- A novel route to the anti-HIV nucleoside d4T
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A novel 2-pot process involving cyclonucleoside formation across C-5' oxyten in the 2'-deoxyribose and C-6 in the base ultimately leads to the little compound.
- Lipshutz, Bruce H.
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- Synthesis of some 5'-thiopentofuranosylpyrimidines as potential anti-tumor agents.
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The preparation of, hitherto unknown, 2',3'-didehydro-3'-deoxythymidine derived 5'-thioether, sulfoxide, sulfone [4-9] is described. The key steps of this synthesis are the nucleophilic displacements of a halogen by a thioalkyl sodium salt, and the later oxidation of the sulfur group into sulfone and sulfoxide analogues. These compounds have been evaluated for their inhibition of L1210 cells proliferation. None of the compounds were active except the 5'-ethylthio analogue 4b that showed a moderate activity (IC50 Of 90.2 μM).
- Girard, Frederic,Leonce, Stephane,Agrofoglio, Luigi A.
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- 2′,3′-Didehydro-3′-deoxythymidine N-methyl-2-pyrrolidone solvate (D4T·NMPO)
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The title compound, 1-(2′,3′-dideoxy-β-D-glycero-pent-2-enofuranosyl)thymine 1-methyl-2-pyrrolidone solvate, C10H12 N2O4·C5H9NO, is an NMPO solvate of the anti-AIDS agent D4T. In its crystal structure, both the pyrimidine and the furanose rings are planar and approximately perpendicular [82.1 (4)°]. The value of the torsion angle defining the orientation of the thymine with respect to the joined furane, X = -100.8 (4)°, and that of the torsion angle giving the orientation of the hydroxyl group linked to the furane ring, γ = 52.9 (5)°, show that the glycosylic link adopts the so-called high-anti conformation and the 5′-hydroxyl group is in the +sc position. The NMPO solvate is linked to the nucleoside through a fairly strong hydrogen bond.
- Viterbo, Davide,Milanesio, Marco,Pomes Hernandez, Ramon,Rodriguez Tanty, Chryslaine,Colas Gonzalez, Ivan,Sablon Carrazana, Marquiza,Duque Rodriguez, Julio
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- Lymphotropic prodrugs based on 2′,3′-Didehydro-3′- deoxythymidine. Synthesis and sensitivity to hydrolysis
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Glycerolipid derivatives of 2′,3′-didehydro-3′- deoxythymidine were synthesized, and their sensitivity to enzymatic and chemical hydrolysis was studied. Pleiades Publishing, Ltd., 2011.
- D'yakova,Shastina,Shvets
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- Synthesis of 5'-thioalkyl, sulfoxide and sulfone pyrimidine nucleosides
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The preparation of 5'-thioalkyl, sulfoxide and sulfone pyrimidine nucleosides is [4-11] is described. The key steps of this synthesis are the nucleophilic displacements of a chlorine by a thioalkyl sodium salt or the direct introduction of the thioalkyl group under Mitsunobu conditions.
- Agrofoglio,Girard,Fleury,Leonce
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- The synthesis and NMR investigation on novel boron derivatives of stavudine
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Preparation and spectroscopic properties of novel boron-containing derivatives of anti-HIV agent stavudine are presented, The new compounds, (5′-O-(4,4,5,5-tetramethyl-1,3,2-dioxaboronate)-2′-3′-didehydro-2′-3′-dideoxythymidine and 5′-O-(dihydroxyboronate)-2′-3′-didehydro-2′-3′-dideoxythymidine), were prepared by direct reaction between stavudine and reagents containing B{single bond}H moieties - pinacolborane and borane-dimethylsulfide complexes, respectively. The boron coordination equilibrium of those compounds was analyzed by water titration monitored by NMR. Results of the DFT calculations and NMR experiments pointed to structural and electronic similarity of tetrahedral boron complexes to phosphate group.
