- Synthesis and evaluation of 3′-fluorinated 7-deazapurine nucleosides as antikinetoplastid agents
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Kinetoplastid parasites are the causative agents of neglected tropical diseases with an unmet medical need. These parasites are unable to synthesize the purine ring de novo, and therefore rely on purine salvage to meet their purine demand. Evaluating purine nucleoside analogs is therefore an attractive strategy to identify antikinetoplastid agents. Several anti-Trypanosoma cruzi and anti-Trypanosoma brucei 7-deazapurine nucleosides were previously discovered, with the removal of the 3′-hydroxyl group resulting in a significant boost in activity. In this work we therefore decided to assess the effect of the introduction of a 3′-fluoro substituent in 7-deazapurine nucleosides on the anti-kinetoplastid activities. Hence, we synthesized two series of 3′-deoxy-3′-fluororibofuranosyl and 3′-deoxy-3′-fluoroxylofuranosyl nucleosides comprising 7-deazaadenine and -hypoxanthine bases and assayed these for antiparasitic activity. Several analogs with potent activity against T. cruzi and T. brucei were discovered, indicating that a fluorine atom in the 3′-position is a promising modification for the discovery of antiparasitic nucleosides.
- Bouton, Jakob,Caljon, Guy,Furquim d'Almeida, Arno,Hulpia, Fabian,Maes, Louis,Van Calenbergh, Serge
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- The Chiron Approach to (3 R,3 aS,6 aR)-Hexahydrofuro[2,3- b]furan-3-ol, a Key Subunit of HIV-1 Protease Inhibitor Drug, Darunavir
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We describe an enantioselective synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol which is a key subunit of darunavir, a widely used HIV-1 protease inhibitor drug for the treatment of HIV/AIDS patients. The synthesis was achieved in optically pure form utilizing commercially available sugar derivatives as the starting material. The key steps involve a highly stereoselective substrate-controlled hydrogenation, a Lewis acid catalyzed anomeric reduction of a 1,2-O-isopropylidene-protected glycofuranoside, and a Baeyer-Villiger oxidation of a tetrahydrofuranyl-2-aldehyde derivative. This optically active ligand alcohol was converted to darunavir efficiently.
- Ghosh, Arun K.,Markad, Shivaji B.,Robinson, William L.
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p. 1216 - 1222
(2020/12/22)
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- CYCLIC DINUCLEOTIDES AS STING AGONISTS
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Disclosed herein are cyclic di-nucleotide compounds and derivatives thereof that may be useful as STING agonists, and a pharmaceutical composition comprising the same. Also disclosed herein is the process for synthesis and to uses of such cyclic di-nucleo
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Paragraph 0086-0087
(2021/01/29)
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- SELECTIVE INHIBITOR OF PROTEIN ARGININE METHYLTRANSFERASE 5 (PRMT5)
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The disclosure is directed to crystalline forms of the compound of Formula I, pharmaceutically acceptable salts of the compound of Formula I, and crystalline forms thereof. Pharmaceutical compositions comprising said crystalline forms and salts, as well a
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Paragraph 00308
(2020/08/28)
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- SELECTIVE INHIBITORS OF PROTEIN ARGININE METHYLTRANSFERASE 5
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The disclosure is directed to methods of treating disease using compounds of Formula (I).
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Paragraph 0247
(2020/10/20)
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- SYNTHESIS OF 1,2,5-TRI-0-BENZ0YL-3-DIBENZYLAMIN0-3-DE0XYRIB0SE AS INTERMEDIATE FOR PRODUCING 3'-AMINO-3'-DEOXYADENOSINE AND 3'-AMINO-3'-DEOXYGUANOSINE AND THE PROTECTED DERIVATIVES THEREOF
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The invention generally relates to improved processes for the preparation of intermediates of a cyclic dinucleotide which is useful as a STING agonist.
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Page/Page column 18; 31
(2020/08/22)
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- CYCLIC DINUCLEOTIDES AS ANTICANCER AGENTS
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The present invention is directed to compounds of the formulae I, II and III as shown below wherein all substituents are defined herein, as well as pharmaceutically acceptable compositions comprising compounds of the invention and methods of using said compositions in the treatment of various disorders.
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- CD73 INHIBITORS
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Described herein are CD73 inhibitors and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of cancer, infections, and neurodegenerative diseases.
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Paragraph 00427
(2019/05/22)
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- Selective Inhibitors Of Protein Arginine Methyltransferase 5 (PRMT5)
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The disclosure is directed to compounds of Formula I Pharmaceutical compositions comprising compounds of Formula I, as well as methods of their use and preparation, are also described.
