- Synthesis and cytokine modulation properties of pyrrolo[2,3.d]-4- pyrimidone nucleosides
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A series of pyrrolo[2,3-d]pyrimidone nucleosides were synthesized and evaluated for their ability to enhance Type 2 cytokines and to suppress Type 1 cytokines in human T cells activated in vitro. Compounds 16b, 16c, 16d, 18c, and 19b induced substantial enhancement of IL-4 (a Type 2 cytokine) levels while three compounds (16b, 16c, and 16f) showed significant suppression of IFNγ (a Type 1 cytokine) levels. The results revealed a strict structural requirement for the nucleoside-mediated enhancement of IL- 4. Modifications of the ribofuranose moiety of the nucleosides either abolished or dramatically reduced the activity. Both the 5'-hydroxy and 5- carboxamidine are crucial for the activity. Of the few nucleoside analogues that demonstrated enhancement on Type 2 cytokine production, 7-(β-D- ribofuranosyl)pyrrolo[2,3d]-4-pyrimidone-5-carboxamidine (16c) showed a dramatic enhancement (> 200%) of IL-4 levels and a significant enhancement (36%) of IL-5 levels. Moreover, this compound showed substantial suppression of the Type 1 cytokines, IFNγ (42%), IL-2 (54%), and TNFα (55%). Similarly, compound 16b showed a substantial enhancement of IL-4 (46%) and suppression of IL-2 (35%), IFNγ (30%), and TNFα (26%). To our knowledge, these are the first nucleoside analogues that induce a Type 2 cytokine bias in T cells. The cytokine modulation property of 16c and 16b merits the therapeutic evaluation of these compounds in treating diseases in which immunopathology is associated with polarized Type 1 cytokine responses.
- Wang, Guangyi,Tam, Robert C.,Gunic, Esmir,Du, Jinfa,Bard, Josie,Pai, Bharati
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- A Novel Method for the Deoxygenation of Acetylated Sugars
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The conversion of acetylated sugars 1 to deoxy sugars 2 by the action of triphenylsilane under homolytic conditions is reported.Both furanoses and pyranoses bearing an acetylated primary or seondary alcohol are effectively deoxygenated.
- Sano, Hiroshi,Takeda, Toshimitsu,Migita, Toshihiko
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- Synthesis of 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose from D-ribose
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A practical route towards the synthesis of 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose from D-ribose is described. The key steps include deoxygenation of methyl 2,3-O-isopropylidene-5-O-sulfonyloxy-β-D-ribofuranoside by reductive displacement employing hydride reagents. Subsequent total hydrolysis followed by acetylation led to the title compound in 56% overall yield from D-ribose. The sequence is simple, inexpensive, high yielding and clearly suitable for multi-gram preparations.
- Sairam, Pothukuchi,Puranik, Ramachandra,Sreenivasa Rao, Bhatraju,Veerabhadra Swamy, Ponnapalli,Chandra, Sharad
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- Computer Modelling and Synthesis of Deoxy and Monohydroxy Analogues of a Ribitylaminouracil Bacterial Metabolite that Potently Activates Human T Cells
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5-(2-Oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU) is a natural product formed during bacterial synthesis of vitamin B2. It potently activates mucosal associated invariant T (MAIT) cells and has immunomodulatory, inflammatory, and anticancer properties. This highly polar and unstable compound forms a remarkably stable Schiff base with a lysine residue in major histocompatibility complex class I–related protein (MR1) expressed in antigen-presenting cells. Inspired by the importance of the ribityl moiety of 5-OP-RU for binding to both MR1 and the T cell receptor (TCR) on MAIT cells, each OH was removed in silico. DFT calculations and MD simulations revealed a very stable hydrogen bond between the C3′?OH and uracil N1H, which profoundly restricts flexibility and positioning of each ribityl-OH, potentially impacting their interactions with MR1 and TCR. By using deoxygenation strategies and kinetically controlled imine formation, four monodeoxyribityl and four monohydroxyalkyl analogues of 5-OP-RU were synthesised as new tools for probing T cell activation mechanisms.
- Ler, Geraldine J. M.,Xu, Weijun,Mak, Jeffrey Y. W.,Liu, Ligong,Bernhardt, Paul V.,Fairlie, David P.
