A.,Ricordi, Vanessa Gentil,Freitas, Camilo S.,Perin, Gelson,Schumacher, Ricardo F.,Alves, Diego
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supporting information
p. 1057 - 1061
(2014/02/14)
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- Simple and catalyst-free method for the synthesis of diaryl selenides by reactions of arylselenols and arenediazonium salts
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We describe here a simple and catalyst-free method to synthesize diaryl selenides by reaction of arenediazonium tetrafluoroborate salts with arylselenols, generated in situ by using diaryl diselenides and hypophosphorous acid (H3PO2), using THF as solvent. This is a direct nucleophilic aromatic substitution (SNAr) reaction performed with diaryl diselenides and arenediazonium salts bearing electron-withdrawing and electron-donating groups affording the corresponding diaryl selenides in moderated to good yields.
- Balaguez, Renata A.,Ricordi, Vanessa Gentil,Freitas, Camilo S.,Perin, Gelson,Schumacher, Ricardo F.,Alves, Diego
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supporting information
p. 1057 - 1061
(2015/02/19)
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- In situ generation of redox active peptides driven by selenoester mediated native chemical ligation
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Redox active peptides are generated through selenoester mediated native chemical ligation (NCL). Distinct nanostructures, such as nanotubes to nanofibrillar architectures, were observed for self-assembling soft materials. the Partner Organisations 2014.
- Rasale, Dnyaneshwar B.,Maity, Indrajit,Das, Apurba K.
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supporting information
p. 11397 - 11400
(2014/11/27)
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- Reaction of L2Zn2 with Ph2E 2-synthesis of LZnEPh and reactions with oxygen and H-acidic substrates
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L2Zn2 (L = HC[C(Me)N(2,4,6-Me3C 6H2)]2) and Ph2E2 (E = Se, Te) react to form LZnSePh (1) and LZnTePh (2). 1 and 2 further react with H2O and EtOH to form LZ
- Gondzik,Schulz,Blaeser,Woelper
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p. 1189 - 1191
(2014/01/17)
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- Reactivity of auranofin with selenols and thiols - Implications for the anticancer activity of gold(I) compounds
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The enzyme thioredoxin reductase (TrxR) is attracting much interest as a potential target for cancer therapy. The presence of a selenium atom in the catalytic site makes it sensitive to inhibition by electrophilic molecules, including the AuI complex auranofin [2,3,4,6-tetra-O-acetyl-1-thio- β-D-glucopyranosato-S-(triethylphosphane)gold]. The reactions between auranofin and models of thiol and selenol nucleophiles present in TrxR (PhSH and PhSeH) have been investigated in chloroform and methanol by means of 1H, 31P, and 77Se NMR spectroscopy. In chloroform, auranofin undergoes ligand substitution of the tetraacetylthioglucose moiety by a PhS or PhSe group. The reaction is reversible in both cases, but it is characterized by widely different equilibrium constants (ca. 1 for S and at least 103 for Se). In polar solvents, such as methanol, the reaction is more complex, and the phosphane moiety also undergoes ligand exchange. Some features have been clarified through the investigation of Et3PAuCl. The elementary processes involved have been characterized by DFT calculations. Copyright
- Di Sarra, Francesca,Fresch, Barbara,Bini, Riccardo,Saielli, Giacomo,Bagno, Alessandro
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p. 2718 - 2727
(2013/07/11)
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- Synthesis and preclinical evaluation of QS-21 variants leading to simplified vaccine adjuvants and mechanistic probes
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QS-21 is a potent immunostimulatory saponin that is currently under clinical investigation as an adjuvant in various vaccines to treat infectious diseases, cancers, and cognitive disorders. Herein, we report the design, synthesis, and preclinical evaluation of simplified QS-21 congeners to define key structural features that are critical for adjuvant activity. Truncation of the linear tetrasaccharide domain revealed that a trisaccharide variant is equipotent to QS-21, while the corresponding disaccharide and monosaccharide congeners are more toxic and less potent, respectively. Modification of the acyl chain domain in the trisaccharide series revealed that a terminal carboxylic acid is well-tolerated while a terminal amine results in reduced adjuvant activity. Acylation of the terminal amine can, in some cases, restore adjuvant activity and enables the synthesis of fluorescently labeled QS-21 variants. Cellular studies with these probes revealed that, contrary to conventional wisdom, the most highly adjuvant active of these fluorescently labeled saponins does not simply associate with the plasma membrane, but rather is internalized by dendritic cells.