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Paragraph 0275; 0276
(2019/02/24)
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- NUCLEOSIDE ANALOGUES FOR THE TREATMENT OF PARASITIC INFECTIONS
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The present invention relates to novel nucleoside analogues and compositions containing said nucleoside analogues. Moreover, the present invention provides processes for the preparation of the disclosed compounds, as well as methods of using them, for instance as a medicine, in particular for the diagnosis, prevention and/or treatment of parasitic infections, more specifically for use in the diagnosis, prevention and/or treatment of a Trypanosoma infection.
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Page/Page column 31
(2019/05/10)
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- Amipurimycin: Total Synthesis of the Proposed Structures and Diastereoisomers
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The proposed diastereoisomers (1 a–d) together with their C8′-epimers (1 e–h) of amipurimycin, a unique antifungal peptidyl nucleoside antibiotic, have been synthesized for the first time. The synthetic approach is efficient and stereodivergent, and features a stereoselective aldol condensation to build the branched C9 sugar amino acid skeleton and a regio- and stereocontrolled gold(I)-catalyzed N-glycosylation to furnish the purine nucleoside. Analysis of the NMR data suggests that the previously assigned configuration of the tertiary C3′ in amipurimycin should be of opposite configuration.
- Wang, Shengyang,Sun, Jiansong,Zhang, Qingju,Cao, Xin,Zhao, Yachen,Tang, Gongli,Yu, Biao
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p. 2884 - 2888
(2018/02/16)
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- A total synthesis of mycalisine A
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In this paper, we report a total synthesis of a naturally occurring pyrrolo[2,3-d]pyrimidine nucleoside, mycalisine A. Our synthetic strategy uses d-xylose as the starting material and Vorbrüggen glycosylation as the key step. Mycalisine A was synthesized in 11 steps with a 15% overall yield.
- Dou, Yan-Hui,Ding, Hai-Xin,Yang, Ru-Chun,Li, Wei,Xiao, Qiang
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p. 379 - 382
(2013/07/04)
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- Chemoenzymatic synthesis of 3'-deoxy-3'-(4-substituted-triazol-1-YL)-5- methyluridine
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An efficient protocol has been developed for the synthesis of a small library of 3'-deoxy-3'- (4-substituted-triazol-1-yl)-5-methyluridine using Cu(I)-catalyzed Huisgen-Sharpless-Meldal 1,3- dipolar cycloaddition reaction of 3'-azido-3'-deoxy-5-methyluridine with different alkynes under optimized condition in an overall yields of 76%-92%. Here, the azido precursor compound, i.e., 3'-azido-3'-deoxy-5-methyluridine was chemoenzymatically synthesized from D-xylose in good yield. Some of the alkynes used in cycloaddition reaction were synthesized by the reaction of hydroxycoumarins or naphthols with propargyl bromide in acetone using K2CO3 in excellent yields. All synthesized compounds were unambiguously identified on the basis of their spectral (IR, 1H-, 13C NMR spectra, and high-resolution mass spectra) data analysis.
- Arya, Anu,Mathur, Divya,Tyagi, Abhilash,Kumar, Rajesh,Kumar, Vinod,Olsen, Carl E.,Saxena, Rajendra K.,Prasad, Ashok K.
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p. 646 - 659
(2014/01/06)
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- Synthesis of 3-fluoro-oxetane δ-amino acids
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Starting from d-xylose, 2,4-anhydro-5-N-(tert-butoxycarbonyl)amino-5-deoxy- 3-fluoro-d-arabinonic acid 11 was synthesized over 10 steps including ring contraction, fluorination, and ester hydrolysis. Bromine oxidation of d-xylose followed by benzylidenati
- Lucas, Susana Dias,Rauter, Amelia Pilar,Schneider, Josef,Wessel, Hans Peter
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experimental part
p. 431 - 446
(2011/06/19)
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- Novel D-xylose derivatives stimulate muscle glucose uptake by activating AMP-activated protein kinase α
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Type 2 diabetes mellitus has reached epidemic proportions; therefore, the search for novel antihyperglycemic drugs is intense. We have discovered that D-xylose increases the rate of glucose transport in a non-insulin-dependent manner in rat and human myot
- Gruzman, Arie,Shamni, Ofer,Yakir, Moriya Ben,Sandovski, Daphna,Elgart, Anna,Alpert, Evgenia,Cohen, Guy,Hoffman, Amnon,Katzhendler, Yehoshua,Cerasi, Erol,Sasson, Shlomo
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body text
p. 8096 - 8108
(2009/12/07)
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- Deoxygenation of 5-O-benzoyl-1,2-isopropylidene-3-O-imidazolylthiocarbonyl-α-d-xylofuranose using dimethyl phosphite: an efficient alternate method towards a 3′-deoxynucleoside glycosyl donor
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An efficient radical deoxygenation reaction of thiocarbonylimidazolyl activated glycoside analogue using dimethyl phosphite as hydrogen source and radical chain carrier was performed as a key step in a multi step synthesis towards a common 3-deoxy glycosyl donor for 3′-deoxynucleosides. This method has safety and cost advantages compared to the generally used radical reduction reagents.