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p. 15594 - 15608
(2019/11/16)
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- Preparation method of high-purity capecitabine key intermediate
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The invention discloses a preparation method of a high-purity capecitabine key intermediate. The preparation method comprises the following steps: taking D-ribose as an initial raw material, performing hydroxyl protection, 5-site tosylation, reduction, deprotection and acetylation to obtain high-purity 1,2,3-O-triacetyl-5-deoxo-D-ribose, wherein the 5-site tosylation reaction is carried out in anorganic solvent 1 by adopting inorganic base 1. Meanwhile, the acetylation reaction is carried in the presence of alkali 2 by taking water as a reaction solvent and taking 4-dimethylamiopryidine as acatalyst. The preparation method disclosed by the invention is mild in reaction conditions, high in yield, economic and effective, the purity of the prepared 1,2,3-O-triacetyl-5-deoxo-D-ribose can reach 99.0%, the alpha-isomer is small in content even is not detected, and the preparation method is applicable to large-scale industrial production.
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- AMPHIPHILE PRODRUGS
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Amphiphilic prodrugs of general formula A-X are disclosed, wherein A is a biologically active agent or may be metabolised to a biologically active agent; and X is selected from the group consisting of R, or up to three R moieties attached to a linker, Y1, Y2 or Y3, wherein R is selected from a group consisting of alkyl, alkenyl, alkynyl, branched alkyl, branched alkenyl, branched alkynyl, substituted alkyl, substituted alkenyl and substituted alkynyl groups and their analogues; Y1 is a linker group which covalently attached to an R group at one site and is attached to A at a further independent site; Y2 is a linker group which is covalently attached to two R groups at two independent sites and is attached to A at a further independent site; and Y3 is a linker group which is covalently attached to three R groups at three independent sites and is attached to A at a further independent site. Self-assembly of the amphiphilic prodrugs into reverse lyotropic phases, particularly hexagonal, cubic and sponge, is disclosed. In preferred embodiments A is dopamine or a 5-fluorouracil prodrug.
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- Synthesis of Nucleosides through Direct Glycosylation of Nucleobases with 5-O-Monoprotected or 5-Modified Ribose: Improved Protocol, Scope, and Mechanism
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Simplifying access to synthetic nucleosides is of interest due to their widespread use as biochemical or anticancer and antiviral agents. Herein, a direct stereoselective method to access an expansive range of both natural and synthetic nucleosides up to a gram scale, through direct glycosylation of nucleobases with 5-O-tritylribose and other C5-modified ribose derivatives, is discussed in detail. The reaction proceeds through nucleophilic epoxide ring opening of an in situ formed 1,2-anhydrosugar (termed “anhydrose”) under modified Mitsunobu reaction conditions. The scope of the reaction in the synthesis of diverse nucleosides and other 1-substituted riboside derivatives is described. In addition, a mechanistic insight into the formation of this key glycosyl donor intermediate is provided.
- Downey, A. Michael,Pohl, Radek,Roithová, Jana,Hocek, Michal
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supporting information
p. 3910 - 3917
(2017/03/27)
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- Synthesizing method of capecitabine intermediate
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The invention discloses a synthesizing method of a capecitabine intermediate and particularly relates to a synthesizing method of 1-methyl-5-deoxy-2, 3-O-isopropylidene-beta-D-furan riboside. The method includes: in N, N-dimethyl acetamide and in the presence of a boron reducing agent, using 1-methoxy-2, 3-O-isopropylidene-5-O-tosyl-beta-D-furan riboside to perform reduction reaction to obtain the 1-methyl-5-deoxy-2, 3-O-isopropylidene-beta-D-furan riboside. The synthesizing method has the advantages that the method is mild in reaction conditions, high in yield, environmentally friendly and suitable for industrial production, and the reaction solvent used by the method is easy to recycle and reusable.
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Paragraph 0041-0048
(2018/03/13)
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- Safe and Alternate Process for the Reductions of Methanesulfonates: Application in the Synthesis of 1,2,3-Triacetyl-5-deoxy-d-ribofuranoside
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Diethylene glycol dimethyl ether, diglyme, and 1,2-bis(2-methoxyethoxy)ethane, triglyme, are found to be suitable and safe alternate solvents to DMSO for the reduction of methanesulfonate in sodium borohydride. Addition of anhydrous lithium chloride led to the complete reduction of methanesulfonate esters to the corresponding alkanes in the presence of sodium borohydride in these solvents (diglyme and triglyme). This protocol is useful in the preparation of 1,2,3-triacetyl-5-deoxy-d-ribofuranoside, 7, a key intermediate of Capecitabine, 1, on the commercial scale.