- Chea, Eric K.,Fernandez-Tejada, Alberto,Damani, Payal,Adams, Michelle M.,Gardner, Jeffrey R.,Livingston, Philip O.,Ragupathi, Govind,Gin, David Y.
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supporting information; experimental part
p. 13448 - 13457
(2012/10/08)
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- Iron salt, a cheap, highly efficient and environment-friendly metal catalyst for Se-Se bond cleavage and the further reaction with methylenecyclopropanes under mild conditions
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FeCl3 was found to be a good catalyst in Se-Se bond cleavage. Further electrophilic additions to methylenecyclopropanes provide a convenient access to diphenylselenylcyclobutanes. Comparing with other Lewis acids, FeCl3 is much cheaper and the reaction conditions are milde and more tolerance to air and moisture.
- Yu, Lei,Ren, Lingfeng,Yi, Rong,Wu, Yulan,Chen, Tian,Guo, Rong
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supporting information; experimental part
p. 2228 - 2233
(2011/06/22)
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- Biomaterials based on low cytotoxic vinyl esters for bone replacement application
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In recent days, additive manufacturing technologies (AMT) based on photopolymerization have also found application in tissue engineering. Although acrylates and methacrylates have excellent photoreactivity and afford photopolymers with good mechanical properties, their cytotoxicity and degradation products disqualify them from medical use. Within this work, (meth)acrylate-based monomers were replaced by vinyl esters with exceptional low cytotoxicity. The main focus of this paper lies on the determination of the photoreactivity and investigations concerning mechanical properties and degradation behavior of the new materials. Tested monomers provide sufficient photoreactivity for processing by AMT. Mechanical properties similar to natural bone could be obtained by adding suitable fillers like hydroxylapatite (HA). The right ratio of hydrophobic and hydrophilic monomers allows the tuning of the degradation behavior. Finally, with the optimum formulation, cellular 3D structures were built using digital light processing.
- Husar, Branislav,Heller, Christian,Schwentenwein, Martin,Mautner, Andreas,Varga, Franz,Koch, Thomas,Stampfl, Juergen,Liska, Robert
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experimental part
p. 4927 - 4934
(2012/06/01)
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- Rhodium-catalyzed highly stereoselective hydroselenation of internal alkynes bearing an electron-withdrawing group
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Rhodium-catalyzed highly regio- and stereoselective hydroselenation of internal alkynes bearing an electron-withdrawing group took place to give (E)-vinyl selenides in good yields. The excellent syn stereoselectivity of this rhodium-catalyzed hydroselenation is of great importance in terms of complementing the previously reported hydroselenation of alkynes.
- Kawaguchi, Shin-Ichi,Kotani, Mao,Atobe, Shingo,Nomoto, Akihiro,Sonoda, Motohiro,Ogawa, Akiya
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experimental part
p. 6766 - 6769
(2012/02/05)
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- Design and synthesis of potent Quillaja saponin vaccine adjuvants
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The success of antitumor and antiviral vaccines often requires the use of an adjuvant, a substance that significantly enhances the immune response to a coadministered antigen. Only a handful of adjuvants have both sufficient potency and acceptable toxicity for clinical investigation. One promising adjuvant is QS-21, a saponin natural product that is the immunopotentiator of choice in many cancer and infectious disease vaccine clinical trials. However, the therapeutic promise of QS-21 adjuvant is curtailed by several factors, including its scarcity, difficulty in purification to homogeneity, dose-limiting toxicity, and chemical instability. Here, we report the design, synthesis, and evaluation of chemically stable synthetic saponins. These novel, amide-modified, non-natural substances exhibit immunopotentiating effects in vivo that rival or exceed that of QS-21 in evaluations with the GD3-KLH melanoma conjugate vaccine. The highly convergent synthetic preparation of these novel saponins establishes new avenues for discovering improved molecular adjuvants for specifically tailored vaccine therapies.
- Adams, Michelle M.,Damani, Payal,Perl, Nicholas R.,Won, Annie,Hong, Feng,Livingston, Philip O.,Ragupathi, Govind,Gin, David Y.