- Zlatev, Ivan,Vasseur, Jean-Jacques,Morvan, Fran?ois
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p. 3288 - 3290
(2008/09/20)
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- Synthesis of different 3,5-diazidofuranoses: A new and general synthesis pathway
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Diamino- and diazidofuranoses represent useful precursors, for example, for the synthesis of substituted nucleosides and metal complexes, respectively. Known procedures for their synthesis lack the availability of cheap starting materials, adequate yields, and the access to all possible diastereomeres. Therefore, 3,5-diazido-3,5-dideoxy- and -2,3,5-trideoxyfuranoses both with ribo- and xylo-configuration were prepared using different approaches.
- Koth, Daniel,Fiedler, Andrea,Scholz, Sandy,Gottschaldt, Michael
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p. 267 - 278
(2008/02/12)
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- Synthesis and antiviral evaluation of AZT analogues with a spacer arm between glucidic and base moieties. Part II
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This article describes the synthesis of a series of AZT analogues bearing an acyclic chain between the sugar and the base moieties is described. These new compounds were readily obtained using microwave irradiation. The compounds were characterized by 1H
- Roy, Vincent,Zerrouki, Rachida,Krausz, Pierre,Laumond, Geraldine,Aubertin, Anne Marie
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p. 413 - 421
(2008/02/14)
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- Revisited 3′-deoxy-3′-C-methyl-β-D-ribonucleoside series
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The synthesis of some 3′-deoxy-3′-C-methylnucleoside analogues bearing naturally occuring nucleic acid bases was achieved from the preparation of a suitable peracylated 3-deoxy-3-C-methyl sugar using a stereoselective pathway. In addition, examples of chemical modifications at the 2′ position are presented. Copyright Taylor & Francis Group, LLC.
- Aljarah, Mohamed,Couturier, Sarah,Gosselin, Gilles,Mathe, Christophe,Perigaud, Christian
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p. 1125 - 1128
(2008/09/17)
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- Thermodynamic and kinetic considerations in the chemoselective O-acylation by mixed anhydrides. A semiempirical MO approach
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A simple methodology to achieve high chemoselective O-acylation of primary hydroxy groups, in the presence of secondary ones, was performed by means of the quick generation of a mixed anhydride using mild and inexpensive conditions. Steric and electronic
- Mota, Antonio J.,Robles, Rafael,De Cienfuegos, Luis álvarez,Lamenca, Alberto
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p. 3349 - 3353
(2007/10/03)
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- Aplysia californica mediated cyclisation of novel 3′-modified NAD+ analogues: A role for hydrogen bonding in the recognition of cyclic adenosine 5′-diphosphate ribose
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Cyclic ADP-ribose mobilizes intracellular Ca2+ in a variety of cells. To elucidate the nature of the interaction between the C3′ substituent of cADP-ribose and the cADPR receptor, three analogues of NAD + modified in the adenosine ri
- Mort, Christopher J. W.,Migaud, Marie E.,Galione, Antony,Potter, Barry V. L.
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p. 475 - 487
(2007/10/03)
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- Nucleosides and nucleotides. Part 212: Practical large-scale synthesis of 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (ECyd), a potent antitumor nucleoside. Isobutyryloxy group as an efficient anomeric leaving group in the Vorbrüggen glycosylation reaction
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A practical synthetic route to the antitumor nucleoside, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (ECyd, 1) from 1,2-O-isopropylidene-D-xylofuranose (3) has been developed. Since most of the compounds were obtained as crystals, the target ECyd was prepared without any chromatographic purification in 31% overall yield from compound 3. The isobutyryloxy group was found to be an effective leaving group at the anomeric position of the 3-β-C-ethynyl glycosyl donors in the key Vorbru?ggen glycosylation reaction. Using a similar procedure without chromatographic purification, the uracil congener EUrd [1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)uracil (2), which also has a potent antitumor effect, was synthesized from 3 in 39% overall yield.
