Conformational analysis of 5-thio-D-glucose

Lambert, Joseph B.; Wharry, Stephen M.

doi:10.1021/jo00329a009

Cited by 32 publications

(9 citation statements)

References 5 publications

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“…In the compounds with an α- N -glycosidic bond, this coupling a−e was found to be about 5 Hz, while in the compounds with a β- N -glycosidic bond, the coupling a−a was found to be about 9 Hz. Moreover, 1 H− 13 C correlations allowed unambiguously the assignment of C 1 ‘ which was shifted at >90 ppm values for compounds having an α- N -glycosidic bond, in agreement with that observed for α-glucopyranose (C 1 ‘ shifted at 92.8 ppm) …”

Section: Chemistrysupporting

confidence: 84%

“…Moreover, 1 H- 13 C correlations allowed unambiguously the assignment of C 1′ which was shifted at >90 ppm values for compounds having an R-N-glycosidic bond, in agreement with that observed for R-glucopyranose (C 1′ shifted at 92.8 ppm). 26 Molecular modeling experiments for conformational searches using the SYBYL software package (Tripos Associates Inc.) were carried out on compound 3 (simulated annealing process, using Tripos force field with a dielectric constant of water ) 78) and yielded conformation 3′ shown in Chart 2 with a global energy of 57.46 kcal. Conformation 3′ is derivated from 3 by chairchair inversion and is stabilized by one hydrogen bond, between the hydrogen of the indolic NH and the oxygen of the carbonyl on C 4′ , and electrostatic interactions between the hydrogen of the indolic NH and the oxygens of the sugar ring and of the carbonyl on C 2′ .…”

Section: Chemistrymentioning

confidence: 99%

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Syntheses and Biological Activities (Topoisomerase Inhibition and Antitumor and Antimicrobial Properties) of Rebeccamycin Analogues Bearing Modified Sugar Moieties and Substituted on the Imide Nitrogen with a Methyl Group

et al. 1997

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As a part of studies on structure-activity relationships, several potential topoisomerase I inhibitors were prepared. Different analogues of the antitumor antibiotic rebeccamycin substituted on the imide nitrogen with a methyl group were synthesized. These compounds bore either the sugar residue of rebeccamycin, with or without the chlorine atoms on the indole moieties, or modified sugar residues (galactopyranosyl, glucopyranosyl, or fucopyranosyl) linked to the aglycone via a beta- or alpha-N-glycosidic bond. Their inhibitory properties toward protein kinase C, topoisomerase I, and topoisomerase II were examined, and their DNA-binding properties were investigated. Their in vitro antitumor activities against murine B16 melanoma and P388 leukemia cells were determined. Their antimicrobial activities were tested against Gram-positive bacteria Bacillus cereus and Streptomyces chartreusis, Gram-negative bacterium Escherichia coli, and yeast Candida albicans. These compounds are inactive toward topoisomerase II but inhibit topoisomerase I. A substitution with a methyl group on the imide nitrogen led to a loss of proteine kinase C inhibition in the maleimide indolocarbazole series but did not prevent topoisomerase I inhibition. Compounds possessing a beta-N-glycosidic bond, which fully intercalated into DNA, were more efficient at inhibiting topoisomerase I than their analogues with an alpha-N-glycosidic bond; however, both were equally toxic toward P388 leukemia cells. Dechlorinated rebeccamycin possessing a methyl group on the imide nitrogen was about 10 times more efficient in terms of cytotoxicity and inhibition of topoisomerase I than the natural metabolite.

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Section: Chemistrysupporting

confidence: 84%

Section: Chemistrymentioning

confidence: 99%

Syntheses and Biological Activities (Topoisomerase Inhibition and Antitumor and Antimicrobial Properties) of Rebeccamycin Analogues Bearing Modified Sugar Moieties and Substituted on the Imide Nitrogen with a Methyl Group

et al. 1997

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“…However, the R-anomer of these compounds suffers a puckering of the ring as deduced from the decrease of the 3 J 1,2 coupling constant (5.5-7.2 Hz). These data are in agreement with the prediction reported by Lambert et al 115 for 5-thio-Dglucose. Unambiguous assignment of the 13 Once the efficiency of the method described above for the synthesis of L-thio sugars was demonstrated, the strategy was applied in the synthesis of 5-thio-L-fucose and 2-deoxy-4-thiofuranoses, both important because of their biological significance.…”

