- Microwave-assisted Synthesis of Hybrid Heterocyclics as Biological Potent Molecules
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A series of novel 5-((1H-benzo[d]imidazol-2-yl)methyl)-2-((3aR,5S,6S,6aR)-2,2-dimethyl-6-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-3-phenylthiazolidin-4-ones 9a–n has been synthesized from triazole-linked thiazolidinone derivatives 8a–g with o-phenylenediamine and characterized by IR, NMR, MS, and elemental analyses. Further, these compounds were screened for their antibacterial activity against Gram-positive bacteria, namely, Bacillus subtilis (ATCC 6633), Staphylococcus aureus (ATCC 6538p), and Micrococcus luteus (IFC 12708), and Gram-negative bacteria, namely, Proteus vulgaris (ATCC 3851), Salmonella typhimurium (ATCC 14028), and Escherichia coli (ATCC 25922). Among the screened compounds, compounds 9b, 9d, 9h, and 9i are highly active against almost all selected bacterial strains; the remaining compounds showed moderate to good activity and emerged as potential molecules for further development.
- Srinivas,Sunitha,Vasumathi Reddy,Karthik,Rajesh Kumar
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Read Online
- Synthesis and In Vitro Study of Hybrid Heterocyclic's as Potential Nematicidal Agents
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A series of novel 5-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-3-(4-fluorophenyl)-6-phenyl-3,3a,5,6-tetrahydroisoxazolo[3,4-d]thiazoles 10a–g were synthesized by the reaction of chalcone derivatives of 2-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-3-phenylthiazolidin-4-one 9 with hydroxylamine hydrochloride. The chemical structures of newly synthesized compounds were elucidated by IR, NMR, MS, and elemental analysis. The compounds 10 a–g were evaluated for their nematicidal activity against Dietylenchus myceliophagus and Caenorhabditis elegans; compound 10e and 10f showed appreciable nematicidal activity. Further, the compounds 10a – g were screened for their antifungal activity against Candida albicans (ATCC 10231), Aspergillus fumigates (HIC 6094), Trichophyton rubrum (IFO 9185), and Trichopyton mentagrophytes (IFO 40996). The compounds 10b and 10f displayed notable antifungal activity against all the microorganisms employed. The activity of these compounds is almost equal to the standard. It is also interesting to note that the compounds 10b and 10f and 10g showed activity towards C. albicans at the concentration of 3.75?μM, which is less than the concentration of the standard Amphotericin B.
- Srinivas,Sunitha,Karthik,Nikitha,Raju,Ravinder,Anusha,Rajasri,Swapna,Swaroopa,Srinivas,Vasumathi Reddy
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Read Online
- TLR7 AGONISTS
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The present invention relates to TLR7 agonists according to Formula I and their use in the treatment of diseases such as cancer and infectious disease.
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Paragraph 0247; 0250; 0252
(2021/05/28)
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- Mechanistic Investigation of 1,2-Diol Dehydration of Paromamine Catalyzed by the Radical S-Adenosyl- l -methionine Enzyme AprD4
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AprD4 is a radical S-adenosyl-l-methionine (SAM) enzyme catalyzing C3′-deoxygenation of paromamine to form 4′-oxo-lividamine. It is the only 1,2-diol dehydratase in the radical SAM enzyme superfamily that has been identified and characterized in vitro. The AprD4 catalyzed 1,2-diol dehydration is a key step in the biosynthesis of several C3′-deoxy-aminoglycosides. While the regiochemistry of the hydrogen atom abstraction catalyzed by AprD4 has been established, the mechanism of the subsequent chemical transformation remains not fully understood. To investigate the mechanism, several substrate analogues were synthesized and their fates upon incubation with AprD4 were analyzed. The results support a mechanism involving formation of a ketyl radical intermediate followed by direct elimination of the C3′-hydroxyl group rather than that of a gem-diol intermediate generated via 1,2-migration of the C3′-hydroxyl group to C4′. The stereochemistry of hydrogen atom incorporation after radical-mediated dehydration was also established.
- Yeh, Yu-Cheng,Kim, Hak Joong,Liu, Hung-Wen
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supporting information
p. 5038 - 5043
(2021/05/04)
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- Triethylamine-methanol mediated selective removal of oxophenylacetyl ester in saccharides
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A highly selective, mild, and efficient method for the cleavage of oxophenylacetyl ester protected saccharides was developed using triethylamine in methanol at room temperature. The reagent proved successful against different labile groups like acetal, ketal, and PMB and also generated good yields of the desired saccharides bearing lipid esters. Further, we also observed DBU in methanol as an alternative reagent for the deprotection of acetyl, benzoyl, and oxophenylacetyl ester groups. This journal is
- Rasool, Javeed Ur,Kumar, Atul,Ali, Asif,Ahmed, Qazi Naveed
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p. 338 - 347
(2021/01/29)
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- A method for preparing N-alkylated kanosamines from diacetone D-glucose
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The aminoglycoside (AG) antibiotics have seen a resurgence in their clinical use given the increase in multi drug resistant bacterial infections. Campaigns to generate novel analogs show promise that structural modification can lead to compounds with improved pharmacological properties. The results described herein include a new method to synthesize mono-, di-, and mixed N-alkylated kanosamine sugars and their elaboration into novel glycosides that inhibit bacterial protein synthesis in vitro.
- Cannone, Zachary P.,Peczuh, Mark W.
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p. 1830 - 1833
(2019/06/19)
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- NOVEL PROCESS FOR MAKING ALLOFURANOSE FROM GLUCOFURANOSE
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The present invention relates to the manufacture of allofuranose from glucofuranose as defined in the description and in the claim. Allofuranos is an intermediate in the manufacture of oligonucleotides which can be used as a medicament.