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supporting information; experimental part
p. 1939 - 1945
(2010/05/11)
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- Enantioselective synthesis of α-methylene-β-hydroxy carboxylic acid derivatives via a diastereoselective aldol/β-elimination sequence: Application to the C(15)-C(21) fragment of tedanolide C
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An enantioselective synthesis of α-methylene-β-hydroxy carboxylic acid derivatives via a highly diastereoselective, one-pot syn-aldol and β-elimination sequence utilizing the chiral β-(phenylselenyl) propionyl imide 15 is described. This new method, which constitutes an alternative to the Baylis-Hillman reaction, has been applied to the synthesis of the C(15)-C(21) fragment of tedanolide C.
- Barth, Roland,Roush, William R.
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supporting information; experimental part
p. 2342 - 2345
(2010/07/13)
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- General approach to the total synthesis of 9-methoxy-substituted indole alkaloids: Synthesis of mitragynine, as well as 9-methoxygeissoschizol and 9-methoxy-Nb-methylgeissoschizol
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(Chemical Equation Presented) Herein, the full details of the synthesis of the 9-methoxy-substituted Corynanthe indole alkaloids mitragynine (1), 9-methoxygeissoschizol (3), and 9-methoxy-Nb-methylgeissoschizol (4) are described. Initially, an efficient synthetic route to the optically active 4-methoxytryptophan ethyl ester 20 on a multigram scale was developed via a Mori-Ban-Hegedus indole synthesis. The ethyl ester of D-4-methoxytryptophan 20 was obtained with a radical-mediated regioselective bromination of indoline 12 serving as a key step. Alternatively, the key 4-methoxytryptophan intermediate 22 could be synthesized by the Larock heteroannulation of aryl iodide 10b with the internal alkyne 21a. The use of the Boc-protected aniline 10b was crucial to the success of this heteroannulation. The α,β-unsaturated ester 6 was synthesized via the Pictet-Spengler reaction as the pivotal step. This was followed by a Ni(COD)2-mediated cyclization to set up the stereocenter at C-15. The benzyloxy group in 31 was removed to provide the intermediate ester 5. This chiral tetracyclic ester 5 was employed to accomplish the first total synthesis of 9-methoxygeissoschizol (3) and 9-methoxy-N b-methylgeissoschizol (4) as well as the opioid agonistic indole alkaloid mitragynine (1).
- Ma, Jun,Yin, Wenyuan,Zhou, Hao,Liao, Xuebin,Cook, James M.
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supporting information; experimental part
p. 264 - 273
(2009/04/10)
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- Syntheses of bioactive bisabolane-type cryptomeria japonica sesquiterpenes
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The first diastereoselective synthesis of (1S,6R)-1- hydroxy-2,7(14),10- bisabolatrien-4-one, an antifeedant against Acusta despesta and Locusta migratoria, was produced from Cryptomeria japonica (commonly known as Japanese cedar), starting from (R)-(-)-carvone via (R)-(-)-cryptomerione. The enantiomer was transformed into (1S,3R,6R)-1-hydroxy-7(14),10-bisaboladien- 4-one, a novel antifeedant against L. migratoria from the same tree, by 1,4-selective reduction of the enone moiety.
- Shimizu, Nobuhiro,Kuwahara, Yasumasa
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experimental part
p. 588 - 591
(2010/04/26)
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- TRITERPENE SAPONINS, METHODS OF SYNTHESIS, AND USES THEREOF
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The present invention relates to triterpene glycoside saponin-derived adjuvants, syntheses thereof, intermediates thereto, and uses thereof. QS-7 is a potent immuno-adjuvant that is significantly less toxic than QS-21, a related saponin that is currently the favored adjuvant in anticancer and antiviral vaccines. Tedious isolation and purification protocols have hindered the clinical development of QS-7. A novel semi-synthetic method is provided wherein a hydrolyzed prosapogenin mixture is used to synthesize QS-7, QS-21, and related analogs, greatly facilitating access to QS-7 and QS-21 analogs for preclinical and clinical evaluation.
