- Chloromethyl Glycosides as Versatile Synthons to Prepare Glycosyloxymethyl-Prodrugs
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This work investigates the addition of monosaccharides to marketed drugs to improve their pharmacokinetic properties for oral absorption. To this end, a set of chloromethyl glycoside synthons were developed to prepare a variety of glycosyloxymethyl-prodrugs derived from 5-fluorouracil, thioguanine, propofol and losartan. Drug release was studied in vitro using β-glucosidase confirming rapid conversion of the monosaccharide prodrugs to release the parent drug, formaldehyde and the monosaccharide. To showcase this prodrug approach, a glucosyloxymethyl conjugate of the tetrazole-containing drug losartan was used for in vivo experiments and showed complete release of the drug in a dog-model.
- Boltje, Thomas J.,Derks, Maik G. N.,Elferink, Hidde,Rutjes, Floris P. J. T.,Titulaer, Willem H. C.,Veeneman, Gerrit H.
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- Concise Synthesis of 1-Thioalkyl Glycoside Donors by Reaction of Per-O-acetylated Sugars with Sodium Alkanethiolates under Solvent-Free Conditions
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A relatively green method for synthesizing 1-thioalkyl glycosides has been developed, where sodium alkanethiolates were used to react with per-O-acetylated sugars instead of odorous alkyl mercaptans in the presence of BF3·Et2O without the use of solvents under mild conditions. Furthermore, we found that 1,2-trans-β-thioglycosides can be converted into corresponding 1,2-cis-α-thioglycosides in the presence of trifluoromethanesulfonic acid in nonpolar solvents under mild conditions. This provides a simple and efficient new approach for synthesizing challenging 1,2-cis-α-thioglycosides.
- Dong, Hai,Feng, Guang-Jing,Guo, Yang-Fan,Liu, Chun-Yang,Luo, Tao
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- Carbohydrate-Based NK1R Antagonists with Broad-Spectrum Anticancer Activity
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NK1R antagonists, investigated for the treatment of several pathologies, have shown encouraging results in the treatment of several cancers. In the present study, we report on the synthesis of carbohydrate-based NK1R antagonists and their evaluation as anticancer agents against a wide range of cancer cells. All of the prepared compounds, derived from either-arabinose, have shown high affinity and NK1R antagonistic activity with a broad-spectrum anticancer activity and an important selectivity, comparable to Cisplatin. This strategy has allowed us to identify the galactosyl derivative 14α , as an interesting hit exhibiting significant NK1R antagonist effect (kinact0.209 ± 0.103 μM) and high binding affinity for NK1R (IC50= 50.4 nM,Ki= 22.4 nM by measuring the displacement of [125I] SP from NK1R). Interestingly, this galactosyl derivative has shown marked selective cytotoxic activity against 12 different types of cancer cell lines.
- Recio, Rocío,Lerena, Patricia,Pozo, Esther,Calderón-Monta?o, José Manuel,Burgos-Morón, Estefanía,López-Lázaro, Miguel,Valdivia, Victoria,Pernia Leal, Manuel,Mouillac, Bernard,Organero, Juan ángel,Khiar, Noureddine,Fernández, Inmaculada
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p. 10350 - 10370
(2021/07/28)
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- Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of α-Oxo-vinylsulfones to Prepare C-Aryl Glycals and Acyclic Vinyl Ethers
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We demonstrate that readily available and bench-stable α-oxo-vinylsulfones are competent electrophiles in Ni-catalyzed Suzuki-Miyaura cross-coupling reactions. The C-sulfone bond in the α-oxo-vinylsulfone motif is cleaved chemoselectively in these reactions, furnishing C-aryl glycals or acyclic vinyl ethers in high yields. These reactions proceed under mild conditions and tolerate a remarkable scope of heterocycles and functional groups. Preliminary mechanistic studies revealed the importance of an α-heteroatom in facilitating these transformations.
