- InCl3 catalyzed highly diastereoselective [3 + 2] cycloaddition of 1,2-cyclopropanated sugars with aldehydes: A straightforward synthesis of persubstituted bis -tetrahydrofurans and perhydrofuro[2,3- b ]pyrans
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A mild and efficient strategy for the construction of persubstituted bis-tetrahydrofuran and perhydrofuro[2,3-b]pyran derivatives has been developed. Persubstituted cyclization products were obtained in good to excellent yields. The [3 + 2] cycloaddition of 1,2-cyclopropanated sugars with aldehydes in the presence of InCl3 is highly diastereoselective.
- Ma, Xiaofeng,Tang, Qin,Ke, Jun,Yang, Xinglong,Zhang, Jichao,Shao, Huawu
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Read Online
- A mild and efficient method for chemoselective deprotection of acetonides by bismuth(III) trichloride
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Acetonides undergo chemoselective deprotection to afford the corresponding 1,2-diols in excellent yields using bismuth trichloride in acetonitrile/dichloromethane at ambient temperature.
- Swamy, N.Raghavendra,Venkateswarlu
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Read Online
- ANTIBODY-STING AGONIST CONJUGATES AND THEIR USE IN IMMUNOTHERAPY
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The present disclosure relates to, among other things, antibody-drug conjugates comprising a STING agonist cyclic di-nucleotide conjugated to an antibody, preparation methods therefor, and uses therefor.
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Paragraph 00284; 00285
(2021/01/29)
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- Synthesis and in vitro antitumour activity of 4(R)-methyl-3-O-phosphonomethyl-α-L-threose nucleosides
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A series of novel α-L-threose nucleoside phosphonate analogs, 4(R)-methyl-3-O-phosphonomethyl-α-L-threose nucleosides, were synthesized in multistep sequences starting from D-xylose. The synthetic sequence consisted of the following key stages: (i) the multistep synthesis of 1,2-O-isopropylidenyl-4(R)-methyl-3-O-phosphonomethyl-L-threose, (ii) the transformation of 1,2-O-isopropylidenyl sugar into suitable 1,2-di-O-acyl L-threose precursor, and (iii) the construction of target α-L-threose nucleoside phosphonate analogs by Vorbrüggen glycosidation reaction, deprotection of acyl group, and hydrolysis of diethyl group on phosphonate. The target nucleoside phosphonates were evaluated for their antitumour activities in cell culture-based assays. Compound 8g, 2-fluroadenosine phosphonate, showed remarkable activity against human breast cancer cell lines (MCF-7 and MDA-MB-231) with IC50 values of 0.476 and 0.391 μM, corresponding to 41- and 47-fold higher potency than the reference compound 5-FU, respectively. Subsequent investigations found that the compound 8g can inhibit the proliferation of breast cancer cells and cell cloning. The mechanistic studies indicated that compound 8g could cause DNA damage to breast cancer cells through the ATM-Chk1/Chk2-cdc25c pathway, leading to blockage of the G2/M phase cycle of breast cancer cells, which ultimately led to apoptosis. Moreover, 8g could inhibit the PI3K/AKT signaling pathway and induce apoptosis. These results indicate that compound 8g holds promising potential as an antitumour agent.
- Liu, Feng-Wu,Ji, Shujie,Gao, Yingying,Meng, Yao,Xu, Wenke,Wang, Haixia,Yang, Jing,Huang, Hao,Herdewijn, Piet,Wang, Cong
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- Synthesis and evaluation of 3′-fluorinated 7-deazapurine nucleosides as antikinetoplastid agents
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Kinetoplastid parasites are the causative agents of neglected tropical diseases with an unmet medical need. These parasites are unable to synthesize the purine ring de novo, and therefore rely on purine salvage to meet their purine demand. Evaluating purine nucleoside analogs is therefore an attractive strategy to identify antikinetoplastid agents. Several anti-Trypanosoma cruzi and anti-Trypanosoma brucei 7-deazapurine nucleosides were previously discovered, with the removal of the 3′-hydroxyl group resulting in a significant boost in activity. In this work we therefore decided to assess the effect of the introduction of a 3′-fluoro substituent in 7-deazapurine nucleosides on the anti-kinetoplastid activities. Hence, we synthesized two series of 3′-deoxy-3′-fluororibofuranosyl and 3′-deoxy-3′-fluoroxylofuranosyl nucleosides comprising 7-deazaadenine and -hypoxanthine bases and assayed these for antiparasitic activity. Several analogs with potent activity against T. cruzi and T. brucei were discovered, indicating that a fluorine atom in the 3′-position is a promising modification for the discovery of antiparasitic nucleosides.
- Bouton, Jakob,Caljon, Guy,Furquim d'Almeida, Arno,Hulpia, Fabian,Maes, Louis,Van Calenbergh, Serge
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- Control of Crystallinity and Stereocomplexation of Synthetic Carbohydrate Polymers from d- and l-Xylose
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Manipulating the stereochemistry of polymers is a powerful method to alter their physical properties. Despite the chirality of monosaccharides, reports on the impact of stereochemistry in natural polysaccharides and synthetic carbohydrate polymers remain absent. Herein, we report the cocrystallisation of regio- and stereoregular polyethers derived from d- and l-xylose, leading to enhanced thermal properties compared to the enantiopure polymers. To the best of our knowledge, this is the first example of a stereocomplex between carbohydrate polymers of opposite chirality. In contrast, atactic polymers obtained from a racemic mixture of monomers are amorphous. We also show that the polymer hydroxyl groups are amenable to post-polymerisation functionalization. These strategies afford a family of carbohydrate polyethers, the physical and chemical properties of which can both be controlled, and which opens new possibilities for polysaccharide mimics in biomedical applications or as advanced materials.