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Page/Page column 149-150
(2009/11/29)
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- Catalytic asymmetric ring-opening reaction of meso-epoxides with aryl selenols and thiols catalyzed by a heterobimetallic gallium-titanium-salen complex
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A chiral heterobimetallic Lewis acid complex has been developed as an efficient catalyst. The enantioselective desymmetrization of meso-epoxides with aryl selenols and thiols catalyzed by the heterobimetallic complex has been optimized. The optically active β-arylseleno alcohols and β-hydroxy sulfides were obtained in good yields and high enantioselec- tivities (up to 97% ee and 92% ee, respectively). A strong synergistic effect between different Lewis acids was exhibited in the catalytic process. & copy; 2009 Wiley-VCH Verlag GmbH & Co. KGaA.
- Sun, Jiangtao,Yang, Minghua,Yuan, Fang,Jia, Xuefeng,Yang, Xia,Pan, Yi,Zhu, Chengjian
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supporting information; experimental part
p. 920 - 930
(2009/11/30)
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- A simple zinc-mediated preparation of selenols
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Under acidic conditions zinc reduces diselenides to afford selenols, which can be either isolated or treated in situ with alkyl halides to produce alkyl selenides or with epoxides to give β-hydroxyselenides. Georg Thieme Verlag Stuttgart.
- Santi, Claudio,Santoro, Stefano,Testaferri, Lorenzo,Marcello Tiecco
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scheme or table
p. 1471 - 1474
(2009/04/07)
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- Reliable and general method for the cleavage of α-arylheteroatom- substituted carboxylic acids
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Bonds between arylheteroatom moieties and α-carbons of carboxylic acids are efficiently cleft by azide transfer and subsequent Curtius rearrangement. The scope of the one-pot protocol covers differently substituted carboxylic acids and heteroatoms like O, S, Se, and N. Georg Thieme Verlag Stuttgart.
- Spurg, Anke,Waldvogel, Siegfried R.
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p. 3042 - 3044
(2008/03/12)
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- A general synthesis of N-vinyl nitrones
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A general synthesis of a new type of heterodiene, the N-vinyl nitrone, is described. The synthetic sequence begins with the conjugate addition of benzeneselenol to nitroalkenes (in turn derived from Henry reaction of an aldehyde and a nitroalkane) to provide 2-selenenylnitroalkenes. These selenonitroalkanes are reduced to the corresponding hydroxylamines which are combined with aldehydes to form nitrones. The phenylselenenyl-containing nitrones are then oxidized to selenoxides which undergo syn-selenoxide elimination to provide N-vinyl nitrones. Three X-ray crystal structures of substituted N-vinyl nitrones were obtained. In addition, the first [4+2] cycloaddition of an N-vinyl nitrone is reported.
- Denmark, Scott E.,Montgomery, Justin I.
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p. 6211 - 6220
(2007/10/03)
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- Enantioselective Total Synthesis of the Potent Antitumor Agent (-)-Mucocin Using a Temporary Silicon-Tethered Ring-Closing Metathesis Cross-Coupling Reaction
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The enantioselective total synthesis of the annonaceous acetogenin (?)-mucocin (1) was accomplished using a triply convergent 12-step sequence (longest linear sequence) in 13.6% overall yield. This represents the first application of the temporary silicon-tethered (TST) ring-closing metathesis (RCM) cross-coupling reaction and the enantioselective alkyne/aldehyde addition to the synthesis of a complex annonaceous acetogenin. Moreover, all three fragments required for the coupling reactions are conveniently prepared in 5?6 steps from two readily available enantiomerically enriched epoxides. Finally, this synthesis stimulated the development of a new approach for the construction of 3-hydroxy-2,6-disubstituted tetrahydropyrans, using the bismuth tribromide-mediated reductive etherification reaction, which represents a motif that is prevalent in a wide range of pharmacologically significant natural products. Copyright
- Evans, P. Andrew,Cui, Jian,Gharpure, Santosh J.,Polosukhin, Alexei,Zhang, Hai-Ren
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p. 14702 - 14703
(2007/10/03)
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- Inter-element linkage in 1,2- and 1,4-bis(arylselanyl)benzenes with halogens
