- RADIOLABELED SUGARS FOR IMAGING OF FUNGAL INFECTIONS
-
Disclosed herein are compounds having a structure according to Formula I and optionally Formula IV. Formula I Formula IV. The compounds may be radiolabeled compounds useful for diagnosis and/or imaging fungal infections. In such embodiments, at least one substituent is a radionuclide, such as 18F. Also disclosed are precursor compounds according to Formula I and/or IV that are useful for making the radiolabeled compounds. In such embodiments, the precursor compound comprises at least one leaving group suitable for introducing a radionuclide, such as 18F, at a desired position. Also disclosed are methods for making and using the compounds, including embodiments of a method for imaging and/or diagnosing a fungal infection in a subject.
- -
-
Page/Page column 28; 30
(2021/02/12)
-
- Synthetic Fluorinated l -Fucose Analogs Inhibit Proliferation of Cancer Cells and Primary Endothelial Cells
-
Fucosylation is one of the most prevalent modifications on N- and O-glycans of glycoproteins, and it plays an important role in various cellular processes and diseases. Small molecule inhibitors of fucosylation have shown promise as therapeutic agents for sickle cell disease, arthritis, and cancer. We describe here the design and synthesis of a panel of fluorinated l-fucose analogs bearing fluorine atoms at the C2 and/or C6 positions of l-fucose as metabolic fucosylation inhibitors. Preliminary study of their effects on cell proliferation revealed that the 6,6-difluoro-l-fucose (3) and 6,6,6-trifluoro-l-fucose (6) showed significant inhibitory activity against proliferation of human colon cancer cells and human umbilical vein endothelial cells. In contrast, the previously reported 2-deoxy-2-fluoro-l-fucose (1) had no apparent effects on proliferations of all the cell lines tested. To understand the mechanism of cell proliferation inhibition by the fluorinated l-fucose analogs, we performed chemoenzymatic synthesis of the corresponding GDP-fluorinated l-fucose analogs and tested their inhibitory activities against the mammalian α1,6-fucosyltransferase (FUT8). Interestingly, the corresponding GDP derivatives of 6,6-difluoro-l-fucose (3) and 6,6,6-trifluoro-l-fucose (6), which are the stronger proliferation inhibitors, showed much weaker inhibitory activity against FUT8 than that of the 2-deoxy-2-fluoro-l-fucose (1). These results suggest that FUT8 is not the major target of the 6-fluorinated fucose analogs (3 and 6). Instead, other factors, such as the key enzymes involved in the de novo GDP-fucose biosynthetic pathway and/or other fucosyltransferases involved in the biosynthesis of tumor-associated glyco-epitopes are most likely the targets of the fluorinated l-fucose analogs to achieve cell proliferation inhibition. To our knowledge, this is the first comparative study of various fluorinated l-fucose analogs for suppressing the proliferation of human cancer and primary endothelial cells required for angiogenesis.
- Dai, Yuanwei,Hartke, Ruth,Li, Chao,Yang, Qiang,Liu, Jun O.,Wang, Lai-Xi
-
p. 2662 - 2672
(2020/11/26)
-
- Radiosynthesis of 18F-labeled D-allose
-
Rare sugars are defined as monosaccharides that exist in nature but are only present in limited quantities. D-Allose is a rare sugar that has been reported to have some unique physiological effects. The present study describes suitable synthetic procedures for novel rare sugars of D-allose that are 18F-labeled at the C-3 and C-6 positions and the preparation of the appropriate labeling precursors. The goal is to facilitate in vivo, noninvasive positron emission tomography (PET) investigation of the behavior of rare sugar analogs of D-allose in organs. We found five precursors that were practical for labeling, three for 3-deoxy-3-[18F]fluoro-D-allose ([18F]3FDA) and two for 6-deoxy-6-[18F]fluoro-D-allose ([18F]6FDA). With manual operation synthesis, the highest radiochemical conversion rates were 75% for [18F]3FDA with a precursor of 1,2,4,6-tetra-O-acetyl-3-O-trifluoromethanesulfonyl-β-D-glucopyranose and 69% for [18F]6FDA with a precursor of 1,2,3,4-tetra-O-acetyl-6-O-trifluoromethanesulfonyl-β-D-allopyranose. Furthermore, the practical yields of [18F]3FDA and [18F]6FDA using an automated synthesizer were also investigated. Radiochemical yields of 67% and 49% were obtained for [18F]3FDA and [18F]6FDA, respectively, in an automated synthesizer. As basic assessment of stability for use in PET scanning, high performance liquid chromatography analysis showed no decomposition of [18F]3FDA and [18F]6FDA after up to 6 h in rabbit blood plasma.