- McGuire, Thomas M.,Bowles, Jessica,Deane, Edward,Farrar, Elliot H. E.,Grayson, Matthew N.,Buchard, Antoine
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supporting information
p. 4524 - 4528
(2021/01/12)
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- Synthesis and Antiviral Evaluation of 3'-C-Hydroxymethyl-3'-O-Phosphonomethyl-β-D-5'-deoxyxylose Nucleosides
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L-2'-deoxythreose nucleoside phosphonates PMDTA and PMDTT possess potent anti-HIV activity. Herein, a novel class of 3'-C-branched-l-threose nucleoside phosphonate analogs, 5'-deoxy-3'-C-hydroxymethyl-3'-O-phosphonomethyl-d-xylose nucleosides, were synthesized and biologically evaluated. The key sugar intermediate 3-C-benzyloxymethyl-3-O-diethylphosphonomethyl-1,2-O-isopropylidene-α-d-5-deoxyxylose (8) was firstly synthesized, which may be an interesting scaffold for access to diverse 3'-C-branched l-threosyl nucleoside phosphonate derivatives. And the key synthesis involved Wittig olefination of 1,2-O-isopropylidene-3-oxo-α-d-5-deoxyxylose, stereoselective dihydroxylation of alkenes by aqueous KMnO4, selective benzylation of hydroxymethyl group under activation of dibutyltin oxide, and introduction of phosphonate group by nucleophilic substitution. Eventually, glycosylation under Vorbrüggen conditions provided 3'-C-hydroxymethyl-3'-O-phosphonomethyl-β-d-5'-deoxyxylose nucleoside analogs in satisfying yield.
- Gao, Yingying,Herdewijn, Piet,Huo, Xiangyu,Ji, Shujie,Liu, Feng-Wu,Wang, Haixia,Wang, Song,Xu, Wenke
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- PRMT5 INHIBITORS
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The present invention provides a compound of formula (I) Formula (I) and the pharmaceutically acceptable salts, esters, and prodrugs thereof, are PRMT5 inhibitors. Also provided are methods of making compounds of formula (I), pharmaceutical compositions comprising compounds of formula (I), and methods of using these compounds to treat cancer, sickle cell, and hereditary persistence of foetal hemoglobin (HPFH) mutations.
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Page/Page column 59-60
(2020/03/02)
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- Antitumor (4' R)-methyl - α-L . (by machine translation)
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The invention discloses novel α-L - fucosa nucleoside phosphonate analogs, and particularly relates to (4 ′). R- Methyl -3 ' - methyl phosphonic acid - α-L . It has the structure shown in Formula 1. Wherein R ' represents H, Na, K or NH. 4 Ions; B stands for uracil, thymine, 5 - chlorouracil, 5 - fluorouracil, 5 -bromouracil, 5 -fluorouracil, cytosine, 5 - fluorocytosine, adenine, 2 - fluoroadenine, 2 - chloroadenine, 2 - aminoadenine and guanine. The compound has anti-tumor activity and good development prospect. (by machine translation)
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Paragraph 0050-0051
(2020/06/09)
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- Nascent-HBr-Catalyzed Removal of Orthogonal Protecting Groups in Aqueous Surfactants
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Organic reactions in the aqueous environment have recently emerged as a promising research area. The generation of nascent-HBr from the slow hydrolysis of the dispersed catalyst, benzyl bromide, with the interior water present in the hydrophobic core of the confined micellar medium in aqueous surfactant is described for the first time. The sustained-release nascent-HBr enabled the chemoselective cleavages of acid-sensitive orthogonal functionalities present in carbohydrates, amino alcohols, and hydroxylated acyclic compounds in good to excellent yields.
- Bera, Smritilekha,Gupta, Shilpi,Mondal, Dhananjoy
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- Structure and preparation method of furanose cyclic phosphoric ester fire retardant
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The invention relates to a structure and preparation method of a furanose cyclic phosphoric ester fire retardant. The preparation method is simple in technology, the raw materials are low in cost, theenvironmental pollution is low, and the prepared cyclic phosphoric ester fire retardant is prominent in fire retardance and industrialization is easy to realize.
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Paragraph 0030-0032
(2020/06/24)
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- Computer Modelling and Synthesis of Deoxy and Monohydroxy Analogues of a Ribitylaminouracil Bacterial Metabolite that Potently Activates Human T Cells
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5-(2-Oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU) is a natural product formed during bacterial synthesis of vitamin B2. It potently activates mucosal associated invariant T (MAIT) cells and has immunomodulatory, inflammatory, and anticancer properties. This highly polar and unstable compound forms a remarkably stable Schiff base with a lysine residue in major histocompatibility complex class I–related protein (MR1) expressed in antigen-presenting cells. Inspired by the importance of the ribityl moiety of 5-OP-RU for binding to both MR1 and the T cell receptor (TCR) on MAIT cells, each OH was removed in silico. DFT calculations and MD simulations revealed a very stable hydrogen bond between the C3′?OH and uracil N1H, which profoundly restricts flexibility and positioning of each ribityl-OH, potentially impacting their interactions with MR1 and TCR. By using deoxygenation strategies and kinetically controlled imine formation, four monodeoxyribityl and four monohydroxyalkyl analogues of 5-OP-RU were synthesised as new tools for probing T cell activation mechanisms.
- Ler, Geraldine J. M.,Xu, Weijun,Mak, Jeffrey Y. W.,Liu, Ligong,Bernhardt, Paul V.,Fairlie, David P.
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p. 15594 - 15608
(2019/11/16)
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- Synthesis of Terminal Ribose Analogues of Adenosine 5′-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2
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TRPM2 (transient receptor potential cation channel, subfamily M, member 2) is a nonselective cation channel involved in the response to oxidative stress and in inflammation. Its role in autoimmune and neurodegenerative diseases makes it an attractive pharmacological target. Binding of the nucleotide adenosine 5′-diphosphate ribose (ADPR) to the cytosolic NUDT9 homology (NUDT9H) domain activates the channel. A detailed understanding of how ADPR interacts with the TRPM2 ligand binding domain is lacking, hampering the rational design of modulators, but the terminal ribose of ADPR is known to be essential for activation. To study its role in more detail, we designed synthetic routes to novel analogues of ADPR and 2′-deoxy-ADPR that were modified only by removal of a single hydroxyl group from the terminal ribose. The ADPR analogues were obtained by coupling nucleoside phosphorimidazolides to deoxysugar phosphates. The corresponding C2″-based analogues proved to be unstable. The C1″- and C3″-ADPR analogues were evaluated electrophysiologically by patch-clamp in TRPM2-expressing HEK293 cells. In addition, a compound with all hydroxyl groups of the terminal ribose blocked as its 1″-β-O-methyl-2″,3″-O-isopropylidene derivative was evaluated. Removal of either C1″ or C3″ hydroxyl groups from ADPR resulted in loss of agonist activity. Both these modifications and blocking all three hydroxyl groups resulted in TRPM2 antagonists. Our results demonstrate the critical role of these hydroxyl groups in channel activation.