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The criteria to distinguish the structure of halogen adducts of aryl chalcogenides in solutions based on the NMR chemical shifts are confirmed by ab initio molecular orbitals (MO) calculations based on the gauge-including atomic orbitals (GIAO) theory. The criteria are applied to determine the structure of halogen adducts of 1,2-bis(phenylselanyl)benzene (1), 1,4-bis(phenylselanyl)benzene (2), and 1,4-bis(p-tert-butylphenylselanyl)benzene (3) (1·nX2, 2·nX2, and 3·nX2, respectively: n = 1 and 2 and X = Cl, Br, and I) in CDCl3. The structure of 1·Br2 is demonstrated to be trigonal bipyramidal (TB) not only in the solution but also in crystals. The TB formation of 1·Br2 is just the opposite of the MC (molecular complexes) formation of selenanthrene with bromine in the solution. The driving force for the TB and MC formation is discussed based on the structure of the parent selenides. The structure of 2·2X2 and 3·2X2 is (TB, TB) for X = Cl and Br and (MC, MC) for X = I. On the other hand, the structure of 1·2Br2 is revealed to be TB at one SeBr2 moiety but MC for the other SeBr2 group, which is described as (TB, MC). The bromine exchange is observed in 1·2Br2 in the conditions of NMR measurements. The rate of bromine exchange becomes sharp as excess bromine is added to the 1·2Br2 solution, which shows that the structural (TB, MC) ? (MC, TB) site exchange in 1·2Br2 is accelerated by the excess bromine and/or its derivatives. Ab initio MO calculations are performed on the adducts to understand their structural features and on the proposed intermediate to confirm the mechanism.
- Nakanishi, War?,Hayashi, Satoko
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p. 178 - 189
(2007/10/03)
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- Synthesis of oligosaccharide fragments of the glycosylinositolphospholipid of Trypanosoma cruzi: a new selenoglycoside glycosyl donor for the preparation of 4-thiogalactofuranosyl analogues
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A new selenoglycoside, phenyl 2,3,5,6-tetra-O-acetyl-4-thio-1-selenogalactofuranose, has been synthesized. This 4-thiogalactofuranosyl donor was used in the syntheses of heteroatom analogues of the di-, tri-, and tetrasaccharides corresponding to the oligosaccharide β-D-Galf-(1→3)-α-D-Manp-(1→2)-(β-D-Galf-(1→3))-α-D-Manp. These compounds represent fragments of the terminal end of the glycosylinositolphospholipid oligosaccharide found in the protozoan Trypanosoma cruzi, the causative agent of Chagas disease, and are intended for use as inhibitors of the enzymes that construct the native oligosaccharides. The syntheses employed the selective activation of a phenyl 4-thio-1-selenogalactofuranoside glycosyl donor over ethyl 1-thioglycoside glycosyl acceptors with NIS/TfOH. Copyright (C) 2000 Elsevier Science Ltd.
- Randell, Karla D.,Johnston, Blair D.,Lee, Ernest E.,Pinto, B. Mario
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p. 207 - 222
(2007/10/03)
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- Diverging effects of steric congestion on the reaction of tributylstannyl radicals with areneselenols and aryl bromides and their mechanistic implications
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The effects of bulky ortho,ortho' groups on the reactions of aryl bromides and areneselenols with tributylstannane have been studied. Bulky ortho,ortho' groups accelerate the reaction of the bromides with the stannane but retard the reactions of the selenols. On the other hand, ab initio and force field calculations show that introducing bulky ortho substituents into selenols causes a greater increase in strain than in the corresponding bromides. Two possible explanations for the divergent reactivity patterns are advanced. On one hand, it is possible that bromine abstraction by stannyl radicals from aryl bromides proceeds in a single step through a linear transition state whereas the abstraction of sell from the selenols involves a T-shaped, hypervalent intermediate. Alternatively, it may be that both reactions are concerted with the bromine abstraction having a late transition state and the sell abstraction an early one. Approximate second-order rate constants for the reaction of tributylstannane with a range of hindered aryl bromides are derived from competition reactions. 2,4,6-Tri-tert- butylbenzeneselenol is able to function moderately well as a catalyst for the stannane-mediated reactions of vinyl bromides. The X-ray crystal structure of bis(2,4,6-triisopropylphenyl) diselenide is presented.
- Crich, David,Hwang, Jae-Taeg,Gastaldi, Stephane,Recupero, Francesco,Wink, Donald J.