Section: Resultssupporting

confidence: 94%

“…These data are in agreement with the prediction reported by Lambert et al. for 5-thio-d-glucose. Unambiguous assignment of the 13 C NMR signals was possible by 2D correlation experiments in compounds 44 , 47 − 51 , and 53 − 55 .…”

Section: Resultssupporting

confidence: 93%

Applications of Cyclic Sulfates ofvic-Diols: Synthesis of Episulfides, Olefins, and Thio Sugars

et al. 1997

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A new efficient and expeditious one-pot synthesis of thiiranes and olefins from cyclic sulfates of vic-diols is described. Opening of cyclic sulfates with potassium thioacetate or potassium thiocyanate followed by treatment with sodium methoxide led to episulfides. Olefins were obtained when potassium selenocyanate was used as nucleophile, and the obtained monoesters were treated with sodium borohydride. This method was applied to acyclic polyols derived from chiral glycerine, 1,2-isopropylidenehexofuranoses with different subtituents at C-3, and dimethyl acetals derived from pentoses and hexoses. The methodology is highly versatile, and its applicability has been demonstrated by the synthesis of different 4- and 5-thiosugars by opening of the thiirane ring with sodium acetate or lithium aluminum hydride. Reduction with lithium aluminum hydride of the thiocyanate sulfate potassium salt obtained by the opening of cyclic sulfate with KSCN allowed the direct synthesis of 5-deoxy-4-thio- and 6-deoxy-5-thiosugars. Cyclic thiosugars with the sulfur atom in the ring are obtained by acidic hydrolysis of the 5-thiol derivatives of 1,2-O-isopropylidenehexofuranoses and 4-thiopentose dimethyl acetals. Using this method, an efficient synthesis of 5-thio-l-fucose as well as the synthesis of 2,5-dideoxy-4-thiofuranose is described.

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“…Interestingly, in cases where the GT-catalyzed glycosyl transfer from nucleotide 5-thiosugar donors has been assayed, the efficiency of transfer is only between 0.2 and 5% compared to the natural nucleotide sugar donor 26 - 28 . This less efficient transfer of 5-thiosugars may be due to the distorted conformation of the pyranose ring that is known to be adopted by these compounds relative to their oxygen counterparts 29 . Therefore, we speculated that OGT would be inhibited by uridine diphospho-5-thio- N -acetylglucosamine (UDP-5SGlcNAc, 4 , Figure 1a ) and that, although UDP-5SGlcNAc ( 4 ) might be turned over, the rate of transfer would be sufficiently slow that it would essentially act as an inhibitor in cells.…”

mentioning

confidence: 99%

Hijacking a biosynthetic pathway yields a glycosyltransferase inhibitor within cells

et al. 2011

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Glycosyltransferases (GTs) are ubiquitous enzymes that catalyze the assembly of glycoconjugates found throughout all kingdoms of nature. A longstanding problem is the rational design of probes that can be used to manipulate GT activity in cells and tissues. Here we describe the rational design and synthesis of a nucleotide sugar analogue that inhibits, with high potency both in vitro and in cells, the human GT responsible for the reversible post-translational modification of nucleocytoplasmic proteins with O-linked N-acetylglucosamine residues (O-GlcNAc). We show the enzymes of the hexosamine biosynthetic pathway can transform, both in vitro and in cells, a synthetic carbohydrate precursor into the nucleotide sugar analogue. Treatment of cells with the precursor decreases O-GlcNAc in a targeted manner with a single digit micromolar EC50. This approach to inhibition of GTs should be applicable to other members of this increasingly interesting superfamily of enzymes and enable their manipulation in a biological setting.

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Conformational analysis of 5-thio-D-glucose

Cited by 32 publications

References 5 publications

Syntheses and Biological Activities (Topoisomerase Inhibition and Antitumor and Antimicrobial Properties) of Rebeccamycin Analogues Bearing Modified Sugar Moieties and Substituted on the Imide Nitrogen with a Methyl Group

Syntheses and Biological Activities (Topoisomerase Inhibition and Antitumor and Antimicrobial Properties) of Rebeccamycin Analogues Bearing Modified Sugar Moieties and Substituted on the Imide Nitrogen with a Methyl Group

Applications of Cyclic Sulfates ofvic-Diols: Synthesis of Episulfides, Olefins, and Thio Sugars

Hijacking a biosynthetic pathway yields a glycosyltransferase inhibitor within cells

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