- Baszczyňski, Ond?ej,Watt, Joanna M.,Rozewitz, Monika D.,Guse, Andreas H.,Fliegert, Ralf,Potter, Barry V.L.
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p. 6143 - 6157
(2019/05/24)
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- CYCLIC DINUCLEOTIDES AS ANTICANCER AGENTS
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The present invention is directed to compounds of the formulae I, II and III as shown below wherein all substituents are defined herein, as well as pharmaceutically acceptable compositions comprising compounds of the invention and methods of using said compositions in the treatment of various disorders.
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- Sugar based γ-amino alcohol organocatalyst for asymmetric Michael addition of β-keto esters with nitroolefins
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Sugar based γ-amino alcohol was used in asymmetric Michael addition of β-keto esters with nitroolefins for the first time affording the corresponding several chiral Michael adducts bearing quaternary chiral carbon center in moderate to good chemical yields and stereoselectivities (up to 98%, up to dr. 95:5, up to 84% ee).
- Begum, Zubeda,Chennapuram, Madhu,Ganesan, Divakar,Kwon, Eunsang,Nakano, Hiroto,Okuyama, Yuko,Seki, Chigusa,Takeshita, Mitsuhiro,Tokiwa, Michio,Tokiwa, Suguru,Uwai, Koji
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p. 1536 - 1545
(2020/01/28)
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- Synthesis and antimicrobial evaluation of amino sugar-based naphthoquinones and isoquinoline-5,8-diones and their halogenated compounds
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Antibiotic resistance has emerged as a serious global public health problem and lately very few antibiotics have been discovered and introduced into clinical practice. Therefore, there is an urgent need for the development of antibacterial compounds with new mechanism of action, especially those capable of evading known resistance mechanisms. In this work two series of glycoconjugate and non-glycoconjugate amino compounds derived from of isoquinoline-5,8-dione and 1,4-naphthoquinone and their halogenated derivatives were synthesized and evaluated for antimicrobial activity against Gram-positive (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. epidermidis ATCC 12228, S. simulans ATCC 27851) and Gram-negative bacteria (E. coli ATCC 25922, Proteus mirabilis ATCC 15290, K. pneumoniae ATCC 4352 and P. aeruginosa ATCC 27853) strains of clinical importance. This study revealed that glycoconjugate compounds derived from halogeno-substituted naphthoquinones were more active against Gram-negative strains, which cause infections whose treatment is even more difficult, according to the literature. These molecules were also more active than isoquinoline-5,8-dione analogues with minimum inhibitory concentration (MIC = 4–32 μg/mL) within Clinical and Laboratory Standard Institute MIC values (CLSI 0.08–256 μg/mL). Interestingly the minimal bactericidal concentration (MBC) values of the most active compounds were equal to MIC classifying them as bactericidal agents against Gram-negative bacteria. Sixteen compounds among eighteen carbohydrate-based naphthoquinones tested showed no hemolytic effects on health human erythrocytes whereas more susceptibility to hemolytic cleavage was observed when using non-glycoconjugate amino compounds. In silico Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) evaluation also pointed out that these compounds are potential for oral administration with low side effects. In general, this study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials more effective against Gram-negative bacteria.
- Dias, Flaviana R.F.,Novais, Juliana S.,Devillart, Talita A. do Nascimento Santos,da Silva, Wanderson Amaral,Ferreira, Matheus O.,Loureiro, Raquel de S.,Campos, Vinícius R.,Ferreira, Vitor F.,de Souza, Maria C.B.V.,Castro, Helena C.,Cunha, Anna C.
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- Phosphorus pentachloride promoted gem-dichlorination of 2′- and 3′-deoxynucleosides
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Halogen substitution at various positions of canonical nucleosides has generated a number of bioactive structural variants. Herein, the synthesis of two unique series of sugar modified nucleosides bearing a gem-dichloro group is presented. The synthetic plan entails the controlled addition of phosphorus pentachloride to suitably protected 2′- or 3′-ketodeoxynucleoside intermediates as the key step, facilitating the rapid construction of such functionalized molecules. Under the same reaction conditions, the highest chemoselectivity was observed for the formation of 2′,2′-dichloro-2′,3′-dideoxynucleosides, while a competing 2′,3′-elimination process occurred in the case of the 3′,3′-dichloro counterparts.
- Da Paixao Soares, Fabio,Groaz, Elisabetta,Herdewijn, Piet
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- An eco-compatible strategy for the diversity-oriented synthesis of macrocycles exploiting carbohydrate-derived building blocks
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An efficient, eco-compatible diversity-oriented synthesis (DOS) approach for the generation of library of sugar embedded macrocyclic compounds with various ring size containing 1,2,3-triazole has been developed. This concise strategy involves the iterative use of readily available sugar-derived alkyne/azide-alkene building blocks coupled through copper catalyzed azide-alkyne cycloaddition (CuAAC) reaction followed by pairing of the linear cyclo-adduct using greener reaction conditions. The eco-compatibility, mild reaction conditions, greener solvents, easy purification and avoidance of hazards and toxic solvents are advantages of this protocol to access this important structural class. The diversity of the macrocycles synthesized (in total we have synthesized 13 macrocycles) using a set of standard reaction protocols demonstrate the potential of the new eco-compatible approach for the macrocyclic library generation.
- Maurya, Sushil K.,Rana, Rohit
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supporting information
p. 1106 - 1118
(2017/06/21)
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- PROCESSES FOR PREPARING 2-DIHALO RIBOLACTONES
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Methods for forming 2-bromo, 2-fluoro ribofuranose intermediates and 2-chloro, 2- fluoro ribofuranose intermediates for use in preparing antiviral nucleosides are disclosed. Methods for forming nucleosides, and nucleoside prodrugs, using the intermediates, are also disclosed. The methods all produce intermediates, and the resulting nucleosides and prodrugs thereof, wherein the chirality of the carbon at the 2-position is controlled. In some embodiments, the chemistry involves using chiral auxiliaries, such as (R)-2,2-dimethyl-l,3- dioxolane-4-carbaldehyde, and in other embodiments, the chemistry involves using chiral starting materials, such as D-xylose.