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p. 2877 - 2882
(2007/10/03)
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- Absolute Rate Constants for Alkoxycarbonyl Radical Reactions
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PTOC oxalates (anhydrides of an oxalic acid monoester and N-hydroxypyridine-2-thione) were used in laser flash photolysis (LFP) kinetic studies. Irradiation of the PTOC oxalates gave the following alkoxycarbonyl radicals ROC(·)=O: 2a, R = PhCH2; 2b, R = (trans-2-phenylcyclopropyl)methyl; 2c, R = (2,2-diphenylcyclopropyl)methyl. Rate constants for decarboxylation of radical 2a measured by LFP were in agreement with those obtained previously by indirect kinetic methods. Rate constants for decarboxylation of radical 2c were measured by LFP over the temperature range 3-48°C; the reaction is described by log k = 12.2-9.6/2.3RT (kcal/mol). Reactions of Bu3SnH with radical 2c produced from the corresponding phenylseleno carbonate gave inconsistent kinetic results apparently due to the production of small amounts of PhSeH that reacted rapidly with 2c. An approximate rate constant at 2°C for reaction of Bu3SnH with 2c produced from the PTOC oxalate was obtained. Tin hydride reacts with the alkoxycarbonyl radical approximately 1 order of magnitude less rapidly than it reacts with alkyl radicals. Rate constants for 5-exo cychzations of simple alkoxycarbonyl radicals were estimated from previous results and the approximate rate constant for tin hydride trapping; the cyclizations are slightly faster than 5-exo cyclizations of structurally related alkyl radicals.
- Simakov, Pavel A.,Martinez, Felix N.,Horner, John H.,Newcomb, Martin
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p. 1226 - 1232
(2007/10/03)
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- Thermal reactions of organyl chalcogenides with α,β-unsaturated aldehydes
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Thermalgas-phase reactions of acrolein, cinnamaldehyde, and benzaldehyde with diorganyl chalcogenides and diorganyl dichalcogenides were studied.Acrolein does not react with chalcogenides at 300-600 deg C but completely decomposes under reaction conditions.At 600-650 deg C, cinnamaldehyde reacts only with diorganyl selenides and diselenides to give benzoselenophene.Its highest yield (53percent) is achieved in the reaction with dimethyl diselenide at 630 deg C and at an equimolar ratio of the reactants.The gas-phase reactions of benzaldehyde at 400-500 deg C afford chalcogen-containing derivatives of several types, among which thioanisole and its selenium or tellurium analogs predominate.The mechanisms of the above reactions were discussed in terms of homolytic substitution of the formyl group at unsaturated carbon atoms by chalcogenyl radicals. - Keywords: gas-phase reactions; cinnamaldehyde; benzaldehyde; chalcogenyl radicals; benzoselenophene, selenoanisole, telluroanisole.
- Deryagina, E. N.,Korchevin, N. A.,Shilkina, T. A.,Sukhomazova, E. N.,Levanova, E. P.
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p. 447 - 450
(2007/10/03)
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- Carbonyl transposition on organoselenium compounds
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Carbonyl conjugated vinylic selenides undergo 1,3 and 1,5-carbonyl transposition sequences through organometallic reagents addition reactions followed by acid hydrolysis.
- Comasseto, Joao V.,Lo, Wai L.,Petragnani, Nicola
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p. 7445 - 7460
(2007/10/03)
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- Stereoselective synthesis of (E)-vinylic selenides by palladium catalyzed cross-coupling reactions
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Hydrozirconation of arylselenoethynes gives zirconium (IV) complexes 3, which are cross-coupled with aryl halides in the presence of tetrakis (triphenylphosphine) palladium catalyst to afford (E)-vinylic selenides 5 in high yield.
- Huang, Xian,Zhu, Liu-Sheng
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- Reaction of Difluoromethyl Phenyl Selenoxide with Acetic Anhydride. A Route to Difluoro(phenylseleno)methylation of Ethers
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Difluoromethyl phenyl selenoxide (2) has been prepared and allowed to react with acetic anhydride in the presence of cyclic ethers and sulfides.Difluorophenylselenomethylation occurred smoothly on reacting 2 with Ac2O in refluxing dichloromethane to give ω-alkyl acetates 4 in 34-87percent yields.A sequential reaction of Pummerer type rearrangement, difluorocarbene formation, electrophilic addition of the carbene to oxygen of ethers leading to oxonium ylide, and trapping with phenylselenyl acetate is proposed.