- Gong, Liang,Sun, Hong-Bao,Deng, Li-Fan,Zhang, Xia,Liu, Jie,Yang, Shengyong,Niu, Dawen
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- Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of α-Oxo-vinylsulfones to Prepare C-Aryl Glycals and Acyclic Vinyl Ethers
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We demonstrate that readily available and bench-stable α-oxo-vinylsulfones are competent electrophiles in Ni-catalyzed Suzuki-Miyaura cross-coupling reactions. The C-sulfone bond in the α-oxo-vinylsulfone motif is cleaved chemoselectively in these reactions, furnishing C-aryl glycals or acyclic vinyl ethers in high yields. These reactions proceed under mild conditions and tolerate a remarkable scope of heterocycles and functional groups. Preliminary mechanistic studies revealed the importance of an α-heteroatom in facilitating these transformations.
- Gong, Liang,Sun, Hong-Bao,Deng, Li-Fan,Zhang, Xia,Liu, Jie,Yang, Shengyong,Niu, Dawen
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p. 7680 - 7686
(2019/05/22)
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- ANTAGONISTS OF NK1 RECEPTORS DERIVED FROM CARBOHYDRATES, PRODUCTION METHOD AND MEDICAL USE
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The invention relates to a compound of general formula (I), and to the use thereof in medicine, or for the production of a medicament for the treatment of different diseases, preferably a cancer such as melanoma, lung carcinoma or breast cancer. For this purpose, the invention also relates to a pharmaceutical composition comprising said compound. In addition, the invention relates to a method for producing the compound of general formula (I).
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Paragraph 0055; 0056; 0057; 0058
(2018/04/19)
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- Dehydrative Thioglycosylation of 1-Hydroxyl Glycosides Catalyzed by In Situ-Generated AlI3
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Thioglycosylation of 1-hydroxyl glycosides catalyzed by in situ-generated AlI3 from elemental aluminium and molecular iodine has been developed. This method provides an alternative route to access anomeric thioglycosides without the use of hazard Lewis acidic activators or per-modified activated thiol sources. The major advantages of this dehydrative procedure are environmental friendly, ease of operation, high anomeric diastereoselectivity, and mild reaction conditions.
- Weng, Shiue-Shien,Hsieh, Kun-Yi,Zeng, Zih-Jian
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p. 464 - 473
(2017/05/19)
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- Efficient one-pot per-: O -acetylation-thioglycosidation of native sugars, 4,6- O -arylidenation and one-pot 4,6- O -benzylidenation-acetylation of S -/ O -glycosides catalyzed by Mg(OTf)2
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A sequential one-pot per-O-acetylation-S-/O-glycosidation of native mono and disaccharides under solvent free conditions using 0.5 mole% of Mg(OTf)2 as a non-hygroscopic, recyclable catalyst is reported. Regioselective 4,6-O-arylidenation of glycosides and thioglycosides with benzaldehyde or p-methoxybenzaldehyde dimethyl acetal is catalyzed by 10 mole% of Mg(OTf)2 to produce the corresponding 4,6-O-arylidenated product in high yields. Mg(OTf)2 can also mediate sequential one-pot benzylidenation-acetylation of mono and disaccharide based glycosides and thioglycosides in high yield.
- Mukherjee, Mana Mohan,Basu, Nabamita,Chaudhury, Aritra,Ghosh, Rina
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p. 109301 - 109314
(2016/11/30)
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- Atom-Economical Dimerization Strategy by the Rhodium-Catalyzed Addition of Carboxylic Acids to Allenes: Protecting-Group-Free Synthesis of Clavosolide A and Late-Stage Modification
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Natural products of polyketide origin with a high level of symmetry, in particular C2-symmetric diolides as a special macrolactone-based product class, often possess a broad spectrum of biological activity. An efficient route to this important
- Haydl, Alexander M.,Breit, Bernhard
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supporting information
p. 15530 - 15534
(2016/01/26)
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- In(III) triflate-mediated solvent-free synthesis and activation of thioglycosides by ball milling and structural analysis of long chain alkyl thioglycosides by TEM and quantum chemical methods
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Conventional solution-phase synthesis of thioglycosides from glycosyl acetates and thiols in the presence of In(III) triflate as reported for benzyl thioglucoside failed when applied to the synthesis of phenolic and alkyl thioglycosides. But, it was achieved in high efficiency and diastereospecificity with ease by solvent-free grinding in a ball mill. The acetates in turn were also obtained by the homogenization of free sugars with stoichiometric amounts of acetic anhydride and catalytic In(OTf)3 in the mill as neat products. Per-O-benzylated thioglycosides on grinding with an acceptor sugar in the presence of In(OTf)3 yield the corresponding O-glycosides efficiently. The latter in the case of a difficult secondary alcohol was nearly exclusive (>98%) in 1,2-cis-selectivity. In contrast, the conventional methods for this purpose require use of a coreagent such as NIS along with the Lewis acid to help generate the electrophilic species that actually is responsible for the activation of the thioglycoside donor in situ. The distinctly different self-assembling features of the peracetylated octadecyl 1-thio-α- and β-d-galactopyranosides observed by TEM could be rationalized by molecular modeling.