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Page/Page column 73; 74
(2017/06/21)
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- Synthesis of Ribonucleosidic Dimers with an Amide Linkage from D-Xylose
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An original and efficient stereocontrolled synthesis of ribonucleosidic homo- and heterodimers has been achieved from inexpensive d-xylose. This successful strategy involved the sequential introduction of nucleobases, using two stereocontrolled N-glycosidation reactions, from a common two-furanoside amide-linked scaffold offering the possibility of obtaining any given base sequence. The pertinence of this approach is illustrated through the preparation of the homodimers UU-34 and TT-35 in 18 steps with an excellent overall yield of more than 10% from d-xylose, while the heterodimer route led to UT-39 in 19 steps with around 10% overall yield.
- Arzel, Laurence,Dubreuil, Didier,Dénès, Fabrice,Silvestre, Virginie,Mathé-Allainmat, Monique,Lebreton, Jacques
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p. 10742 - 10758
(2016/11/29)
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- Discovery of cytochrome bc1 complex inhibitors inspired by the natural product karrikinolide
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The cytochrome bc1 complex (cyt bc1 or complex III) is a promising target of numerous antibiotics and fungicides. With an aim to indentify new lead structures for the bc1 complex, a series of novel inhibitors were discovered from the natural product karrikinolide for the first time. Extensive screening results suggested variable inhibitory activities of these compounds against succinate-cytochrome reductase [SCR, a mixture of respiratory complex II (SQR) and complex III (the bc1 complex)], implying the essential role of a 4-substituted phenyl group for the high potency. Exceptionally, compound 12g showed excellent inhibition potency having an IC50 value in the sub-micromolar range, demonstrating its higher potency than the commercial control amisulbrom by over two orders of magnitude. Further experiments inferred that these newly prepared compounds mainly target the bc1 complex. Seemingly, this work has presented a new lead scaffold for further development of bc1 complex inhibitors.
- Chen, Cheng,Wu, Qiong-You,Shan, Lian-Ying,Zhang, Bei,Verpoort, Francis,Yang, Guang-Fu
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p. 97580 - 97586
(2016/10/31)
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- Syntheses and complexing ability of α-d-gluco- and α-d-xylofuranoside-based lariat ethers
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Chiral monoaza-15-crown-5 lariat ethers attached to a 1,2-O-isopropylidene-α-d-glucofuranoside unit (10–13), monoaza-16-crown-5 lariat ethers fused to 1,2-O-isopropylidene-α-d-glucofuranoside- (18) and to 1,2-O-isopropylidene-α-d-xylofuranoside units (23 and 24) have been synthesized. The alkali metal- and ammonium picrate extracting ability of these macrocycles was investigated in dichloromethane–water system. In general, the 15-membered macrocycles (10–13) showed, for almost all cations, a more considerable extracting ability, than the 16-membered lariat ethers (18, 23 and 24). Plasticized PVC membrane electrodes (ISEs) were prepared from the α-d-glucofuranoside-based triphenylmetyl (trityl) ether derivative (18), and its potentiometric selectivities and complex formation constants were determined with the segmented sandwich membrane method. Furthermore, the binding affinities of ionophores to different metal ions were also measured by competitive ESI–MS experiments. One of the 1,2-O-isopropylidene-α-d-glucofuranoside-based lariat ethers (13) exhibited a high selectivity for silver ion (Ag+).
- Rapi, Zsolt,Ozohanics, Oliver,Tóth, Gábor,Bakó, Péter,H?fler, Lajos,Nemcsok, Tamás,Kánya, Nándor,Keglevich, Gy?rgy
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- Palladium-catalyzed enantioselective allylic substitution in the presence of monodentate furanoside phosphoramidites
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A library of monodentate furanoside phosphoramidites, easily synthesized from inexpensive D-xylose and optically pure 1,1-bi-2-naphthol (BINOL), was used as ligands for the palladium-catalyzed allylic alkylation and amination. The matched pair was formed from D-xylose-derivatives and (S)-BINOL. The asymmetric induction depends strongly on the substituent at the C5 of the carbohydrate backbone; both bulky 5-O-pivaloyl and 5-deoxy derivatives gave excellent results, whereas ligands with trityl protection at position C5 induced low ee values with reversal of configuration. The solvent used for the addition is also of great importance with highest enantioselectivities observed in diethyl ether. The best results for both alkylation and amination, up to 98-99 ee, were obtained for sterically demanding allylic acetates. Single is better: New carbohydrate ligands bearing a single 1,1-bi-2-naphthol (BINOL)-derived phosphoramidite moiety are developed and successfully applied to the palladium-catalyzed asymmetric allylic substitution. The enantioselectivities are equal or better than those obtained for similar systems containing two BINOL moieties and reach up to 99 ee.
- Majdecki, Maciej,Jurczak, Janusz,Bauer, Tomasz
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p. 799 - 807
(2015/03/14)
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- Synthesis of a new class of naphthoquinone glycoconjugates and evaluation of their potential as antitumoral agents
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A novel series of carbohydrate-based naphthoquinones was synthesized and evaluated for cytotoxicity against different cancer cell lines. The compounds derived from 5-hydroxy-1,4-naphthoquinone (juglone) showed better cytotoxicity profiles against HCT-116, A-549 and MDA-MB 435 human cancer cells than the parent compound. The results suggest that the hydroxyl group on the aromatic ring increased the pro-oxidant activity of these new naphthoquinone derivatives. Furthermore, two derivatives were found to be more active against melanoma cells (MDA-MB435) than the clinically useful anticancer agent doxorubicin, and none of the compounds caused mouse erythrocyte lysis.
- Campos, Vinicius R.,Cunha, Anna C.,Silva, Wanderson A.,Ferreira, Vitor F.,Santos De Sousa, Carla,Fernandes, Patrícia D.,Moreira, Vinícius N.,Da Rocha, David R.,Dias, Flaviana R. F.,Montenegro, Raquel C.,De Souza, Maria C. B. V.,Boechat, Fernanda Da C. S.,Franco, Caroline F. J.,Resende, Jackson A. L. C.
