83159-91-5Relevant academic research and scientific papers
Synthesis and anti-HCV activity of a series of β-D-2′-deoxy-2′-dibromo nucleosides and their corresponding phosphoramidate prodrugs
Chen, Zhe,Cox, Bryan D.,Garnier-Amblard, Ethel C.,McBrayer, Tamara R.,Coats, Steven J.,Schinazi, Raymond F.,Amblard, Franck
, p. 5296 - 5299 (2017)
Several β-D-2′-deoxy-2′-substituted nucleoside analogs have displayed potent and selective anti-HCV activities and some of them have reached human clinical trials. In that regard, we report herein the synthesis of a series of 2′-deoxy,2′-dibromo substituted U, C, G and A nucleosides 10a–d and their corresponding phosphoramidate prodrugs 13a–d. The synthesized nucleosides 10a–d and prodrugs 13a–d were evaluated for their inhibitory activity against HCV as well as cellular toxicity. The results showed that the most potent compound was prodrug 13a, which exhibited micromolar inhibitory activity (EC50 = 1.5 ± 0.8 μM) with no observed toxicity. In addition, molecular modeling and free energy perturbation calculations for the 5′-triphosphate formed from 13a and related 2′-modified nucleotides are discussed.
COMPOSITIONS AND METHODS FOR TREATING HCV INFECTION
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Paragraph 0064, (2018/06/06)
The present invention features compositions and methods for the treatment of HCV infection. In one embodiment, the compositions of the invention comprise (1) Compound 1 or a pharmaceutically acceptable salt thereof, and (2) Compound 2a or a pharmaceutically acceptable salt thereof. In another embodiment, the compositions of the invention comprise (1) Compound 1 or a pharmaceutically acceptable salt thereof, and (2) a prodrug of Compound 2a (e.g., one of Compounds 2b-2k or Examples 3-1 to 3-10) or a pharmaceutically acceptable salt of said prodrug.
Synthesis of isomeric analogues of S-ribosylhomocysteine analogues with homocysteine unit attached to C2 of ribose
Chbib, Christiane
, p. 1681 - 1685 (2017/04/04)
LuxS (S-ribosylhomocysteinase; EC 4.4.1.21) is an enzyme that catalyzes the cleavage of the thioether linkage in the catalytic pathway of S-ribosylhomocysteine (SRH) which produces homocysteine and 4,5-dihydroxy-2,3-pentanedione (DPD). DPD is the precursor of the signaling molecules known as autoinducer 2 (AI-2) responsible for the bacterial quorum sensing (QS) identified as cell to cell communication. Inhibitors of LuxS should be able to interfere with its catalytic pathway thus preventing the formation of the autoinducer molecules. In this work, the synthesis of 2-deoxy-2-bromo-SRH analogues was attempted by the coupling of the corresponding 2-bromo-2-deoxypentafuranosyl sugars with the homocysteinate anion. The displacement of the bromide from C2 rather than the expected substitution of the mesylate group from C5 was observed leading to a novel isomeric analogue of SRH in which Hcy moiety is attached to a ribose ring via C2-sulfur bond.
Anti-Viral Compounds
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Paragraph 0433; 0434, (2017/03/21)
The present invention features compounds effective in inhibiting active against Hepatitis C virus (“HCV”) polymerase. The invention also features processes of making such compounds, compositions comprising such compounds, and methods of using such compounds to treat HCV infection.
2'-DICHLORO AND 2'-FLUORO-2'-CHLORO NUCLEOSIDE ANALOGUES FOR HCV INFECTION
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Paragraph 00292, (2015/06/11)
Provided herein are compounds, compositions and methods for the treatment of Flaviviridae infections, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents. In certain embodiments, the compounds are 2'-dichloro or 2'-fluoro-2'-chloro nucleoside analogue compounds which display remarkable efficacy and bioavailability for the treatment of, for example, HCV infection in a human. In certain embodiments, the compounds are of Formula (I):or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof; wherein each of RA and RB is independently Cl or F, wherein at least one of RA and RB is C1; and Base, PD and Z are as described herein.
Nucleophilic addition to silyl-protected five-membered ring oxocarbenium ions governed by stereoelectronic effects
Tran, Vi Tuong,Woerpel
, p. 6609 - 6621 (2013/07/26)
A series of fused-bicyclic acetals containing a disiloxane ring was investigated to evaluate the source of selectivity in silyl-protected 2-deoxyribose systems. The disiloxane ring unexpectedly enables the diaxial conformer of the cation to be stabilized by an electronegative atom at C-3. This low energy conformer subsequently undergoes stereoelectronically controlled nucleophilic addition to give substituted tetrahydrofurans with high diastereoselectivity.