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Page/Page column 35-37; 46-48
(2019/12/15)
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- Palladium-Catalyzed One-Pot Stereospecific Synthesis of 2-Deoxy Aryl C-Glycosides from Glycals and Anilines in the Presence of tert-Butyl Nitrite
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The palladium-catalyzed one-pot synthesis of 2,3-deoxy-3-keto aryl C-glycosides is achieved from glycals and anilines in the presence of tert-butyl nitrite and aqueous HBF 4 under mild conditions. This one-pot method stereospecifically provides α-and β-Aryl glycosides (≥19:1 by NMR) in good yields at room temperature. The configuration at the C-3 position in the glycal determines the anomeric selectivity (i.e., α or β) of the desired products.
- Kandasamy, Jeyakumar,Singh, Adesh Kumar,Venkatesh, Rapelly
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p. 4215 - 4230
(2019/11/14)
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- GLUCOSIDE MONOMER, POLYMERIZATION COMPOSITION COMPRISING THE SAME AND HYDROGEL LENS USING THE SAME
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The present invention relates to a glucoside-based monomer represented by chemical formula 1, a polymeric composition for producing hydrogel comprising the same, and a hydrogel lens using the same. In the chemical formula 1, R_1 to R_4 is hydrogen, an alkyl group of C_1-C_4, or AA, R_6 is hydrogen or an alkyl group of C_1-C_4, at least one of the R_1 to R_4 is BB, R_5 is selected from hydrogen or CC, and m is an integer selected from 0 to 10. According to the present invention, hydrogel lenses having improved wettability can be provided.COPYRIGHT KIPO 2019
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Paragraph 0124-0130
(2019/08/22)
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- Synthesis, photophysical properties, and photodynamic activity of positional isomers of TFPP-glucose conjugates
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The synthesis and characterization of a ‘complete set’ of positional isomers of tetrakis(perfluorophenyl)porphyrins (TFPP)-glucose conjugates (1OH, 2OH, 3OH, 4OH, and 6OH) are reported herein. The cellular uptake and photocytotoxicity of these conjugates were examined in order to investigate the influence of location of the TFPP moiety on the D-glucose molecule on the biological activity of the conjugates. An In vitro biological evaluation revealed that the certain of these isomers have a greater effect on cellular uptake and cytotoxicity than others. The TFPP-glucose conjugates 1OH, 3OH, and 4OH were found to exert exceptional photocytotoxicity in several types of cancer cells compared to 2OH and 6OH substituted isomers.
- Fadlan, Arif,Tanimoto, Hiroki,Ito, Tatsuya,Aritomi, Yusuke,Ueno, Maho,Tokuda, Masaya,Hirohara, Shiho,Obata, Makoto,Morimoto, Tsumoru,Kakiuchi, Kiyomi
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supporting information
p. 1848 - 1858
(2018/03/06)
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- Synthesis, nematicidal and antifungal properties of hybrid heterocyclics
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A new series of 5-((3aR, 5S, 6S, 6aR)-6-((1-(4-chlorophenyl)-1H-1, 2, 3-triazol-4-yl)methoxy)-2, 2-dimethyltetrahydrofuro[ 2, 3-d][1, 3]dioxol-5-yl)-3-(4-fluorophenyl)-2, 6-diphenyl-3, 3a, 5, 6-tetrahydro-2H-pyrazolo[3, 4-d]thiazoles 10a-r was synthesized by the reaction of chalcone derivatives of 2-((3aR, 5S, 6S, 6aR)-6-((1-(4-chlorophenyl)-1H-1, 2, 3-triazol-4-yl)methoxy)-2, 2-dimethyltetrahydrofuro[2, 3-d][1, 3]dioxol-5-yl)-3-phenylthiazolidin-4-one 9 with aryl/alkyl hydrazines. The chemical structures of newly synthesized compounds were elucidated by IR, NMR, MS and elemental analysis. The compounds 10a-r were evaluated for their nematicidal activity against Dietylenchus myceliophagus and Caenorhabditis elegans by aqueous in vitro screening technique. Among them, compounds containing N-benzylpyrazole moiety (10d, 10j, 10p), and N-methylpyrazole moiety (10f, 10i, 10r) showed significant nematicidal activity against both tested nematodes with LD50 160-210 ppm, almost equal to oxamyl standard. Further, these compounds 10a-r were screened for their antifungal (MZI, MIC, and MFC) activity against four fungal organisms viz, Candida albicans (ATCC 102331), Aspergillus fumigates (HIC 6094), Trichophyton rubrum (IFO 9185) and Trichophyton mentagrophytes (IFO 40996). Most of the new compounds showed appreciable activity against the tested fungi, and emerged as potential molecules for further development.
- Srinivas, Avula,Sunitha, Malladi,Karthik, Pulluri,Reddy, K. Vasumathi
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p. 1030 - 1041
(2018/01/17)
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- C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies
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To obtain key sugar derivatives for making homooligomeric foldamers or α/β-chimera peptides, economic and multigram scale synthetic methods were to be developed. Though described in the literature, the cost-effective making of both 3-amino-3-deoxy-ribofuranuronic acid (H–tX–OH) and its C-3 epimeric stereoisomer, the 3-amino-3-deoxy-xylofuranuronic acid (H–cX–OH) from d-glucose is described here. The present synthetic route elaborated is (1) appropriate for large-scale synthesis; (2) reagent costs reduced (e.g. by a factor of 400); (3) yields optimized are ~80% or higher for all six consecutive steps concluding –tX– or –cX– and (4) reaction times shortened. Thus, a new synthetic route step-by-step optimized for yield, cost, time and purification is given both for d-xylo and d-ribo-amino-furanuronic acids using sustainable chemistry (e.g. less chromatography with organic solvents; using continuous-flow reactor). Our study encompasses necessary building blocks (e.g. –X–OMe, –X–OiPr, –X–NHMe, Fmoc–X–OH) and key coupling reactions making –Aaa–tX–Aaa– or –Aaa–tX–tX–Aaa– type “inserts”. Completed for both stereoisomers of X, including the newly synthesized Fmoc–cX–OH, producing longer oligomers for drug design and discovery is more of a reality than a wish.