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p. 96222 - 96229
(2015/11/24)
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- 2-Substituted thiazole-4-carboxamide derivatives as tiazofurin mimics: Synthesis and in vitro antitumour activity
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Tiazofurin analogues bearing a 5-hydroxymethyl-2-methyl-tetrahydrofuro[2,3- d][1,3]dioxol-6-ol moiety as a sugar mimic (2 and 3), and two novel thiazole-based acyclo-C-nucleosides 4 and 16 have been synthesized in multistep sequences starting from d-xylose (compounds 2 and 3) or from d-arabinose (compounds 4 and 16). All synthesized analogues showed potent in vitro antitumour activities against a panel of human tumour cell lines. Flow cytometry data suggest that cytotoxic effects of analogues 2-4 and 16 in the culture of K562 cells might be mediated by apoptosis. It was also found that these analogues induced changes in cell cycle distribution of K562 cells. Results of western blot analysis (upregulation of Bax and downregulation of Bcl-2, activation of caspase-3 and the presence of a PARP cleavage product) suggest that tiazofurin mimics (2-4 and 16) in K562 cells induced apoptosis in a caspase-dependent way.
- Popsavin, Mirjana,Koji?, Vesna,Spai?, Sa?a,Svir?ev, Milo?,Bogdanovi?, Gordana,Jakimov, Dimitar,Aleksi?, Lidija,Popsavin, Velimir
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supporting information
p. 2343 - 2350
(2014/04/03)
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- Methanesulfonic-acid-catalysed ring opening and glycosylation of 1,2-(Acetylcyclopropane)-annulated d -lyxofuranose
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A mild and effective method for the synthesis of 2-C-branched disaccharides, glycoconjugates, and nucleoside analogues is described. 1,2-(acetylcyclopropane)-annulated D-lyxofuranose underwent ring opening catalysed by CH3SO3H to act as an efficient glycosyl donor and give the glycosylation products in good yields and with high diastereoselectivities. Copyright
- Wang, Cong,Ma, Xiaofeng,Zhang, Jichao,Tang, Qin,Jiao, Wei,Shao, Huawu
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supporting information
p. 4592 - 4599
(2014/08/05)
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- Synthesis of cyclic γ-amino acids for foldamers and peptide nanotubes
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Cyclic γ-amino acids are molecular building blocks of great interest in peptide and foldamer chemistry, as they allow the preparation of new structures that are not found in Nature. In this paper, we describe the synthesis of cyclic γ-amino acids that have a cis relationship between the amino and the carboxylic acid groups. This arrangement, in most cases, induces the resulting peptides to adopt a flat conformation, which makes them appropriate for the design of foldamers that adopt β-sheet-type structures. We describe the synthesis of cyclic γ-amino acids that have a cis relationship between the amino and the carboxylic acid groups. This makes them suitable for the design of foldamers that adopt β-sheet-type structures.
- Rodriguez-Vazquez, Nuria,Salzinger, Stephan,Silva, Luis F.,Amorin, Manuel,Granja, Juan R.
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p. 3477 - 3493
(2013/07/11)
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- Chemoenzymatic synthesis of 3'-deoxy-3'-(4-substituted-triazol-1-YL)-5- methyluridine
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An efficient protocol has been developed for the synthesis of a small library of 3'-deoxy-3'- (4-substituted-triazol-1-yl)-5-methyluridine using Cu(I)-catalyzed Huisgen-Sharpless-Meldal 1,3- dipolar cycloaddition reaction of 3'-azido-3'-deoxy-5-methyluridine with different alkynes under optimized condition in an overall yields of 76%-92%. Here, the azido precursor compound, i.e., 3'-azido-3'-deoxy-5-methyluridine was chemoenzymatically synthesized from D-xylose in good yield. Some of the alkynes used in cycloaddition reaction were synthesized by the reaction of hydroxycoumarins or naphthols with propargyl bromide in acetone using K2CO3 in excellent yields. All synthesized compounds were unambiguously identified on the basis of their spectral (IR, 1H-, 13C NMR spectra, and high-resolution mass spectra) data analysis.
- Arya, Anu,Mathur, Divya,Tyagi, Abhilash,Kumar, Rajesh,Kumar, Vinod,Olsen, Carl E.,Saxena, Rajendra K.,Prasad, Ashok K.
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p. 646 - 659
(2014/01/06)
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- A total synthesis of mycalisine A
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In this paper, we report a total synthesis of a naturally occurring pyrrolo[2,3-d]pyrimidine nucleoside, mycalisine A. Our synthetic strategy uses d-xylose as the starting material and Vorbrüggen glycosylation as the key step. Mycalisine A was synthesized in 11 steps with a 15% overall yield.
- Dou, Yan-Hui,Ding, Hai-Xin,Yang, Ru-Chun,Li, Wei,Xiao, Qiang
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p. 379 - 382
(2013/07/04)
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- Sugar-based monodentate phosphoramidite ligands for Cu-catalyzed enantioselective conjugate addition to enones
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In this paper we present new, monodentate phosphoramidite ligands based on amines derived from the easy available monosaccharide d-xylose and BINOLs. Ligands were used for copper-catalyzed conjugate addition to acyclic and cyclic enones. The highest enantioselectivity achieved in this study was 77% ee for the conjugate addition to trans-chalcone, which is comparable to the best results published to date for phosphoramidite ligands based on carbohydrate-derived amines.
- Bauer, Tomasz,Majdecki, MacIej,Jurczak, Janusz
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p. 1930 - 1939
(2013/04/10)
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- Synthesis and photophysical properties of fluorescent 2,1,3- benzothiadiazole-triazole-linked glycoconjugates: Selective chemosensors for Ni(II)
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The synthesis of new fluorescent 2,1,3-benzothiadiazole-triazole-linked glycoconjugates is described by a straightforward synthetic route, using a copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC). UV-visible (UV-vis) and steady-state fluorescence in solution were applied in order to characterize its photophysical behavior. The dyes present absorption in the violet region with fluorescence emission in the cyan-green region, which can be related to the methoxy derivatives due to an intramolecular charge transfer (ICT) in the excited state. The studied derivatives present potential optical application since combine large extinction coefficient for absorption, large Stokes shift and high fluorescence emission. Additionally, these dyes exhibit binding selectivity to Ni+2 among a series of cations in CH 3CN solution.