- Nomura, Makoto,Sato, Tsutomu,Washinosu, Masato,Tanaka, Motoaki,Asao, Tetsuji,Shuto, Satoshi,Matsuda, Akira
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p. 1279 - 1288
(2007/10/03)
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- Methyl 5-O-benzoyl-2,3-oxazole-D-ribofuranoside: A useful intermediate for the synthesis of conformationally restrained nucleosides
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The synthesis of methyl 5-O-benzoyl-2,3-oxazole-D-ribofuranoside, a tetrahydrofuro [3,4-d]oxazole is described. The key step involves the reaction of methyl 3-amino-3-deoxy-5-O-benzoyl-D-ribofuranoside with N,N-dimethylformamide dimethyl acetal with cyclisation to the 2,3-oxazole via a prototropic rearrangement-elimination reaction.
- Molina,Maslen,Simons
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p. 981 - 983
(2007/10/03)
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- Stereocontrolled Syntheses of Deoxyribonucleosides via Photoinduced Electron-Transfer Deoxygenation of Benzoyl-Protected Ribo- and Arabinonucleosides
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The stereocontrolled, de novo syntheses of β-2′-deoxy-, α-2′-deoxy-, β-3′-deoxy-, and β-2′,3′-dideoxyribonucleosides are described. Strategically protected ribose, arabinose, and xylose glycosylation precursors were synthesized bearing C2-esters capable of directing Vorbrueggen glycosylation. The key step is the regioselective deoxygenation of the desired hydroxyl group as either the benzoyl- or 3-(trifluoromethyl)benzoyl derivative. This deoxygenation is accomplished via a photoinduced electron-transfer (PET) mechanism using carbazole derivatives as the photosensitizer. The syntheses of the desired deoxynucleoside generally proceed in three steps from a common, readily available precursor.
- Wang, Zhiwei,Prudhomme, Daniel R.,Buck, Jason R.,Park, Minnie,Rizzo, Carmelo J.
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p. 5969 - 5985
(2007/10/03)
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- substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives
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Substituted tetrahydrofuran analogs of F-series prostaglandins and methods of their use in treating glaucoma and ocular hypertension are disclosed.
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- Substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives
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Substituted tetrahydrofuran analogs of prostagladins and methods of their use in treating glaucoma and ocular hypertension are disclosed.
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- Synthesis of 1-(5-amino-3,5-dideoxy-3-methoxycarbonylmethyl-β-D-ribofuranosyl)thymine
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In order to synthesize amide-linked antisense oligonucleotides, a general chemical approach was developed for the synthesis of building blocks in which an amino group and a carboxylic group are contained at the 5' and 3' positions of a nucleoside. Copyright (C) 1999 Elsevier Science Ltd.
- Lu, Dong-Mei,Min, Ji-Mei,Zhang, Li-He
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p. 193 - 197
(2007/10/03)
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- Synthesis and antiviral activity of D- and L-isodideoxy nucleosides with exocyclic methylene
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Novel D- and L-isodideoxynucleosides were synthesized starting from D- and Lxylose and evaluated for antiviral activities against HIV-1, HSV-1, HSV- 2, HBV and HCMV, respectively.
- Jeong, Lak Shin,Yoo, Su Jeong,Moon, Hyung Ryong,Chun, Moon Woo,Lee, Chong-Kyo
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p. 655 - 656
(2007/10/03)
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- Transformations of β-D-Xylofuranosyl Nucleosides. Synthesis of 3′-Deoxy-2′,3′-didehydrothymidine (D4T)
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3′-Deoxy-2′,3′-didehydrothymidine was synthesized through a 10-step procedure starting from D-xylose. The overall yield of the target product was 28%.
- Mustafin,Gataullin,Spirikhin,Abdrakhmanov,Tolstikov
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p. 1784 - 1790
(2007/10/03)
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- 3'-C-trifluoromethyl ribonucleosides
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(3-C-trifluoromethyl-β-D-ribofuranosyl) nucleosides of thymine, uracil and adenine were synthesized from 5-O-benzoyl-1,2,3-tri-O-acetyl-3-C-trifluoromethyl-β-D-ribofu ranoside , prepared by addition of CF3SiMe3 to 5-O-benzoyl-1,2-O-i
- Johnson,Bhumralkar,De Clercq
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p. 185 - 194
(2007/10/02)
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- THE SYNTHESIS OF (S) AND (R) ENANTIOMERS OF NOVEL HYDROXYMETHYLATED ISODIDEOXYNUCLEOSIDES
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Novel isomeric dideoxynucleosides, with symmetry introduced at the 2'-position (4'-position using normal nucleoside numbernig) through the introduction of an additional hydroxymethyl group, have been synthesized.Both (R) and (S) enantiomeric series were investigated.The methodologies developed have generality and the presence of the hydroxymethyl group trans to the base may be used to introduce a wide variety of functionalities at this position.