- Nagy, Adrienn,Csordás, Barbara,Zsoldos-Mády, Virág,Pintér, István,Farkas, Viktor,Perczel, András
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p. 223 - 240
(2017/02/05)
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- Larger laboratory scale synthesis of 5-methyluridine and formal synthesis of its L-enantiomer
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A larger laboratory scale synthesis (>60 g per run) of 5-methyluridine is presented. The critical intermediate 1,2-O-isopropylidene-α-D-ribofuranose was prepared from very cheap D-glucose via D-allose. Its L-enantiomer was obtained from L-arabinose via L-glucose, and also from L-xylose. {figure presented}.
- Thiesen, Luciano J. Hoeltgebaum,Cabral, Nadia,Joselice E Silva, Maria,Bezerra, Gilson,Doboszewski, Bogdan
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p. 249 - 264
(2017/06/19)
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- FUCOSIDASE INHIBITORS
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The present disclosure relates, in general, to compounds useful as inhibitors of fucosidase enzymes, and to methods and compositions for the treatment of tumors or cancers, such as liver disorders and liver tumors (e.g., hepatocellular carcinoma), with a compound as disclosed herein.
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Page/Page column 24
(2017/02/24)
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- Synthesis and biological evaluation of triazole linked thiazolidenone glycosides
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In a one pot procedure a series of novel triazole linked thiazolidinone derivatives 8a-g and 9a-g was prepared by condensation of (3aR,5S,6R,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyltetrahydro[2,3-d] [1,3]dioxole-5-carbaldehyde 7 with mercapto acids and primary amines in the presence of ZnCl2 under both microwave irradiation and conventional heating conditions. Compound 7 was prepared from diacetone D-glucose with oxidation followed by reduction, click reaction, primary acetonide deprotection and with oxidative cleavage. Characterization of new compounds has been done by means of IR, NMR, MS and elemental analysis. The nematicidal and antibacterial activity of the compounds has also been evaluated.
- Srinivas, Avula,Santhosh, Madavarapu,Sunitha, Malladi,Karthik, Pulluri,Srinivas, Kontham,Reddy, K.Vasumathi
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p. 827 - 836
(2016/12/18)
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- An efficient method to synthesize novel 5-O-(6′-modified)-mycaminose 14-membered ketolides
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A new and facile procedure was developed to synthesize novel 5-O-(6′-modified)-mycaminose 14-membered ketolides by adopting different protective strategies and comparing various glycosylation conditions. Seven trichloroacetimidate donors which had different types of substituent groups at C-6 position were synthesized to couple with the erythronolide. Nine novel 5-O-(6′-modified)-mycaminose 14-membered ketolides were obtained to verify the utility of the method.
- Wang, A-Peng,Liu, Chao,Yang, Shuang,Zhao, Zhehui,Lei, Pingsheng
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p. 285 - 297
(2015/12/30)
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- 6-Methylpurine derived sugar modified nucleosides: Synthesis and evaluation of their substrate activity with purine nucleoside phosphorylases
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6-Methylpurine (MeP) is cytotoxic adenine analog that does not exhibit selectivity when administered systemically, and could be very useful in a gene therapy approach to cancer treatment involving Escherichia coli PNP. The prototype MeP releasing prodrug, 9-(β-d-ribofuranosyl)-6-methylpurine, MeP-dR has demonstrated good activity against tumors expressing E. coli PNP, but its antitumor activity is limited due to toxicity resulting from the generation of MeP from gut bacteria. Therefore, we have embarked on a medicinal chemistry program to identify non-toxic MeP prodrugs that could be used in conjunction with E. coli PNP. In this work, we report on the synthesis of 9-(6-deoxy-β-d-allofuranosyl)-6-methylpurine (3) and 9-(6-deoxy-5-C-methyl-β-d-ribo-hexofuranosyl)-6-methylpurine (4), and the evaluation of their substrate activity with several phosphorylases. The glycosyl donors; 1,2-di-O-acetyl-3,5-di-O-benzyl-α-d-allofuranose (10) and 1-O-acetyl-3-O-benzyl-2,5-di-O-benzoyl-6-deoxy-5-C-methyl-β-d-ribohexofuran-ose (15) were prepared from 1,2:5,6-di-O-isopropylidine-α-d-glucofuranose in 9 and 11 steps, respectively. Coupling of 10 and 15 with silylated 6-methylpurine under Vorbrüggen glycosylation conditions followed conventional deprotection of the hydroxyl groups furnished 5'-C-methylated-6-methylpurine nucleosides 3 and 4, respectively. Unlike 9-(6-deoxy-α-l-talo-furanosyl)-6-methylpurine, which showed good substrate activity with E. coli PNP mutant (M64V), the β-d-allo-furanosyl derivative 3 and the 5'-di-C-methyl derivative 4 were poor substrates for all tested glycosidic bond cleavage enzymes.
- Hassan, Abdalla E.A.,Abou-Elkhair, Reham A.I.,Parker, William B.,Allan, Paula W.,Secrist, John A.
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- PYRROLO[1,2-f][1,2,4]TRIAZINES USEFUL FOR TREATING RESPIRATORY SYNCITIAL VIRUS INFECTIONS
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Provided herein are formulations, methods and substituted tetrahydrofuranyl-pyrrolo[1,2-f][1,2,4]triazine-4-amine compounds of Formula (I) for treating Pneumovirinae virus infections, including respiratory syncytial virus infections, as well as methods and intermediates for synthesis of tetrahydrofuranyl-pyrrolo[1,2-f][1,2,4]triazine-4-amine compounds.
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Paragraph 0360
(2015/05/26)
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- Anaerobic 5-Hydroxybenzimidazole Formation from Aminoimidazole Ribotide: An Unanticipated Intersection of Thiamin and Vitamin B12 Biosynthesis
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Comparative genomics of the bacterial thiamin pyrimidine synthase (thiC) revealed a paralogue of thiC (bzaF) clustered with anaerobic vitamin B12 biosynthetic genes. Here we demonstrate that BzaF is a radical S-adenosylmethionine enzyme that catalyzes the remarkable conversion of aminoimidazole ribotide (AIR) to 5-hydroxybenzimidazole (5-HBI). We identify the origin of key product atoms and propose a reaction mechanism. These studies represent the first step in solving a long-standing problem in anaerobic vitamin B12 assembly and reveal an unanticipated intersection of thiamin and vitamin B12 biosynthesis.