- Kumar, Vajinder,Taxak, Nikhil,Jangir, Ramniwas,Bharatam, Prasad V.,Kartha, K. P. Ravindranathan
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p. 3427 - 3439
(2014/05/06)
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- Carbohydrate-derived iminium salt organocatalysts for the asymmetric epoxidation of alkenes
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A new family of carbohydrate-based dihydroisoquinolinium salts has been prepared and tested for potential as asymmetric catalysts for the epoxidation of unfunctionalized alkene substrates, providing up to 57% ee in the product epoxides.
- Bulman Page, Philip C.,Chan, Yohan,Liddle, John,Elsegood, Mark R.J.
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p. 7283 - 7305
(2017/09/13)
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- New strategy for synthesis of the disaccharide moiety of the highly potent anticancer natural product OSW-1
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The facile synthesis of a partially protected OSW-1 disaccharide moiety, having a 2-O-p-methoxybenzoyl-β-D-xylopyranosyl-(1 → 3)-2-O-acetyl-L-arabinopyranoside structure, was elaborated by glycosylation in a β-stereoselective fashion. The xylopyranose don
- Kongkathip, Boonsong,Kongkathip, Ngampong,Rujirawanich, Janjira
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supporting information
p. 2248 - 2255
(2014/07/07)
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- New method for regioselective glycosylation employing saccharide oxyanions
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As an alternative concept for glycosylation, the prior activation of acceptor hydroxy groups for selective glycosidic bond formation, was investigated to give complex oligosaccharides. Oxyanions obtained from partially protected saccharides were glycosylated by employing glycopyranosyl halides, and the regiochemical results were studied. Initially, partially methylated methyl-α-D-glucopyranosides were used as a model system to study the underlying mechanistic principles of base-promoted glycosylation. High regioselectivities and stereospecific glycosidic bond formations were achieved, and the scope of the methodology was extended with different perbenzylated glycosyl donors.
- Matwiejuk, Martin,Thiem, Joachim
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experimental part
p. 5860 - 5878
(2011/11/06)
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- Diastereoselective thioglycosylation of peracetylated glycosides catalyzed by in situ generated iron(III) iodide from elemental iodine and iron
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A facile in situ preparation of Fe(III) iodide from cheap, abundant elemental iodine and iron metal served as an efficient catalyst for the thioglycosylation of peracetylated glycosides with various alkyl and aryl mercaptans. Due to neighboring participation, the anomerically pure β-thioglycosides were obtained in good to high yields with exclusive diastereocontrol.
- Weng, Shiue-Shien
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supporting information; experimental part
p. 6414 - 6417
(2010/02/28)
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- Highly diastereoselective thioglycosylation of functionalized peracetylated glycosides catalyzed by MoO2Cl2
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Among 18 oxometallic species, MoO2Cl2 was found to be the most reactive in catalytic thioglycosylation of O-acetylated glycosides with functionalized thiols in CH2Cl2, leading cleanly to 1,2-trans-thioglycosides with exclusive diastereocontrol. The new catalytic protocol is applicable to a monoglycoside building block and β-(1→6)-S-linked-thiodisaccharide synthesis.