- Yamamoto, Hiroyuki,Wada, Kenji,Toyohara, Jun,Tago, Tetsuro,Ibaraki, Masanobu,Kinoshita, Toshibumi,Yamamoto, Yuka,Nishiyama, Yoshihiro,Kudomi, Nobuyuki
-
-
- BIARYL AMIDES WITH MODIFIED SUGAR GROUPS FOR TREATMENT OF DISEASES ASSOCIATED WITH HEAT SHOCK PROTEIN PATHWAY
-
Provided are biaryl amides and coumarin-based compounds with modified sugar groups for treatment of diseases associated with heat shock protein pathway. The compounds having the following formulas, wherein variables are as defined herein. Formulae (I), (II), (III), (IV), and (V), Pharmaceutical compositions of the compounds are also provided. These biaryl amides and coumarin-based derivatives with modified sugar groups are useful for treatment and prevention of diseases and disorders, including neurological disorders, such as neurodegenerative diseases and nerve damaging disorders, for example, diabetic peripheral neuropathy.
- -
-
Page/Page column 165; 180; 224-225
(2019/12/04)
-
- Stereoselective Synthesis of Fluorinated Galactopyranosides as Potential Molecular Probes for Galactophilic Proteins: Assessment of Monofluorogalactoside–LecA Interactions
-
The replacement of hydroxyl groups by fluorine atoms on hexopyranoside scaffolds may allow access to invaluable tools for studying various biochemical processes. As part of ongoing activities toward the preparation of fluorinated carbohydrates, a systematic investigation involving the synthesis and biological evaluation of a series of mono- and polyfluorinated galactopyranosides is described. Various monofluorogalactopyranosides, a trifluorinated, and a tetrafluorinated galactopyranoside have been prepared using a Chiron approach. Given the scarcity of these compounds in the literature, in addition to their synthesis, their biological profiles were evaluated. Firstly, the fluorinated compounds were investigated as antiproliferative agents using normal human and mouse cells in comparison with cancerous cells. Most of the fluorinated compounds showed no antiproliferative activity. Secondly, these carbohydrate probes were used as potential inhibitors of galactophilic lectins. The first transverse relaxation-optimized spectroscopy (TROSY) NMR experiments were performed on these interactions, examining chemical shift perturbations of the backbone resonances of LecA, a virulence factor from Pseudomonas aeruginosa. Moreover, taking advantage of the fluorine atom, the 19F NMR resonances of the monofluorogalactopyranosides were directly monitored in the presence and absence of LecA to assess ligand binding. Lastly, these results were corroborated with the binding potencies of the monofluorinated galactopyranoside derivatives by isothermal titration calorimetry experiments. Analogues with fluorine atoms at C-3 and C-4 showed weaker affinities with LecA as compared to those with the fluorine atom at C-2 or C-6. This research has focused on the chemical synthesis of “drug-like” low-molecular-weight inhibitors that circumvent drawbacks typically associated with natural oligosaccharides.