- Moro, Angélica V.,Ferreira, Patrícia C.,Migowski, Pedro,Rodembusch, Fabiano S.,Dupont, Jairton,Lüdtke, Diogo S.
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p. 201 - 206
(2013/01/15)
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- Ultrasound-assisted selective deprotection of terminal acetonides catalyzed by silica-supported boron trifluoride
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An efficient and convenient method for the selective cleavage of terminal acetonides is described. Treatment of terminal acetonides in the presence of a wide range of functional groups with silica-supported boron trifluoride as a catalyst furnished the corresponding diols in 82-95% yield under ultrasound irradiation conditions. The acid-labile p-methoxybenzyl group as a protecting group remained intact under the conditions employed to the present deprotection condition. Copyright Taylor & Francis Group, LLC.
- Xiong, Junlong,Yan, Shiqiang,Ding, Ning,Zhang, Wei,Li, Yingxia
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p. 184 - 192
(2013/07/27)
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- An efficient and convenient formal synthesis of Jaspine B from d-xylose
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A formal synthesis of Jaspine B was completed in 42.4% overall yield with only three purification steps (one by crystallization and two by column chromatography). The key step in the synthesis involves a regio- and stereoselective epoxide ring-opening reaction and the configuration inversion of the C3-hydroxyl group through oxidation and reduction. All of the reagents and materials used were quite common and inexpensive.
- Zhao, Ming-Li,Zhang, En,Gao, Jie,Zhang, Zhao,Zhao, Yu-Tao,Qu, Wen,Liu, Hong-Min
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scheme or table
p. 126 - 129
(2012/05/07)
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- First total synthesis of a naturally occurring iodinated 5′-deoxyxylofuranosyl marine nucleoside
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4-Amino-7-(5′-deoxy-β-D-xylofuranosyl)-5-iodo-pyrrolo[2,3-d] pyrimidine 1, an unusual naturally occurring marine nucleoside isolated from an ascidan, Diplosoma sp., was synthesized from D-xylose in seven steps with 28% overall yield on 10 g scale. The key step was Vorbrueggen glycosylation of 5-iodo-pyrrolo[2,3-d]pyrimidine with 5-deoxy-1, 2-O-diacetyl-3-O-benzoyl-D- xylofuranose. Its absolute configuration was confirmed.
- Sun, Jianyun,Dou, Yanhui,Ding, Haixin,Yang, Ruchun,Sun, Qi,Xiao, Qiang
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experimental part
p. 881 - 889
(2012/07/14)
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- First total synthesis of a naturally occurring nucleoside disulfide: 9-(5′-Deoxy-5′-thio-β-d-xylofuranosyl)adenine disulfide
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A naturally occurring nucleoside disulfide, 9-(5′-deoxy-5′- thio-β-d-xylofuranosyl)adenine disulfide, was first synthesized from d-xylose over 7 steps in 20% overall yield. The key step involved Vorbru?ggen glycosylation of silylated N6-benzoyladenine with xylose diacetate moiety.
- Ding, Hai Xin,Da, Ling Cui,Yang, Ru Chun,Cao, Ban Peng,Sun, Qi,Xiao, Qiang
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scheme or table
p. 996 - 998
(2012/10/18)
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- Synthesis of triazole-linked analogues of RNA (TLRNA)
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A triazole-linked analogue of RNA (TLRNA) has been developed. Monomeric ribonucleoside analogues bearing natural nucleobases were prepared from D-xylose to afford the elongating units in gram quantities. The puckering of the monomeric analogues was similar to that of natural ribonucleosides and preferred the North-type conformation. An efficient elongation reaction via the copper-catalyzed Huisgen cycloaddition on a solid support was used for the synthesis of trinucleotides.
- Fujino, Tomoko,Endo, Kenta,Yamazaki, Naomi,Isobe, Hiroyuki
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supporting information; scheme or table
p. 403 - 405
(2012/06/30)
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- Synthesis and in vitro antitumour screening of 2-(β-d-xylofuranosyl) thiazole-4-carboxamide and two novel tiazofurin analogues with substituted tetrahydrofurodioxol moiety as a sugar mimic
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2-(β-d-xylofuranosyl)thiazole-4-carboxamide (2) and two new tiazofurin analogues with 5-hydroxymethyl-2-methyl-tetrahydro-furo[2,3-d][1,3]dioxol-6-ol moiety as a sugar mimic (27 and 28) have been synthesized and evaluated for their in vitro antitumour activity against a panel of human tumour cell lines (K562, HL 60, Jurkat, Raji and HeLa). In contrast to previous literature reports, a metabolic MTT assay revealed remarkable cytotoxicity of 2 against K562 (IC50 = 0.15 μM) and HL-60 (IC50 = 0.13 μM) cells. Flow cytometry data suggest that cytotoxic effects of analogue 2 in the culture of K562 cells might be mediated by apoptosis, in opposite to tiazofurin, which did not induce apoptosis of K562 cells after 24 h, thus suggesting a different mechanism of action. All three analogues 2, 27 and 28 were also active against Jurkat, Raji and HeLa cells, with IC50 values in the range from 0.06 to 5.61 μM, but were completely inactive against the normal foetal lung fibroblasts (MRC-5).
- Popsavin, Mirjana,Spai?, Sa?a,Svir?ev, Milo?,Koji?, Vesna,Bogdanovi?, Gordana,Popsavin, Velimir
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p. 6700 - 6704
(2013/01/14)
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- Construction of the octose 8-phosphate intermediate in lincomycin A biosynthesis: Characterization of the reactions catalyzed by LmbR and LmbN
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Lincomycin A is a potent antimicrobial agent noted for its unusual C1 methylmercapto-substituted 8-carbon sugar. Despite its long clinical history for the treatment of Gram-positive infections, the biosynthesis of the C 8-sugar, methylthiolincosamide (MTL), is poorly understood. Here, we report our studies of the two initial enzymatic steps in the MTL biosynthetic pathway leading to the identification of d-erythro-d-gluco-octose 8-phosphate as a key intermediate. Our experiments demonstrate that this intermediate is formed via a transaldol reaction catalyzed by LmbR using d-fructose 6-phosphate or d-sedoheptulose 7-phosphate as the C3 donor and d-ribose 5-phosphate as the C5 acceptor. Subsequent 1,2-isomerization catalyzed by LmbN converts the resulting 2-keto C8-sugar (octulose 8-phosphate) to octose 8-phosphate. These results provide, for the first time, in vitro evidence for the biosynthetic origin of the C8 backbone of MTL.