- Mehta, Angad P.,Abdelwahed, Sameh H.,Fenwick, Michael K.,Hazra, Amrita B.,Taga, Michiko E.,Zhang, Yang,Ealick, Steven E.,Begley, Tadhg P.
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supporting information
p. 10444 - 10447
(2015/09/28)
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- Titanocene dihalides and ferrocenes bearing a pendant α-d- xylofuranos-5-yl or α-d-ribofuranos-5-yl moiety. synthesis, characterization, and cytotoxic activity
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Titanocene dichlorides of general formula [(η5-C 5H5)(η5-C5H4R) TiCl2] (where R = 5-deoxy-1,2-di-O-isopropylidene-3-O-benzyl-α- d-xylofuranos-5-yl (Xylf) (8a); R = 5-deoxy-1,2-di-O-isopropylidene-3-O-benzyl- α-d-ribofuranos-5-yl (Ribf) (8b)) and [(η5-C 5H4R)2TiCl2] (R = Xylf (9a); R = Ribf (9b)) were prepared by reaction of the corresponding lithium cyclopentadienides 7a,b with an equimolar amount of [(η5-C 5H5)TiCl3] or a 0.5 mol amount of [TiCl 4(THF)2]. Titanocene difluorides of the general formula [(η5-C5H4R1)(η5- C5H4R2)TiF2] (R1 = H and R2 = Ribf (10); R1 = R2 = Xylf (11a); R 1 = R2 = Ribf (11b)) were obtained by fluorination of the corresponding titanocene dichlorides 8b and 9 with the fluorinating agent {2-(CH2NMe2)C6H4-κC,N}(n-Bu) 2SnF in high yields. Alternatively, complexes 11 were prepared in a straightforward way by direct reaction of [TiF4(THF)2] with 2 equiv of the corresponding lithium cyclopentadienide 7a,b. Ferrocene complexes [(η5-C5H4R)2Fe] (R = Xylf (12a); R = Ribf (12b)) were synthesized by metathesis of 2 equiv of lithium cyclopentadienide 7a,b and 1 equiv of anhydrous FeCl2. Deprotection of the benzyl group in ferrocenes 12 proceeded cleanly by a catalytic hydrogenation on Pd/C and afforded the ferrocene diols [(η5- C5H4R)2Fe] (R = 5-deoxy-1,2-di-O- isopropylidene-α-d-xylofuranos-5-yl (Xylf-OH) (14a); R = 5-deoxy-1,2-di-O-isopropylidene-α-d-ribofuranos-5-yl (Ribf-OH) (14b)). A scaled up benzyl deprotection with Et3SiH as a hydrogen source led to the replacement of only one benzyl group, which gave the ferrocene alcohol [(η5-C5H4R1)(η5- C5H4R2)Fe] (R1 = Xylf and R 2 = Xylf-OH (13)). The prepared complexes were characterized by elemental analysis, melting point determination, NMR, IR, and ESI-MS, and the molecular structure of 9b was determined by X-ray diffraction analysis. The cytotoxic activity of complexes 8-14 against A2780 and A2780cis cancer cells was evaluated by MTT tests. Titanocene difluorides 10 and 11 and ferrocene diol 14a showed cytotoxicity against A2780 cells in the medium to low micromolar range, while the most active species, 11b, displayed about 40% higher cytotoxicity against A2780cis in comparison to a cisplatin standard.
- Hodik, Tomas,Lamac, Martin,Cervenkova St'Astna, Lucie,Karban, Jindrich,Koubkova, Lucie,Hrstka, Roman,Cisarova, Ivana,Pinkas, Jiri
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p. 2059 - 2070
(2014/05/20)
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- Glucose positions affect the phloem mobility of glucose-fipronil conjugates
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In our previous work, a glucose-fipronil (GTF) conjugate at the C-1 position was synthesized via click chemistry and a glucose moiety converted a non-phloem-mobile insecticide fipronil into a moderately phloem-mobile insecticide. In the present paper, fipronil was introduced into the C-2, C-3, C-4, and C-6 positions of glucose via click chemistry to obtain four new conjugates and to evaluate the effects of the different glucose isomers on phloem mobility. The phloem mobility of the four new synthetic conjugates and GTF was tested using the Ricinus seedling system. The results confirmed that conjugation of glucose at different positions has a significant influence on the phloem mobility of GTF conjugates.
- Lei, Zhiwei,Wang, Jie,Mao, Genlin,Wen, Yingjie,Tian, Yuxin,Wu, Huawei,Li, Yufeng,Xu, Hanhong
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p. 6065 - 6071
(2015/04/22)
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- Glucose positions affect the phloem mobility of glucose-fipronil conjugates
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In our previous work, a glucose-fipronil (GTF) conjugate at the C-1 position was synthesized via click chemistry and a glucose moiety converted a non-phloem-mobile insecticide fipronil into a moderately phloem-mobile insecticide. In the present paper, fipronil was introduced into the C-2, C-3, C-4, and C-6 positions of glucose via click chemistry to obtain four new conjugates and to evaluate the effects of the different glucose isomers on phloem mobility. The phloem mobility of the four new synthetic conjugates and GTF was tested using the Ricinus seedling system. The results confirmed that conjugation of glucose at different positions has a significant influence on the phloem mobility of GTF conjugates.