- Weng, Shiue-Shien,Lin, Yow-Dzer,Chen, Chien-Tien
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p. 5633 - 5636
(2007/10/03)
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- METHOD OF SYNTHESIZING SUGAR CHAIN
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An object of the present invention is to provide a method for efficiently chemically synthesizing biomolecules including a nucleotide (nucleic acid), a peptide (protein), or a sugar chain, as representative examples. The present invention provides a metho
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Page/Page column 25
(2010/11/08)
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- Modifying the regioselectivity of glycosynthase reactions through changes in the acceptor
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Successful glycosynthase-mediated reactions have been performed on 6-O-benzyl-, 6-O-(4-nitrobenzyl)-, and 6-O-benzoyl-D-glucopyranose to give 1,2-β- and 1,3-β-D-glycosylated products; 4-O-benzyl-D-xylopyranose gave only a 1,2-β-glycosylated product. A rat
- Stick, Robert V.,Stubbs, Keith A.,Watts, Andrew G.
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p. 779 - 786
(2007/10/03)
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- Total synthesis of the anticancer natural product OSW-1
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The highly potent anticancer natural saponin OSW-1 has been successfully synthesized from commercially available 5-androsten-3β-ol-17-one 79 in 10 operations with 28% overall yield. The key steps in the total synthesis included a highly regio- and stereoselective selenium dioxide-mediated allylic oxidation of 80 and a highly stereoselective 1,4-addition of α-alkoxy vinyl cuprates 68 to steroid 17(20)-en-16-one 12E to introduce the steroid side chain. This total synthesis demonstrated once again the versatile synthetic applications of α-halo vinyl ether chemistry developed in our laboratories.
- Yu, Wensheng,Jin, Zhendong
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p. 6576 - 6583
(2007/10/03)
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- New prototypical O-linked-glycopeptidomimetics corresponding to the linkage region of proteoglycans
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A new class of glycopeptidomimetic composed of N-substituted oligoglycine (peptoid) mimicking the β-D-Xy1-(1 → 3)-O-L-Ser linkage region of proteoglycans was synthesized using a convergent approach. Reiterative N-alkylation-N-bromoacetylation reactions we
- Kim, Jin Mi,Roy, Rene
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p. 173 - 179
(2007/10/03)
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- Enzymatic β-galactosidation of modified monosaccharides: Study of the enzyme selectivity for the acceptor and its application to the synthesis of disaccharides
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The selectivity of the E. coli β-galactosidase-catalyzed glycosylation of monosaccharides differently substituted at the anomeric position has been studied. Substituents bearing a phenyl ring increase the enzyme-acceptor binding; however, partial enzyme inhibition occurs. The regioselectivity of the glycosylation was dependent on small variations in the monosaccharide acceptor, such as the atom linked to the anomeric carbon and the number of methylenes between this atom and aromatic ring. A schematic model is proposed that accounts for the results. The information from this study allows the direct synthesis of disaccharides, with high regioselectivity and yields ranging from 30 to 40%.
- Lopez,Fernandez-Mayoralas
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p. 737 - 745
(2007/10/02)
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- Reaction of sugar thiocyanates with Grignard reagents. New synthesis of thioglycosides
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Glycosyl thiocyanates having hydroxyl groups protected with acetyl or benzoyl groups react readily at -40°C with Grignard reagents to afford the corresponding alkyl or aryl thioglycosides in good yields. Monosaccharide derivatives having the SCN grouping at other positions form under similar conditions thioethers. Axial thiocyanates do not react. Elevated temperatures induce side reactions leading to mercaptans.
- Pakulski, Zbigniew,Pierozynski, Donat,Zamojski, Aleksander
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p. 2975 - 2992
(2007/10/02)
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- New Entry to the C-Glycosilation by means of Carbenoid Displacement Reaction. Its Application to the Synthesis of Showdomycin
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The novel and stereoselective carbon-carbon bond-forming reaction at the anomeric center of carbohydrates has been developed by means of a carbenoid displacement reaction with phenyl thioglycosides.This reaction was suggested to proceed via the oxonium ion intermediates and has the following advantages: (i) the preferential participation of a carbenoid with a sulfur atom can restrict the reaction site; (ii) the reaction can be carried out under neutral reaction condition; and (iii) the introduction of various functionalities can be accomplished by manipulation of the organosulfur groups of the products.This synthetic strategy was successfully applied to the synthesis of antitumor agent, (+)-showdomycin, and would provide a general route to the other C-glycosides.
- Kametani, Tetsuji,Kawamura, Kuniaki,Honda, Toshio
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p. 3010 - 3017
(2007/10/02)
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