- Sasaki, Eita,Lin, Chia-I,Lin, Ke-Yi,Liu, Hung-Wen
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supporting information
p. 17432 - 17435
(2013/01/15)
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- Alkyloxycarbonyl group migration in furanosides
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A migration of methyloxycarbonyl group from secondary to primary hydroxyl was observed in furanosides (ribosides and xylosides) under usual desilylation conditions using tetrabutylammonium fluoride. The migration was studied further on several alkyloxycarbonyl furanosides under either basic or acidic conditions. As follows from 13C labelling experiments and product distribution, the migration in xylosides, proceeds intramolecularly via six-membered cyclic carbonate, whereas in ribosides, the migration is intermolecular. Acidic conditions prevented the migration in ribosides whereas the migration in xylosides was circumvented under neutral conditions.
- Dvorakova, Marcela,Pribylova, Marie,Pohl, Radek,Migaud, Marie E.,Vanek, Tomas
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p. 6701 - 6711
(2012/08/29)
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- Synthesis of a furanosyl-pyranone derivative related to the tri-o-heterocyclic core of herbicidins
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A new compound that is structurally related to the undecose ring structure of herbicidins has been prepared. The synthesis of this novel furanosyl-pyranone derivative was made possible through the regioselective reductive ring-opening of a 3,5-O-benzylidene-D-xylofuranose and the hetero-Diels-Alder reaction of an aldehyde and a Danishefsky-type diene. The highly functionalized pyranone derivative can be a useful precursor for the synthesis of herbicidins.
- Hsu, Ching-Yun,Lee, I-Chi,Lico, Larry S.,Uang, Biing-Jiun,Hung, Shang-Cheng
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experimental part
p. 421 - 425
(2012/08/08)
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- Carbohydrate-derived PSE acetals: Controlled base-induced ring cleavage
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Retro-Michael type reactions applied to PSE acetals protecting monosaccharides led either to complete removal or to ring-cleavage. In protic medium, application of standard basic conditions resulted in acetal deprotection, while the use of butyl lithium in aprotic medium allowed controlled ring-cleavage. A regio- and stereoselective C- over O-alkylation was observed during the process. Furthermore, depending on the substrates and the reaction conditions involved, new carbohydrate-derived β-alkoxyvinyl sulfones were obtained with varying regioselectivity.
- Chéry, Florence,Cabianca, Elena,Tatibou?t, Arnaud,De Lucchi, Ottorino,Rollin, Patrick
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experimental part
p. 544 - 551
(2012/01/14)
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- Specific biotinylation of IMP dehydrogenase
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IMP dehydrogenase (IMPDH) catalyzes a critical step in guanine nucleotide biosynthesis. IMPDH also has biological roles that are distinct from its enzymatic function. We report a biotin-linked reagent that selectively labels IMPDH and is released by dithiothreitol. This reagent will be invaluable in elucidating the moonlighting functions of IMPDH.
- Hoefler, B. Christopher,Gollapalli, Deviprasad R.,Hedstrom, Lizbeth
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supporting information; experimental part
p. 1363 - 1365
(2011/04/22)
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- Efficient synthesis, structural characterization and anti-microbial activity of chiral aryl boronate esters of 1,2-O-isopropylidene-α-D- xylofuranose
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A simple and efficient synthetic approach toward a series of chiral aryl boronate esters, starting from d-xylose, as anti-microbial agents, is described herein. Minimum inhibitory concentration and zone of inhibition revealed that these derivatives exhibit potent anti-bacterial and anti-fungal properties. Herein, we report the first anti-microbial activity of this class of compounds. All products have been characterized by NMR (1H, 13C and 11B), IR, elemental and mass spectral study.
- Trivedi, Rajiv,Rami Reddy,Kiran Kumar,Sridhar,Pranay Kumar,Srinivasa Rao
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supporting information; scheme or table
p. 3890 - 3893
(2011/08/06)
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- Useful methods for the synthesis of isopropylidenes and their chemoselective cleavage
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A catalytic amount of phosphotungstic acid (PTA) has been found to be a very effective catalyst for isopropylidenation of 1,2-diols and their deprotection at room temperature. The ease of handling, cost and activity of the catalyst, good to excellent yields and chemoselectivity for deprotection are some of the highlights of the reported method.
- Vanlaldinpuia, Khiangte,Bez, Ghanashyam
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supporting information; experimental part
p. 3759 - 3764
(2011/08/06)
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- Metal-free deprotection of terminal acetonides by using tert -butyl hydroperoxide in aqueous medium
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Employing aqueous tert-butyl hydroperoxide (70%) as an inexpensive reagent a useful methodology for the regioselective and chemoselective deprotection of terminal acetonide groups in aqueous medium is developed. A variety of acetonide derivatives on reaction with aqueous tert-butyl hydroperoxide in water:tert-butanol (1:1) furnish the corresponding acetonide deprotected diols in good yields. A large number of acid labile protecting functional groups and other functional moieties were found to be unaffected under the conditions employed for the present deprotection. This method has been successfully applied to sugar derivatives. Georg Thieme Verlag Stuttgart.
- Maddani, Mahagundappa R.,Prabhu, Kandikere R.