- Denavit, Vincent,Lainé, Danny,Bouzriba, Chahrazed,Shanina, Elena,Gillon, émilie,Fortin, Sébastien,Rademacher, Christoph,Imberty, Anne,Giguère, Denis
-
p. 4478 - 4490
(2019/03/07)
-
- CARRIER-FREE RADIOACTIVE HALOGEN LABELED DEOXYHALOGENO-D-ALLOSE, NON-RADIOACTIVE DEOXYFLUORO-D-ALLOSE, THEIR PRECURSOR, AND THEIR PRODUCTION METHOD
-
PROBLEM TO BE SOLVED: To provide new radioactive halogen labeled substances with a D-allose skeleton, a production method thereof, and the like. SOLUTION: A radioactive halogen labeled deoxyhalogeno-D-allose derivative is a compound represented by the general formula (1) or general formula (2) in the figure or a salt thereof. In the formulas (1) and (2), X is a halogen radioisotope such as 18F. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPO&INPIT
- -
-
Paragraph 0090; 0091
(2018/04/03)
-
- Synthesis method and application of sialylated TF antigen and its fluorination derivatives
-
The invention discloses a synthesis method and an application of a sialylated TF antigen and its fluorination derivatives. The method includes the following steps: (1) chemically synthesizing fluorogalactose and fluorogalactosamine analogues; (2) chemically synthesizing a fluorinated TF antigen; and (3) synthesizing the sialylated TF antigen and its fluorination derivatives through an enzyme technology. The flexibility of a chemical synthesis technology is combined with the high regioselectivity and the high efficiency of the enzyme synthesis technology, so the enzymatic synthesis of the fluorosialylated TF antigen is achieved for the first time, and the disadvantages of many synthesis steps, poor stereoselectivity, low yield and use of a heavy metal salt in existing chemical synthesis ofthe fluorosialylated TF antigen are overcome. A fluorotumor-associated carbohydrate antigen has a higher stability than natural carbohydrate antigen, so the sialylated TF antigen and its fluorinationderivatives have a broad application prospect in the development of novel antitumor vaccines.
- -
-
Paragraph 0075; 0078; 0081
(2018/07/07)
-
- Fluorinated glycosyl amino acids for mucin-like glycopeptide antigen analogues
-
The aberrant glycosylation profiles of mucin glycoproteins on epithelial tumour cells represent attractive target structures for the development of immunotherapy against cancer. Mucin-type glycopeptides have been successfully investigated as molecularly defined vaccine prototypes for triggering humoral immunity but are susceptible to rapid in vivo degradation. As a potential means to enhance the bioavailabilities of the antigenic structures, hydrolysis-resistant carbohydrate analogues with fluorine substituents at positions C6, C2′ and C6′ were synthesised and incorporated into the tandem repeat sequence of the mucin MUC1. The resulting pseudo-glycopeptides can be used to elucidate the effects of chemically modified antibody determinants on metabolic and immunological properties.
- Wagner, Sarah,Mersch, Christian,Hoffmann-Roeder, Anja
-
supporting information; experimental part
p. 7319 - 7330
(2010/09/16)
-
- Synthesis of fluorinated analogues of tumor-associated carbohydrate and glycopeptide antigens
-
Partial structures of tumor-associated mucin glycoproteins are interesting target structures for the development of selective anticancer vaccines. To probe the effect of fluorination on the immunological and metabolic properties of mucin glycopeptides, six novel fluorinated glycosyl-threonine conjugates have been synthesized. The synthesis of the orthogonally protected glycosyl amino acids was achieved using microwave irradiation in key fluorination and glycosylation steps. The 2′-deoxy-2′-fluoro- and 6′-deoxy-6′-fluoro-T antigen building blocks were applied to the synthesis of analogues of MUC1 tandem repeat-glycopeptide antigens via SPPS. Georg Thieme Verlag Stuttgart.