- Uneyama, Kenji,Maeda, Kazuhiro,Tokunaga, Yukio,Itano, Nobuaki
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p. 370 - 375
(2007/10/02)
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- Evidence for a common selenolate intermediate in the glutathione peroxidase-like catalysis of α-(phenylselenenyl) ketones and diphenyl diselenide
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The glutathione peroxidase-like catalysis of α-(phenylselenenyl) ketones was investigated. Degradation studies demonstrated the rapid cleavage of the aliphatic carbon-selenium bond of α-(phenylselenenyl) ketones by glutathione at pH 6.9 in a methanolic phosphate buffer under argon. On treatment with excess glutathione under aerobic conditions, α-(phenylselenenyl) ketones, S- (phenylselenenyl)glutathione and diphenyl diselenide were all shown to give benzeneselenolate. This material was found to be oxidized by hydrogen peroxide considerably faster than α-(phenylselenenyl) ketones, S- (phenylselenenyl)glutathione or diphenyl diselenide. A catalytic mechanism involving benzeneselenolate, benzeneselenenic acid and S- (phenylselenenyl)glutathione as crucial intermediates was proposed to account for the glutathione peroxidase-like catalysis of α-(phenylselenenyl) ketones and diphenyl diselenide.
- Engman, Lars,Andersson, Claes,Morgenstern, Ralf,Cotgreave, Ian A.,Andersson, Carl-Magnus,Hallberg, Anders
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p. 2929 - 2938
(2007/10/02)
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- Synthesis of sulfur analogues of methyl and allyl kojibiosides and methyl isomaltoside and conformational analysis of the kojibiosides
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The synthesis of methyl and allyl 5'-thio-α-D-kojibiosides and methyl 5'-thio-α-D-isomaltoside is described. The phenylselenoglycoside and trichloroacetimidate of 2,3,4,6-tetra-O-acetyl-5-thioglucose have been employed as glycosyl donors to glycosylate glucopyranosyl acceptors with 2-OH and 6-OH positions free. The disaccharides thus obtained are potential glucosidase inhibitors. The conformational preferences of allyl 5'-thiokojibioside (34) were studied by comparison of experimental NOE curves with the theoretical counterparts for the corresponding methyl glycoside 25, derived from a Boltzman-averaged gird search using the program PIMM91. Very good agreement of experimental NOE curves derived from selective NOE measurements with the theoretical curves is found. The data are consistent with the population of a global minimum structure (Φ = 43, Ψ = 39 degrees) to the extent of 90%, and a second local minimum (Φ = 36, Ψ = 173 degrees) to the extent of 6%. An X-ray crystal structure of 34 at 190 K (R = 4.2%) indicates a conformation (Φ = 46, Ψ = 23 degrees) that is similar to that of the global minimum.
- Mehta,Jordan,Weimar,Kreis,Batchelor,Einstein,Pinto
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p. 2367 - 2396
(2007/10/02)
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- Electrochemical Oxidation of Proline Derivatives: Total Syntheses of Bulgecinine and Bulgecin C
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The influence of structure on the efficiency of the electrochemical C-5 oxidation of (2S,4S)-hydroxyproline carbamate esters is presented.Optimum methoxylation was observed with (2S,4S)-4-acetoxy-1,2-pyrrolidine-dicarboxylic acid 2-methyl 1-(2-(trimethylsilyl)ethyl) ester (19).The corresponding C-5 methoxy derivative 20 was converted into bulgecinine (4) via a stereospecific radical homologation to incorporate the C-5 hydroxymethyl substituent.Bulgecin C (1c) was prepared via a β-stereoselective glycosidation reaction using a 2-azido-2-deoxy-α-D-glucopyranosyl trichloroacetimidate derivative, regiospecific C-4' sulfation, and deprotection.
- Barrett, Anthony G. M.,Pilipauskas, Daniel
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p. 2787 - 2800
(2007/10/02)
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- A Synthesis of an Alkylated Taxane Model System
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A new synthesis of the model compound 8,12,15,15-tetramethyltricyclo3,8>pentadecane using LiCMe2SePh in a method to produce highly substituted dienes is reported.
- Bonnert, Roger V.,Jenkins, Paul R.
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p. 413 - 418
(2007/10/02)
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