- Lei, Zhiwei,Wang, Jie,Mao, Genlin,Wen, Yingjie,Tian, Yuxin,Wu, Huawei,Li, Yufeng,Xu, Hanhong
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p. 6065 - 6071
(2014/07/21)
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- N-Thiocarbonyl iminosugars: Synthesis and evaluation of castanospermine analogues bearing oxazole-2(3H)-thione moieties
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A straightforward and efficient synthetic route to a new class of glycosidase inhibitors containing an oxazole-2(3H)-thione moiety has been devised. The approach involves the formation of α-hydroxy ketones, which, after condensation with thiocyanic acid, leads to the formation of the heterocycle. By exploiting the ability of the nitrogen atom of oxazoline-2-thione precursors to act as nucleophiles in intramolecular addition, castanospermine analogues could be readily prepared in good overall yields. Glycosidase inhibitory activity compared to oxazolidinethione analogues showed a strong influence of the double bond, for example with pseudoiminosugar 19, by suppressing α-glucosidase inhibition and introducing, to a moderate level, β-glucosidase inhibitory activity. Reactivities showed the propensity of oxazole-2(3H)-thiones - especially when fused on carbohydrate frames - to convert into 1,3-oxazolidine-2-thione aminals through nucleophilic addition to the double bond, leading to unexpected tricyclic structure 21. Oxazole-2(3H)-thione moieties have been anchored onto carbohydrates in a five-step sequence that allows access to castanospermine analogues. Copyright
- Silva, Sandrina,Sanchez-Fernandez, Elena M.,Ortiz Mellet, Carmen,Tatibouet, Arnaud,Pilar Rauter, Amelia,Rollin, Patrick
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p. 7941 - 7951
(2014/01/06)
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- Design of β-amino acid with backbone-side chain interactions: Stabilization of 14/15-helix in α/β-peptides
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A new C-linked carbo-β-amino acid, (R)-β-Caa(r), having a carbohydrate side chain with d-ribo configuration, was prepared from d-glucose by inverting the C-3 stereocenter to introduce constraints/ interactions. From the NMR studies it was inferred that the new monomer may participate in additional electrostatic interactions, facilitating and enhancing novel folds in oligomeric peptides derived from it. The α/β- peptides, synthesized from alternating l-Ala and (R)-β-Caa(r), have shown the presence of 14/15-helix by NMR (in CDCl3, methanol-d3 and CD3CN), CD and MD calculations. The hybrid peptides showed the presence of electrostatic interactions involving the intraresidue amide proton and the C3-OMe, which helped in the stabilization of the NH(i)???CO(i-4) H-bonds and adoption of 14/15-helix. The importance of such additional interactions has been well defined in recent times to stabilize the folding in a variety of peptidic foldamers. These observations suggest and emphasize that the side chain-backbone interactions are crucial in the stabilization of the desired folding propensity. The designed monomer thus enlarges the opportunities for the synthesis of peptides with novel conformations and expands the repertoire of the foldamers.
- Sharma, Gangavaram V. M.,Yadav, Thota Anupama,Choudhary, Madavi,Kunwar, Ajit C.
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experimental part
p. 6834 - 6848
(2012/10/07)
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- Sugar-amino acid cyclic conjugates as novel conformationally constrained hydroxyethylamine transition-state isosteres
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Hydroxyethylamine (HEA) isosteres have previously been shown to display a multitude of biomedical applications. In fact, the first protease inhibitor, saquinavir is an HEA based peptidomimetic. Herein we describe an easy-to-operate synthetic route to a series of carbohydrate-based conformationally constrained hydroxyethylamine (HEA) isosteres featuring amino acid side chains, starting from d-glucose. This class of novel sugar-amino acid-tethered conformationally restricted HEA systems may have bearing in practical application, particularly in the development of conformationally restricted protease inhibitors.
- Roy, Arup,Sanjayan, Gangadhar J.
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supporting information; scheme or table
p. 3361 - 3363
(2012/07/28)
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- Azetidine iminosugars from the cyclization of 3,5-Di- O -triflates of α-furanosides and of 2,4-Di- O -triflates of β-pyranosides derived from glucose
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Primary amines with either 3,5-di-O-ditriflates of α-furanosides or 2,4-di-O-triflates of β-pyranosides form bicyclic azetidines in high yield.
- Lenagh-Snow, Gabriel M. J.,Araujo, Noelia,Jenkinson, Sarah F.,Martinez, R. Fernando,Shimada, Yousuke,Yu, Chu-Yi,Kato, Atsushi,Fleet, George W.J.
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supporting information; experimental part
p. 2142 - 2145
(2012/07/13)
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- Intramolecular base-free sonogashira reaction for the synthesis of benzannulated chiral macrocycles embedded in carbohydrate templates
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A base-free, intramolecular Sonogashira reaction-based general approach has been established for the diversity-oriented synthesis (DOS) of fused bi- and tricyclic systems containing benzannulated, 10- to 13-membered chiral macrocycles embedded in carbohydrate templates. Macrocycles with different ring sizes have been prepared by pre-designing the chiral building blocks. Base-sensitive groups like acetyl and TBDPS survived the reaction conditions. Copyright
- Hussain, Altaf,Yousuf, Syed Khalid,Kumar, Deepak,Lambu, Malikharjunarao,Singh, Baldev,Maity, Sudip,Mukherjee, Debaraj
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scheme or table
p. 1933 - 1940
(2012/09/22)
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- Synthesis from d-altrose of (5 R,6 R,7 R,8 S)-5,7-dihydroxy-8- hydroxymethylconidine and 2,4-dideoxy-2,4-imino-d-glucitol, azetidine analogues of swainsonine and 1,4-dideoxy-1,4-imino-d-mannitol
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Ring closure of a 3,5-di-O-triflate derived from d-altrose with benzylamine allowed the formation of both monocyclic and bicyclic azetidine analogues of swainsonine.
- Araújo, Noelia,Jenkinson, Sarah F.,Martínez, R. Fernando,Glawar, Andreas F. G.,Wormald, Mark R.,Butters, Terry D.,Nakagawa, Shinpei,Adachi, Isao,Kato, Atsushi,Yoshihara, Akihide,Akimitsu, Kazuya,Izumori, Ken,Fleet, George W. J.