- Mersch, Christian,Wagner, Sarah,Hoffmann-R?der, Anja
-
scheme or table
p. 2167 - 2171
(2011/03/22)
-
- Molecular recognition in the P2Y14 receptor: Probing the structurally permissive terminal sugar moiety of uridine-5′-diphosphoglucose
-
The P2Y14 receptor, a nucleotide signaling protein, is activated by uridine-5′-diphosphoglucose 1 and other uracil nucleotides. We have determined that the glucose moiety of 1 is the most structurally permissive region for designing analogues of this P2Y14 agonist. For example, the carboxylate group of uridine-5′-diphosphoglucuronic acid proved to be suitable for flexible substitution by chain extension through an amide linkage. Functionalized congeners containing terminal 2-acylaminoethylamides prepared by this strategy retained P2Y14 activity, and molecular modeling predicted close proximity of this chain to the second extracellular loop of the receptor. In addition, replacement of glucose with other sugars did not diminish P2Y14 potency. For example, the [5′′]ribose derivative had an EC50 of 0.24 μM. Selective monofluorination of the glucose moiety indicated a role for the 2′′- and 6′′-hydroxyl groups of 1 in receptor recognition. The β-glucoside was twofold less potent than the native α-isomer, but methylene replacement of the 1′′-oxygen abolished activity. Replacement of the ribose ring system with cyclopentyl or rigid bicyclo[3.1.0]hexane groups abolished activity. Uridine-5′-diphosphoglucose also activates the P2Y2 receptor, but the 2-thio analogue and several of the potent modified-glucose analogues were P2Y14-selective.
- Ko, Hyojin,Das, Arijit,Carter, Rhonda L.,Fricks, Ingrid P.,Zhou, Yixing,Ivanov, Andrei A.,Melman, Artem,Joshi, Bhalchandra V.,Kovac, Pavol,Hajduch, Jan,Kirk, Kenneth L.,Harden, T. Kendall,Jacobson, Kenneth A.
-
experimental part
p. 5298 - 5311
(2009/12/04)
-
- Application of the Synthetic Aminosugars for Glycodiversification: Synthesis and Antimicrobial Studies of Pyranmycin
-
A divergent approach was employed for the synthesis of aminosugars, from which a novel library of aminoglycoside antibiotics (pyranmycins) was synthesized. Pyranmycins have comparable antibacterial activity as neomycin, a clinically used aminoglycoside antibiotic, against Escherichia coli, Staphylococcus aureus, Bacillus subtilis, and Mycobacterium smegmatis. In addition, pyranmycins, like streptomycin, are bacteriocidal while isoniazid (INH) is bacteriostatic. Therefore, pyranmycins may provide new therapeutic options in the treatment against tuberculosis. Several members of pyranmycins also manifest modest anti-Tat and anti-Rev activities, which may aid in the development of new anti-HIV agents. Although the antibacterial activity of pyranmycins against aminoglycoside resistant bacteria is less than expected, the synthetic methodologies of utilizing a library of aminosugars can be a model for future studies of glycodiversification or glycorandomization.
- Elchert, Bryan,Li, Jie,Wang, Jinhua,Hui, Yu,Rai, Ravi,Ptak, Roger,Ward, Priscilla,Takemoto, Jon Y.,Bensaci, Mekki,Chang, Cheng-Wei Tom
-
p. 1513 - 1523
(2007/10/03)
-
- Selective synthesis of fluorinated carbohydrates using N,N-diethyl-α, α-difluoro-(m-methylbenzyl)amine
-
Deoxyfluorination of a hydroxy group in carbohydrates was carried out using N,N-diethyl-α,α-difluoro-(m-methylbenzyl)amine. A primary hydroxy group in carbohydrates was effectively converted to the corresponding fluoride under microwave irradiation or at 100°C. Deoxyfluorination of hydroxy groups at the anomeric position proceeded at below room temperature, and glycosyl fluorides could be obtained in good yields. The reaction chemoselectively proceeded, and various protecting groups of carbohydrates can survive under the reaction conditions.