- Zintek, Lawrence B.,Jeon, Geun Sook,Nair, Vasu
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p. 1853 - 1864
(2007/10/02)
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- 3'-C-Phosphonates as Nucleotides Analogues Synthesis Starting from Original C-Phosphonosugars (in ribo- and deoxyribo- series)
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3-C-phosphonosugars were synthetised starting from 2-deoxy-D-ribose and α-D-xylofuranose via the Pudovic rection followed by reduction.Their condensation with nucleobases (thymine and adenine) gave original 3'-C-phosphononucleosides in ribo- and 2-deoxyribo- series, with a stereocontrol of the reactions.Key words: 3-C-phosphonosugar, 3'-C-phosphononucleoside, Pudovic reaction, α-hydroxyphosphonate
- Serra, Corine,Dewynter, Georges,Montero, Jean-Louis,Imbach, Jean-Louis
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p. 8427 - 8444
(2007/10/02)
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- Novel isomeric dideoxynucleosides as potential antiviral agents
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Novel isomeric dideoxynucleosides with S,S absolute stereochemistry and involving the transposition of the base moiety from the normal 1'- to the 2'-position have been regiospecifically and stereospecifically synthesized. The synthetic approaches involved
- Bolon, Pascal J.,Sells, Todd B.,Nuesca, Zoraida M.,Purdy, David F.,Nair, Vasu
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p. 7747 - 7764
(2007/10/02)
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- 1,2-Di-O-acetyl-5-O-benzoyl-3-deoxy-3-fluoro-D-xylofuranose. A versatile precursor for the synthesis of 3-deoxy-3-fluoro-β-D-xylofuranosyl nucleosides as potential antiviral agents
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The title compound has been synthesized from D-xylose for use in the preparation of 3-deoxy-3-fluoro-β-D-xylofuranosyl nucleoside analogues and their 2-deoxy derivatives, as exemplified in the guanine and thymine series. The title compound has been synthe
- Gosselin,Puech,Genu-Dellac,Imbach
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- 3'-Deoxy-2'-phosphoramidites of adenosine and 5-methyluridine used for the solid phase synthesis of unnatural 3'-deoxy-2'-5''-oligonucleotides
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Protected phosphoramidites of 3'-deoxyadenosine and 3'-deoxy-5-methyluridine have been synthesized, and used in solid phase synthesis of 3'-deoxyoligonucleotides with the unusual 2'-5'' linkage.
- Rizzo,Dougherty,Breslow
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p. 4129 - 4132
(2007/10/02)
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- A NEW AND NOVEL APPROACH TOWARDS THE SYNTHESIS OF 3'-DEOXY-3'-HYDROXYMETHYL RIBOFURANOSIDES
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The synthesis of 1,2,5-tri-O-benzoyl-3-deoxy-3--α,β-D-ribofuranose (1) from 1,2-O-isopropylidene-α-D-xylofuranose (2) has been achieved in an overall yield of 37percent.Compound 1 is a properly substituted intermediate for the synthesis
- Pudlo, Jeffrey S.,Townsend, Leroy B.
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p. 3101 - 3104
(2007/10/02)
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- SYNTHESIS OF 9-(3-DEOXY- AND 2,3-DIDEOXY-3-FLUORO-β-D-XYLOFURANOSYL)GUANINES AS POTENTIAL ANTIVIRAL AGENTS
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The first synthesis of the title compounds 8 and 10 was accomplished by a multi-step approach involving prior preparation of a suitably protected fluorosugar 6.
- Puech, Frederic,Gosselin, Gilles,Imbach, Jean-Louis
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p. 3171 - 3174
(2007/10/02)
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- STRUCTURE AND TOTAL SYNTHESIS OF CHRYSCANDIN, A NEW ANTIFUNGAL ANTIBIOTIC
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The structure elucidation and total synthesis of chryscandin (1), a new antifungal antibiotic produced by Chrysosporium pannorum No.4629, is reported.
- Yamashita, Michio,Kawai, Yoshio,Uchida, Itsuo,Komori, Tadaaki,Koshaka, Masanobu,et al.
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p. 4689 - 4692
(2007/10/02)
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