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supporting information; experimental part
p. 4174 - 4177
(2012/10/23)
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- Molecular recognition at the active site of catechol-O-methyltransferase (COMT): Adenine replacements in bisubstrate inhibitors
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L-Dopa, the standard therapeutic for Parkinson's disease, is inactivated by the enzyme catechol-O-methyltransferase (COMT). COMT catalyzes the transfer of an activated methyl group from S-adenosylmethionine (SAM) to its catechol substrates, such as L-dopa, in the presence of magnesium ions. The molecular recognition properties of the SAM-binding site of COMT have been investigated only sparsely. Here, we explore this site by structural alterations of the adenine moiety of bisubstrate inhibitors. The molecular recognition of adenine is of special interest due to the great abundance and importance of this nucleobase in biological systems. Novel bisubstrate inhibitors with adenine replacements were developed by structure-based design and synthesized using a nucleosidation protocol introduced by Vorbrueggen and co-workers. Key interactions of the adenine moiety with COMT were measured with a radiochemical assay. Several bisubstrate inhibitors, most notably the adenine replacements thiopyridine, purine, N-methyladenine, and 6-methylpurine, displayed nanomolar IC50 values (median inhibitory concentration) for COMT down to 6 nM. A series of six cocrystal structures of the bisubstrate inhibitors in ternary complexes with COMT and Mg2+ confirm our predicted binding mode of the adenine replacements. The cocrystal structure of an inhibitor bearing no nucleobase can be regarded as an intermediate along the reaction coordinate of bisubstrate inhibitor binding to COMT. Our studies show that solvation varies with the type of adenine replacement, whereas among the adenine derivatives, the nitrogen atom at position 1 is essential for high affinity, while the exocyclic amino group is most efficiently substituted by a methyl group. Copyright
- Ellermann, Manuel,Paulini, Ralph,Jakob-Roetne, Roland,Lerner, Christian,Borroni, Edilio,Roth, Doris,Ehler, Andreas,Schweizer, W. Bernd,Schlatter, Daniel,Rudolph, Markus G.,Diederich, Francois
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supporting information; experimental part
p. 6369 - 6381
(2011/08/06)
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- Synthesis and biological evaluation of 2′,4′- and 3′,4′-bridged nucleoside analogues
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Most nucleosides in solution typically exist in equilibrium between two major sugar pucker forms, N-type and S-type, but bridged nucleosides can be locked into one of these conformations depending on their specific structure. While many groups have researched these bridged nucleosides for the purpose of determining their binding affinity for antisense applications, we opted to look into the potential for biological activity within these conformationally-locked structures. A small library of 2′,4′- and 3′,4′-bridged nucleoside analogues was synthesized, including a novel 3′,4′- carbocyclic bridged system. The synthesized compounds were tested for antibacterial, antitumor, and antiviral activities, leading to the identification of nucleosides possessing such biological activities. To the best of our knowledge, these biologically active compounds represent the first example of 2′,4′-bridged nucleosides to demonstrate such properties. The most potent compound, nucleoside 33, exhibited significant antiviral activity against pseudoviruses SF162 (IC50 = 7.0 μM) and HxB2 (IC50 = 2.4 μM). These findings render bridged nucleosides as credible leads for drug discovery in the anti-HIV area of research.
- Nicolaou,Ellery, Shelby P.,Rivas, Fatima,Saye, Karen,Rogers, Eric,Workinger, Tyler J.,Schallenberger, Mark,Tawatao, Rommel,Montero, Ana,Hessell, Ann,Romesberg, Floyd,Carson, Dennis,Burton, Dennis
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body text
p. 5648 - 5669
(2011/10/31)
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- Inhibition of nonmammalian glycosidases by azetidine iminosugars derived from stable 3,5-Di-O-triflates of pentoses
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Efficient ring closure of stable crystalline 3,5-di-O-triflates of pentofuranosides with amines to form azetidines allowed preliminary evaluation of four-ring iminosugars as glycosidase inhibitors; significant and specific inhibition of nonmammalian α-glucosidases is shown by l-xylo- and l-arabino-iminosugar azetidines.
- Lenagh-Snow, Gabriel M. J.,Araujo, Noelia,Jenkinson, Sarah F.,Rutherford, Catherine,Nakagawa, Shinpei,Kato, Atsushi,Yu, Chu-Yi,Weymouth-Wilson, Alexander C.,Fleet, George W. J.
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supporting information; experimental part
p. 5834 - 5837
(2012/01/06)
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- Synthesis of mycinose from 1,2:5,6-Di-O-isopropylidene-α-D- glucofuranose
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A facile synthesis of mycinose from commercially available 1,2:5,6-Di-O-isopropylidene-α-D-glucofuranose was developed. A selective and direct reductive debromination of α-hydroxy bromides in a simple NaBH4/EtOH/H2O system was found.
- Bao, Kai,Gao, Hao,Zhu, Zhibin,Wang, Jinhong,Zhang, Guoning,Sun, Jun,Zhang, Weige,Yao, Xinsheng
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scheme or table
p. 592 - 595
(2012/05/31)
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- Synthesis of a MUC1-glycopeptide-BSA conjugate vaccine bearing the 3′-deoxy-3′-fluoro-Thomsen-Friedenreich antigen
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A novel MUC1-glycopeptide-BSA conjugate vaccine with a specifically fluorinated Thomsen-Friedenreich antigen side chain at Thr6 was prepared. Preliminary immunological experiments reveal specific binding of the tumor-associated glycopeptide antigen analog by anti-MUC1-mouse antibodies.
- Hoffmann-Roeder, Anja,Johannes, Manuel
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supporting information; experimental part
p. 9903 - 9905
(2011/10/09)
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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 and antibacterial activity of aminodeoxyglucose derivatives against Listeria innocua and Salmonella typhimurium
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In this study aminodeoxyglucose derivatives were synthesized and evaluated for their antibacterial activity against two food bacteria, Listeria innocua and Salmonella typhimurium. 6-Amino-6-deoxy-α-Dmethylglucopyranose (GSA-6), 3-amino-3-deoxy-D-glucopyranoside (GSA-3), and β-D-glucopyranosylamine (GSA-1) were synthesized and concurrently tested with commercially available D-glucosamine (GSA-2) for antibacterial activity. Results obtained from this study showed a pronounced antagonist effect due to the position of amino groups of aminoglucose derivatives on the antibacterial activity. GSA-3 was the most active compound. At a concentration of 2 × 10 -4 mol mL -1, it delayed the growth of both bacteria with percentages of inhibition of 29 and 15% for L. innocua and S. typhimurium, respectively. At the same concentration the percentages of inhibition for other aminodeoxyglucoses varied between 5 and 18% and between 2 and 11% for L. innocua and S. typhimurium, respectively. All compounds were characterized by FTIR, 1H NMR, and 13C NMR spectroscopy.