- Mekala, Nagaraju,Moturu, Murthy V.R.K.,Dammalapati, Rao V.L.N.,Parimi, Atchuta R.
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p. 609 - 614
(2016/04/04)
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- METHOD FOR THE PREPARATION OF CAPECITABINE AND INTERMEDIATES USED IN SAID METHOD
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A process to obtain capecitabine compound and its pharmaceutically acceptable derivatives is hereby disclosed. Likewise, novel intermediates to be used in the preparation of capecitabine compound and its pharmaceutically acceptable derivatives are also disclosed. The procedure comprises the stage of causing a reaction of N4-(n-pentyloxycarbonyl))-5- fluorocytosine with (1,2,3-tri-O-acetyl-5-deoxy- α,β-D-ribofuranose.
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Page/Page column 8
(2010/11/03)
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- Pyrido[2,3-d]pyrimidine and pyrimido[4,5-d]pyrimidine nucleosides
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A purine nucleoside analog includes a pyrido[2,3-d]pyrimidine or a pyrimido[4,5-d]pyrimidine and further has a sugar moiety that is optionally modified at the C2′, C3′, C4′ and/or C5′ position. Particularly contemplated compounds also include prodrug forms of the purine nucleoside analogs, and both purine nucleoside analogs and the corresponding prodrugs are employed in the reduction of growth of neoplastic cells.
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- Pyrrolo[2,3-d]pyrimidine nucleoside analogs
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Compositions and methods for pyrrolo[2,3-d]pyrimidine nucleoside analogs having substituents at the C4′ and C5′ positions of the ribofuranose moiety are presented. Contemplated compositions exhibit, among other things, anti-cancer and immunomodulating effects at reduced cytotoxicity.
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- An Efficient Synthesis of 5-Deoxy-D-ribohexose
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5-Deoxy-D-ribohexose (1) has been obtained from methyl 2,3-O-isopropylidene-β-D-ribo-pentodialdo-1,4-furanoside via Wittig reaction with methoxymethylenetriphenyl phosphorane and subsequent hydrolytic and deprotection steps. 13C NMR spectrum show, that 1 occurs as two furanoses, two septanoses and an aldehydo form.Peracetylation of 5-deoxy-D-ribohexose leads to both furanose forms and, most probably, to an α-septanose ring.Key words: 5-deoxy-D-ribohexose, Wittig reaction
- Pakulski, Z.,Zamojski, A.
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p. 912 - 917
(2007/10/02)
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- Polysubstituted benzimidazoles as antiviral agents
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This invention relates to novel polysubstituted benzimidazoles and compositions and their use in the treatment of viral infections. The polysubstituted benzimidazoles and compositions of the present invention exhibit antiviral properties against viruses of the herpes family, particularly human cytomegalovirus (HCMV) and herpes simplex viruses (HSV). Preferred polysubstituted benzimidazoles of the invention are 2,5,6-Trichloro-1-(β-D-5-deoxyribofuranosyl)benzimidazole and 2-bromo-5,6-dichloro-1-(5-deoxy-β-D-ribofuranosyl)benzimidazole.
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- The Total Synthesis of (-)-Litsenolides C-1 and C-2
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The total synthesis of (-)-litsenolides C1 and C2 from D-glucose in 12percent overall yield is described in which the α-alkylidene double-bond is formed by a Wittig reaction of a C-2 oxocarbohydrate derivative.
- Wood, William W.,Watson, Graham M.
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p. 2681 - 2688
(2007/10/02)
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- SYNTHESIS AND N.M.R.-SPECTRAL ANALYSIS OF UNENRICHED AND -ENRICHED 5-DEOXYPENTOSES AND 5-O-METHYLPENTOSES
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Chemical methods are described for preparing unenriched and -enriched 5-deoxy- and 5-O-methyl-pentoses in the D or L configuration.The 1H-n.m.r.-spectra of these compounds have been interpreted, and the 13C n.m.r. spectra assigned with the aid of 2-D 13C-1H chemical-shift correlation spectroscopy.Tautomeric forms (furanoses, hydrate, and aldehyde) in solution in 2H2O have been quantified with the aid of -enriched derivatives.Spectra of 5-deoxypentoses, and methyl pentofuranosides have been compared, in order to assess the effect of 5-C-deoxygenation and 5-O-methylation on chemical shifts and coupling constants (1H-1H, 13C-1H, and 13C-13C) and on the pentofuranose conformations.
- Snyder. Joseph R.,Serianni, Anthony S.
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p. 169 - 188
(2007/10/02)
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