Histone-catalyzed cleavage of nucleosomal DNA containing 2-deoxyribonolactone
Zhou, Chuanzheng,Greenberg, Marc M.
, p. 8090 - 8093 (2012/07/14)
Oxidized abasic sites such as 2-deoxyribonolactone (L) are produced in DNA by a variety of oxidizing agents, including potent cytotoxic antitumor natural products. 2-Deoxyribonolactone is labile under alkaline conditions, but its half-life in free DNA at pH 7.5 is approximately 1 week. Independent generation of L at defined positions within nucleosomes reveals that the histone proteins catalyze strand scission and increase the rate between 11- and ～43-fold. Mechanistic studies indicate that DNA-protein cross-links are not intermediates en route to strand scission and that C2 deprotonation is the rate-determining step. The use of mutant histone H4 proteins demonstrates that the lysine-rich tail that is often post-translationally modified in cells contributes to the cleavage of L but is not the sole source of the enhanced cleavage rates. Consideration of DNA repair in cells suggests that L formation in nucleosomal DNA as part of bistranded lesions by antitumor antibiotics results in de facto double strand breaks, the most deleterious form of DNA damage.
HALOGENATED 2-DEOXY-LACTONES, 2'-DEOXY--NUCLEOSIDES, AND DERIVATIVES THEREOF
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Page/Page column 40-41, (2011/02/24)
Disclosed are halogenated 2-deoxy-lactone, 2'-deoxy-nucleosides, and derivatives thereof, for example, a compound of formula (I). Also disclosed are a composition comprising a pharmaceutically acceptable carrier and at least one compound or salt of the invention, and a method of treating a disorder is selected from the group consisting of an abnormal cellular proliferation, a viral infection, and an autoimmune disorder.
Diastereocontrolled electrophilic fluorinations of 2-deoxyribonolactone: Syntheses of all corresponding 2-deoxy-2-fluorolactones and 2′-deoxy- 2′-fluoro-NAD+s
Cen, Yana,Sauve, Anthony A.
experimental part, p. 5779 - 5789 (2010/01/06)
(Chemical Equation Presented) Methods to construct 2′-deoxy-2′- fluoro nucleosides have undergone limited improvement in the last 20 years in spite of the substantially increased value of these compounds as pharmaceuticals and as tools for studying biological processes.We herein describe a consolidated approach to synthesize precursors to these commercially and scientifically valuable compounds via diastereocontrolled fluorination of the readily available precursor 2-deoxy-D-ribonolactone.With employment of appropriate sterically bulky silyl protecting groups at the 3 and 5 positions, controlled electrophilic fluorination of the Liribonolactone enolate by N-fluorodibenzenesulfonamide yielded the corresponding 2-deoxy-2- fluoroarabinolactone in high isolated yield (72%). The protected 2-deoxy-2,2-difluororibonolactone was obtained similarly in high yield from a second round of electrophilic fluorination (two steps, 51%from protected ribonolactone starting material). Accomplishment of the difficult ribofluorination of the lactone was achieved by the directive effects of a diastereoselectively installed α-trimethylsilyl group. Electrophilic fluorination of a protected 2-deoxy-2-trimethylsilylarabinolactone via enolate generation provided the protected 2-deoxy-2-fluororibolactone as the exclusive fluorinated product. The reaction also yielded the starting material, the desilylated protected 2-deoxyribonolactone, which was recycled to provide a 38%chemical yield of the fluorinated product (versus initial protected ribonolactone) after consecutive silylation and fluorination cycles.Using our fluorinated sugar precursors, we prepared the 2′-fluoroarabino-, 2′-fluororibo-, and 2′,2′-difluoronicotinamide adenine dinucleotides (NAD+) of potential biological interest. These syntheses provide the most consolidated and efficient methods for production of sugar precursors of 2′-deoxy-2′-fluoronucleosides and have the advantage of utilizing an air-stable electrophilic fluorinating agent. The fluorinated NAD+s are anticipated to be useful for studying a variety of cellular metabolic and signaling processes.
Direct and facile syntheses of heterocyclic vinyl-C-nucleosides for recognition of inverted base pairs by DNA triple helix formation: First report by direct Wittig route
Rothman, Jeffrey H.
, p. 3945 - 3948 (2008/02/01)
(Chemical Equation Presented) The ability to recognize specific gene sequences canonically would allow precise means for genetic intervention. However, specific recognition of two of the four possible base pairs by triplex-forming oligonucleotides (TFO) as X·T-A and Y·C-G within a triplex currently remains elusive. A series of C1-vinyl nucleosides have been proposed, and their stability and specificity have been evaluated extensively by molecular dynamics simulation. Because most C-nucleoside syntheses extend through direct substitution at the C1-position, a more convenient strategy for their syntheses via a direct Wittig coupling is presented here.