- Theoneste, Muhizi,Stephane, Greller,Veronique, Coma
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experimental part
p. 8770 - 8775
(2010/07/17)
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- Synthesis of fused cyclic systems containing medium-sized rings through tandem ROM-RCM of norbornene derivatives embedded in a carbohydrate template
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A general approach for the synthesis of fused cyclic systems containing medium-sized rings (7-9) has been developed. The key steps involve a diastereoface-selective Diels-Alder reaction of the dienophiles 4a-d attached to a furanosugar with cyclopentadiene and ring opening (ROM)-ring closing metathesis (RCM) of the resulting norbornene derivatives 10a-d and 11a-d. Diels-Alder reaction of the dienophiles 4a-d with cyclopentadiene in the absence of a catalyst produced 10a-d as the major product arising through addition of the diene to the unhindered Si-face. The most interesting and new aspect of the Diels-Alder reaction of these dienophiles is the accessibility of the Re-face that was blocked by the alkenyl chains under Lewis acid catalysis producing the diastereoisomers 11a-d exclusively. The reversal of facial selectivity from an uncatalyzed reaction to a catalyzed one is unprecedented. The observed stereochemical dichotomy is attributed to rotation of the enone moiety along the o bond linking the sugar moiety during formation of the chelate 13. This makes the Re-face of the enone moiety in 4a-d unhindered. Diels-Alder reaction of the carbocyelic analogue 15 under Lewis acid catalysis produced a 1:1 mixture of the adducts 16 and 17 confirming the participation of sugar ring oxygen in chelate formation. Finally ROM-RCM of 10a-d and 11a-d with Grubbs' catalyst afforded the cis-syn-cis and cis-anti-cis bicyclo-annulated sugars 21a-d and 23a-d, respectively, containing 7-9 membered rings.
- Malik, Chanchal K.,Yadav, Ram Naresh,Drew, Michael G. B.,Ghosh, Subrata
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scheme or table
p. 1957 - 1963
(2009/08/07)
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- Large scale synthesis of the acetonides of l-glucuronolactone and of l-glucose: easy access to l-sugar chirons
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1,2-O-Isopropylidene-α-l-glucurono-3,6-lactone may be synthesized on a 100-200 g scale from cheaply available d-glucoheptonolactone in an overall yield of 94% in four steps via l-glucuronolactone. Subsequent elaboration to l-glucose, diacetone-l-glucose (1,2:5,6-di-O-isopropylidene-α-l-glucofuranose), and monoacetone-l-glucose (1,2-O-isopropylidene-α-l-glucofuranose) allows easy access to a range of l-sugar chirons.
- Weymouth-Wilson, Alexander C.,Clarkson, Robert A.,Jones, Nigel A.,Best, Daniel,Wilson, Francis X.,Pino-González, Maria-Soledad,Fleet, George W.J.
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experimental part
p. 6307 - 6310
(2010/01/18)
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- Chemoenzymatic synthesis of GDP-azidodeoxymannoses: Non-radioactive probes for mannosyltransferase activity
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GDP-2-, 3-, 4- or 6-azidomannoses can be successfully prepared from the corresponding azidomannose-1-phosphates and GTP using the enzyme GDP-Mannosepyrophosphorylase (GDP-ManPP) from Salmonella enterica and may serve as useful probes for mannosyltransferase activity. The Royal Society of Chemistry.
- Marchesan, Silvia,Macmillan, Derek
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supporting information; scheme or table
p. 4321 - 4323
(2009/03/12)
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- Synthesis of UDP-glucose derivatives modified at the 3-OH as potential chain terminators of β-glucan biosynthesis
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A series of UDP-d-glucose derivatives and precursors that have been modified at C-3 were synthesised from d-glucose as potential chain terminators of β-glucan biosynthesis. None of the UDP-derivatives or the precursors tested displayed significant anti-fungal activity in a series of germination assays on the dermatophyte Trichophyton rubrum.
- Danac, Ramona,Ball, Lucy,Gurr, Sarah J.,Fairbanks, Antony J.
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p. 1012 - 1022
(2008/09/20)
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- A facile and practical synthesis of peracylated 4-thio-D-ribofuranoses from D-glucose
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(Chemical Equation Presented) A practical synthesis of a peracylated 4-thio-D-ribofuranose 14 starting from inexpensive D-glucose is described. The C2-C6 portion of D-glucose was utilized, in which sulfur was introduced to C5 in two consecutive displacement reactions with net retention of configuration under mild conditions.
- Sun, Zhi-Hua,Wang, Bing
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p. 2462 - 2465
(2008/09/19)
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- Ex-chiral-pool synthesis of β-hydroxyphosphonate nucleoside analogues
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A new series of mononucleotide analogues bearing a nonhydrolysable P-C bond instead of the P-O phosphate linkage is presented. We intend to set up an approach that allows the synthesis of β-hydroxyphosphonate nucleoside analogues as a single diastereoisomer. In this respect, the key "sugar-phosphonate" intermediate was obtained through an Arbusov reaction from an iodosugar derivative in which the stereochemistry of the β-hydroxy group is determined by the choice of the starting material and remains in the resulting nucleotide analogues. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Gallier, Franck,Peyrottes, Suzanne,Perigaud, Christian
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p. 925 - 933
(2008/02/13)
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- Ring-modified analogues and molecular dynamics studies to probe the requirements for fungicidal activities of malayamycin A and its N-nucleoside variants
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(Chemical Equation Presented) The importance of functional group orientations and the integrity of the bicyclic perhydrofuran core of malayamycin A and two equally active N-nucleoside analogues as fungicides were investigated. Two analogues 10 and 11, representing a THP-truncated and a bicyclic aza-variant, were synthesized and found to be inactive. Molecular dynamics studies on malayamycin A and analogues were performed to highlight the importance of properly orientating the urea and methyl ether groups.