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supporting information; experimental part
p. 821 - 825
(2011/06/28)
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- Synthesis of carbohydrates in mineral-guided prebiotic cycles
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One present obstacle to the "RNA-first" model for the origin of life is an inability to generate reasonable "hands off" scenarios for the formation of carbohydrates under conditions where they might have survived for reasonable times once formed. Such scenarios would be especially compelling if they deliver pent(ul)oses, five-carbon sugars found in terran genetics, and exclude other carbohydrates (e.g., aldotetroses) that may also be able to function in genetic systems. Here, we provide detailed chemical analyses of carbohydrate premetabolism, showing how borate, molybdate, and calcium minerals guide the formation of tetroses (C4H8O4), heptoses (C7H14O7), and pentoses (C 5H10O5), including the ribose found in RNA, in "hands off" experiments, starting with formaldehyde and glycolaldehyde. These results show that pent(ul)oses would almost certainly have formed as stable borate complexes on the surface of an early Earth beneath a humid CO2 atmosphere suffering electrical discharge. While aldotetroses form extremely stable complexes with borate, they are not accessible by pathways plausible under the most likely early Earth scenarios. The stabilization by borate is not, however, absolute. Over longer times, material is expected to have passed from borate-bound pent(ul)oses to a branched heptulose, which is susceptible to Cannizzaro reduction to give dead end products. We show how this fate might be avoided using molybdate-catalyzed rearrangement of a branched pentose that is central to borate-moderated cycles that fix carbon from formaldehyde. Our emerging understanding of the nature of the early Earth, including the presence of hydrated rocks undergoing subduction to form felsic magmas in the early Hadean eon, may have made borate and molydate species available to prebiotic chemistry, despite the overall "reduced" state of the planet.
- Kim, Hyo-Joong,Ricardo, Alonso,Illangkoon, Heshan I.,Kim, Myong Jung,Carrigan, Matthew A.,Frye, Fabianne,Benner, Steven A.
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supporting information; scheme or table
p. 9457 - 9468
(2011/08/04)
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- Synthesis, Biological Activity, and Molecular Modeling Studies of 1H-1,2,3-Triazole Derivatives of Carbohydrates as a-Glucosidases Inhibitors
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A class of drugs in use for treating type II diabetes mellitus (T2D), typified by the pseudotetrasaccharide acarbose, act by inhibiting the a-glucosidase activity present in pancreatic secretions and in the brush border of the small intestine. Herein, we report the synthesis of a series of 4-substituted 1,2,3-triazoles conjugated with sugars, including D-xylose, D-galactose, D-allose, and D-ribose. Compounds were screened for a-glucosidase inhibitory activity using yeast maltase (MAL12) as a model enzyme. Methyl2,3-O-isopropylidene-β-D-ribofuranosides, such as the 4-(l-cyclohexenyl)-l,2,3-triazole derivative, were among the most active compounds, showing up to 25-fold higher inhibitory potency than the complex oligosaccharide acarbose. Docking studies on a MAL12 homology model disclosed a binding mode consistent with a transition-state-mimicking mechanism. Finally, the actual pharmacological potential of this triazole series was demonstrated by the reduction of postprandial blood glucose levels in normal rats. These compounds could represent new chemical scaffolds for developing novel drugs against T2D.
- Ferreira, Sabrinab,Sodero, Ana C. R.,Cardoso, Mariana F. C.,Lima, Emerson S.,Kaiser, Carlos R.,Silva Jr., Floriano P.,Ferreira, Vitor F.
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supporting information; experimental part
p. 2364 - 2375
(2010/09/04)
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- Synthesis of 5′-seleno-xylofuranosides
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The synthesis of selenium derivatives of naturally occurring chiral molecules is becoming increasingly important in recent years. In this context, we describe herein an easy, straightforward synthetic route for the preparation of a series of chiral seleno-furanosides, starting from the readily available carbohydrate d-xylose. In addition, selected compounds were screened as inhibitors of the δ-aminolevulinate dehydratase (δ-ALA-D) enzyme. Diselenide 4 was found to reduce significantly the enzymatic activity, while seleno-furanoside 1a increased δ-ALA-D activity.
- Braga, Hugo C.,Stefani, Hélio A.,Paix?o, Márcio W.,Santos, Francielli W.,Lüdtke, Diogo S.
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scheme or table
p. 3441 - 3446
(2010/06/19)
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- 2'-FLUORO-4'-SUBSTITUTED NUCLEOSIDES, THE PREPARATION AND USE
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The present invention provides 2'-fluorine-4'-substituted-nucleoside analogues or their pro-drugs or 5'-phosphate esters (including the pro-drugs of the 5'-phosphate esters), preparation methods and uses thereof. The compounds have the general formula as follows: wherein: R = CH3, CH, N3, C≡CH; R' = H, F; X = F, OH, NH2; Y = H, CH3, F, OH, NH2 The compounds are used in the synthesis of drugs for the treatment of virus infection, especially for the treatment of HBV, HCV or HIV infection.
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Page/Page column 13
(2010/05/13)
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- SYNTHESIS OF OSELTAMIVIR CONTAINING PHOSPHONATE CONGENERS WITH ANTI-INFLUENZA ACTIVITY
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Novel phosphonate compounds are described. The compounds have activity as neuraminidase inhibitors against wild-type and H274Y mutant of H1N1 and H5N1 viruses. The present disclosure also provides an enantioselective synthetic route to known neuraminidase inhibitors oseltamivir and the anti-flu drug Tamiflu, as well as novel phosphonate compounds, via D-xylose. Another efficient and flexible synthesis of Tamiflu and the highly potent neuraminidase inhibitor Tamiphosphor was also achieved in 11 steps and > 20% overall yields from the readily available fermentation product (1S-cis)-3-bromo-3,5- cyclohexadiene-1,2-diol. Most of the reaction intermediates were obtained as crystals without tedious purification procedures. The key transformations include an initial regio- and stereoselective bromoamidation of a bromoarene cis- dihydrodiol, as well as the final palladium-catalyzed carbonylation and phosphonylation.
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Page/Page column 44
(2009/04/25)
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- Novel L-xylose derivatives as selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes
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The prevalence of diabetes throughout the world continues to increase and has become a major health issue. Recently there have been several reports of inhibitors directed toward the sodium-dependent glucose cotransporter 2 (SGLT2) as a method of maintaining glucose homeostasis in diabetic patients. Herein we report the discovery of the novel O-xyloside 7c that inhibits SGLT2 in vitro and urinary glucose reabsorption in vivo. 2009 American Chemical Society.
- Goodwin, Nicole C.,Mabon, Ross,Harrison, Bryce A.,Shadoan, Melanie K.,Almstead, Zheng Y.,Xie, Yiling,Healy, Jason,Buhring, Lindsey M.,DaCosta, Christopher M.,Bardenhagen, Jennifer,Mseeh, Faika,Liu, Qingyun,Nouraldeen, Amr,Wilson, Alan G. E.,Kimball, S. David,Powell, David R.,Rawlins, David B.
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supporting information; experimental part
p. 6201 - 6204
(2010/03/31)
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