- Kobayashi, Shingo,Yoneda, Atushi,Fukuhara, Tsuyoshi,Hara, Shoji
-
p. 1287 - 1289
(2007/10/03)
-
- Deoxyfluorination of alcohols using N,N-diethyl-α,α-difluoro- (m-methylbenzyl)amine
-
Deoxyfluorination of alcohols was carried out using N,N-diethyl-α, α-difluoro-(m-methylbenzyl)amine (DFMBA). Primary alcohols were effectively converted to fluorides under microwave irradiation or conventional heating. Deoxyfluorination of an anomeric hydroxy group in sugars by DFMBA proceeded at below room temperature and glycosyl fluorides could be obtained in good yields. The deoxyfluorination reaction chemoselectively proceeded and various protecting groups on the sugar can survive under the reaction conditions.
- Kobayashi, Shingo,Yoneda, Atushi,Fukuhara, Tsuyoshi,Hara, Shoji
-
p. 6923 - 6930
(2007/10/03)
-
- Synthesis of (6-2H)- and 6-deoxy-6-fluoro-L-galactose derivatives
-
The selective oxidation of trimethylsilylated D-galactose diethyl dithioacetal using Collins reagent provided the corresponding D-galacto-hexodialdo dithioacetal. Successive acid hydrolysis, isopropylidenation, and cleavage of the dithioacetal group gave the 1,2;3,4-di-O-isopropylidene-L-galacto-hexodialdo-1,5-pyranose as a key intermediate for the synthesis of 6-fluoro- and 6-deutero-substituted L-fucose derivatives.
- Brackhagen, Meinolf,Boye, Hanna,Vogel, Christian
-
-
- UDP-6-deoxy-6-fluoro-α-D-galactose binds to two different galactosyltransferases, but neither can effectively catalyze transfer of the modified galactose to the appropriate acceptor
-
The effect of substitution of the HO-6 of D-galactose with fluorine on the ability of α-(1→3)-galactosyltransferase (EC 2.4.1.151) and β-(1→4)-galactosyltransferase (EC 2.4.1.22) to catalyze its transfer from UDP to an appropriate acceptor was determined. HPLC analyses indicated that each transferase properly catalyzed formation of the expected product [β-D-Gal-(1→4)-D-GlcNAc] for the β-(1→4)-galactosyltransferase and α-D-Gal-(1→3)-β-D-Gal-(1→4)-D-GlcNAc for the α-(1→3)-D-galactosyltransferase] when UDP-α-D-Gal was the substrate. When UDP-6-deoxy-6-fluoro-α-D-galactose (6) was used in conjunction with each transferase, no product indicative of transfer of 6-deoxy-6-fluoro-D-galactose to its respective acceptor sugar was identified. 6-Deoxy-6-fluoro-D-galactose (3) was obtained by hydrolysis of methyl 6-deoxy-6-fluoro-α-D-galactopyranoside, synthesized by the selective fluorination of methyl α-D-galactopyranoside with diethylaminosulfur trifluoride (DAST), with aqueous trifluoroacetic acid. Acetylation of 3 gave crystalline 1,2,3,4-tetra-O-acetyl-6-deoxy-6-fluoro-β-D-galactopyranose, which was converted to the corresponding 1-α-phosphate and used for the synthesis of 6. Copyright (C) 1999 Elsevier Science Ltd.