- Loiseleur, Olivier,Ritson, Dougal,Nina, Mafalda,Crowley, Patrick,Wagner, Trixie,Hanessian, Stephen
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p. 6353 - 6363
(2008/02/10)
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- Model for antibiotic optimization via neoglycosylation: Synthesis of liponeoglycopeptides active against VRE
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The neoglycosylation of a methoxyamine-appended vancomycin aglycon with all possible N′-decanoylglucopyranose and N′-biphenoylglucopyranose regioisomers led to the production of a focused set of liponeoglycopeptide variants in good yields and with excellent stereoselectivity. High-throughput antibacterial assays employing a unique set of vancomycin-resistant Enterococci faecalis and Enterococci faecium clinical isolates revealed that the nature and regiochemistry of glycosyl lipidation modulated vancomycin-resistent Enterococci potency. In contrast to prior work with lipoglycopeptides, this study reveals the glucose C3′ or C4′ as the optimal position for neoglycopeptide lipidation. This purely chemical method for the diversification of the glycolipid portion of lipoglycopeptide antibiotics is simple to perform on a large scale, requires minimal synthetic effort in sugar donor preparation, and provides access to highly active antibiotics that are not easily prepared by other state-of-the-art methods.
- Griffith, Byron R.,Krepel, Candace,Fu, Xun,Blanchard, Sophie,Ahmed, Aqeel,Edmiston, Charles E.,Thorson, Jon S.
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p. 8150 - 8155
(2008/02/11)
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- Sulfuric acid immobilized on silica: an efficient reusable catalyst for the synthesis of O-isopropylidene sugar derivatives
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Sulfuric acid immobilized on silica proved to be an efficient catalyst for the synthesis of O-isopropylidene sugar derivatives from reducing sugars. The method is very simple and economic for large-scale synthesis in which the catalyst is recovered and reused several times. Reactions with d-glucose, d-galactose, d-mannose, l-rhamnose, l-arabinose, d-xylose and l-sorbose led to the formation of the corresponding thermodynamically stable di-O- and/or mono-O-isopropylidene derivatives in good to excellent yields.
- Rajput, Vishal Kumar,Mukhopadhyay, Balaram
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p. 5939 - 5941
(2007/10/03)
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- A general strategy for the stereoselective synthesis of l-1-deoxyallonojirimycin and d-1-deoxygulonojirimycin
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A general strategy for the synthesis of deoxyazasugars from d-glucose is described. Ring-closing metathesis and stereoselective dihydroxylation reactions were used as key steps.
- Ghosh, Subhash,Shashidhar,Dutta, Samit Kumar
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p. 6041 - 6044
(2007/10/03)
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- From glycoside hydrolases to thioglycoligases: The synthesis of thioglycosides
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The treatment of various glycosyl acceptors, each containing a reactive thiol group, with the appropriate glycosyl donor and a glycoside hydrolase or glycosynthase, failed to yield any thioglycosides - only the products of O-glycosylation were formed. However, thioglycosides were formed when a thioglycoligase was used to mediate the reaction between acceptor and donor. In fact, pyranose acceptors possessing a thiol group at C3, C4 or C6 (but not C2) were all capable of conversion into thioglycosides. Some comment is given regarding the mechanism of the various processes.
- Stick, Robert V.,Stubbs, Keith A.
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p. 321 - 335
(2007/10/03)
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- Synthesis of polycyclic β-lactams from D-glucose derived chiral template via substrate-controlled radical cyclization
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A highly stereoselective and substrate-controlled synthesis of polycyclic β-lactams from D-glucose derived chiral template via intramolecular radical cyclization is described. The cyclization is highly substrate dependant, proceeding via 6-exo and 7-endo heptenyl type radical cyclization with the radical acceptor allyl group at N-1 and the radical progenitor on a sugar moiety, anchored to the β-lactam ring at C-4. The mode of radical cyclization in N-propargyl substrates is highly stereospecific and controlled by the stereochemistry of the β-lactam ring.
- Deshmukh, Abdul Rakeeb A. S.,Jayanthi, Arumugam,Thiagarajan, Kamanan,Puranik, Vedavati G.,Bhawal, Baburao M.
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p. 2965 - 2974
(2007/10/03)
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- Inactivation of human S-adenosylhomocysteine hydrolase by covalent labeling of cysteine 195 with thionucleoside derivatives
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Thionucleosides 1-4 were synthesized for selectively targeting 195Cys of human placental AdoHcy hydrolase. A new series of 5′-thioadenosine derivatives 1-4 were synthesized for selectively targeting 195Cys of human AdoHcy hydrolase. Their incubation with the enzyme resulted in time- and concentration-dependent inactivation, without major modifications of the NAD+/NADH ratio. The electrospray mass analysis of the inactivated enzyme with 1, 2, 3, and 4b showed that inhibition was accompanied by the formation of a specific and covalent labeling of each AdoHcy hydrolase subunit. Proteolytic cleavage (endo-Lys-C) and subsequent peptide characterization of the labeled enzyme revealed that 195Cys was the residue modified during the inactivation process.
- Guillerm, Georges,Muzard, Murielle,Glapski, Cédric,Pilard, Serge
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p. 5803 - 5807
(2007/10/03)
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- Synthesis of 5-Azacytidine nucleosides with rigid sugar moiety as potential antitumor agents
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The bicyclic 3′-O,5′-C-methylene-linked and 2′-O,5′-C-methylene-linked 5-azacytidine derivatives were readily synthesized from 1,2;5,6-di-O-isopropylidene-D-glucose and evaluated against several cancer cell lines.
- Chun, Moon Woo,Kim, Myong Jung,Kim, Hea Ok,Kim, Hee-Doo,Kim, Joong Hyup,Moon, Hyung Ryong,Jeong, Lak Shin
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p. 915 - 917
(2007/10/03)
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