- Schengrund, Cara-Lynne,Kovac, Pavol
-
-
- Recognition of synthesis deoxy and deoxyfluoro analogs of the acceptor α-L-Fucp-(1 → 2)-B-D-Galp-OR by the blood-group A and B gene-specified glycosyltransferases
-
The disaccharide α-L-Fuc p-(1→2)-B-D-Gal p-O-(CH2 )7CH3(6), is an acceptor for both glycosyl-transferases responsible for the biosynthesis of the A and B blood-group antigens. These enzymes transfer GalNAc and Gal, respect
- Lowary,Hindsgaul
-
p. 163 - 195
(2007/10/02)
-
- SYNTHESIS OF SOME MONODEOOXYFLUORINATED METHYL AND 4-NITROPHENYL α-D-MANNOBIOSIDES AND A RELATED 4-NITROPHENYL α-D-MANNOTRIOSIDE
-
Treatment of methyl 3,4,6-tri-O-benzyl-2-O-(2,3,4-tri-O-acetyl-α-D-mannopyranosyl)-α-D-mannopyranoside with N,N-diethylaminosulfur trifluoride (Et2NSF3), followed by O-deacetylation and catalytic hydrogenolysis, afforded methyl 2-O-(6-deoxy-6-fluoro-α-D-mannopyranosyl)-α-D-mannopyranoside (8).Methyl 6-deoxy-6-fluoro-2-O-α-D-mannopyranosyl-α-D-mannopyranoside (11) was similarly obtained from methyl 3-O-benzyl-2-O-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl-α-D-mannopyranoside. 1,2,3,4-Tetra-O-acetyl-6-deoxy-6-fluoro-β-D- mannopyranose (13), used for the sythesis of the 4-nitrophenyl analogs of 8 and 11, as well as their 3-O-linked isomers, was obtained by treatment of 1,2,3,4-tetra-O-acetyl-β-D-mannopyranose with Et2NSF3.Treatment of 13 with 4-nitrophenol in the presence of tin(IV) chloride, followed by sequential O-deacetylation, isopropylidenation, acetylation, and cleavage of the acetal group, afforded 4-nitrophenyl 4-O-acetyl-6-deoxy-6-fluoro-α-D-mannopyranoside (18).Treatment of 13 with HBr in glacial acetic acid furnished the 6-deoxy-6-fluoro bromide 19.Glycosylation of diol 18 with 20 gave 4-nitrophenyl 4-O-acetyl-6-deoxy-6-fluoro-3-O-(21) and -2-O-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl)-α-D-mannopyranoside (23) in the ratio of ca. 2:1, together with a small proportion of a branched trisaccharide. 4-Nitrophenyl 4,6-di-O-acetyl-α-D-mannopyranoside was similarly glycosylated with bromide 19 to give 4-nitrophenyl 4,6-di-O-acetyl-3-O- and -2-O-(2,3,4-tri-O-acetyl-6-deoxy-6-fluoro-α-D-mannopyranosyl)-α-D-mannopyranoside.The various di- and tri-saccharides were O-deacetylated by Zemplen transesterification.
- Khan, Shaheer H.,Jain, Rakesh K.,Abbas, Saeed A.,Matta, Khushi L.
-
p. 259 - 273
(2007/10/02)
-
- THE SYNTHESIS AND HYDROLYSIS OF A SERIES OF DEOXYFLUORO-D-GLUCOPYRANOSYL PHOSPHATES
-
The synthesis of all four deoxyfluoro-α-D-glucopyranosyl phosphates is described.Rate conctants for their acid-catalyzed hydrolysis were determined, and fluorine substitution was shown to have a significant effect in lowering the rate, particularly when t
- Withers, Stephen G.,MacLennan, David J.,Street, Ian P.
-
p. 127 - 144
(2007/10/02)
-
- Synthesis of Deoxyhalogenosugars. Reaction of Halide Ions with 1,2,3,4-Tetra-O-acetyl-6-O--β-D-glucopyranose
-
The reaction of bromide, chloride, and iodide ions with 1,2,3,4-tetra-O-acetyl-6-O--β-D-glucopyranose under the proper conditions gives excellent yields of the corresponding deoxyhalogeno sugars.Deoxyiodo sugars form readily under all conditions studied.Difficulties with displacements by bromide and chloride are encountered but can be overcome by appropriate modification of reaction conditions.Displacement with fluoride ion is difficult and produces only a low yield of the expected fluorinated carbohydrate.
- Ambrose, Michael G.,Binkley, Roger W.
-
p. 674 - 677
(2007/10/02)
-