- Ruman, Tomasz,Dlugopolska, Karolina,Jurkiewicz, Agata,Rydel, Katarzyna,Les, Andrzej,Rode, Wojciech
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- Simple and efficient method for the synthesis of 2′,3′-didehydro-3′-deoxythymidine (d4T)
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2′,3′-Didehydro-3′-deoxythymidine (d4T) is an orally active antiviral drug used in the treatment of AIDS. A novel two-step synthetic method was developed for the synthesis of d4T using inexpensive reagents. An improvement in the yield was achieved for the conversion of the intermediate oxetane to d4T. This is the first simple and efficient method for the large-scale synthesis of d4T.
- Paramashivappa,Phani Kumar,Subba Rao,Srinivasa Rao
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- 1 (2,3 Dideoxy β-D-glycero-pent-2-enofuranosyl)thymine. A highly potent and selective anti-HIV agent
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The nucleoside analogue 1 (2,3 dideoxy-β-D-glycero-pent-2-enofuranosyl)thymine (d4T, 1) was prepared by ring opening of the 3',5'-anhydro compound 5. This method has been refined such that it can be used to prepare d4T (1) on a large scale. The triphosphate of d4T (8) was also synthesized from 1 in order to examine the mode of action. The in vitro inhibitory activity of d4T was found to be comparable to that of AZT in HIV-infected CEM cells. The triphosphate of d4T (8) and that of AZT inhibited the HIV reverse transcriptase with poly(rA):oligo(dT) as the template:primer with K(i) values of 0.032 and 0.007 μM, respectively. The in vitro toxicity of d4T against normal human hematopoietic progenitor cells (CFU-GM) was measured in comparison to AZT. While d4T reduces colony-forming units by 50% at a concentration of 100 μM, it takes only 1 μM AZT to have a similar toxic effect. With erythrocyte burst forming units (BFU-E) the in vitro toxicities for d4T and AZT have comparable ID50 values of 10 and 6.7 μM, respectively.
- Mansuri,Starrett Jr.,Ghazzouli,Hitchcock,Sterzycki,Brankovan,Lin,August,Prusoff,Sommadossi,Martin
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- Straightforward synthesis of 1-(2,3-dideoxy-β-D-glycero-pent-2- enofuranosyl)-thymine
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A two steps synthesis of the antiviral drug (d4T) 3 from thymidine 1 is proposed, which implies a concomitant deprotection-elimination process by action of t-BuOK in DMF on 5'-O-t-butyldimethylsylil-3'-O-methanesulfonyl- thymidine 2.
- Negron,Islas,Diaz,Cruz,Quiclet-Sire
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Read Online
- SYNTHESIS AND IMPROVEMENT OF A NUCLEOSIDE ANALOGUE AS AN ANTI-CANCER AND ANTI-VIRAL DRUG
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The invention is a drug for anticancer and antiviral therapy, comprising a nucleoside analogue (7) comprising a furan ring irreversibly bound to the RNA/DNA synthesis chain by phosphodiester bonds and having SP3 hybridization, and folic acid (A) bound to the nucleoside analogue (7) comprising furan ring. The synthesis method of the said nucleoside analogue is also contained within the scope of the invention. In this work, a nucleoside-analogue was transformed after converting the furan-ring hybridization from Sp2 to Sp3 to make it more selectivity with different enzymes and linking it via site 5 with the effective folic acid towards entering the substances inside the cells and to become the final compound possessing anti-cancer and anti- virus properties after controlling the replication and reproduction process in DNA.
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- Multistep Continuous Flow Synthesis of Stavudine
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Herein, we demonstrate an elegant multistep continuous flow synthesis for stavudine (d4T), a potent nucleoside chemotherapeutic agent for human immunodeficiency virus, acquired immunodeficiency syndrome (AIDS) and AIDS-related conditions. This was accomplished via six chemical transformations in five sequential continuous flow reactors from an affordable starting material, 5-methyluridine. In the first instance, single step continuous flow synthesis was demonstrated with an average of 97% yield, 21.4 g/h throughput per step, and a total of 15.5 min residence time. Finally, multistep continuous flow synthesis of d4T in 87% total yield with a total residence time of 19.9 min and 117 mg/h throughput without intermediate purification was demonstrated.
- Sagandira, Cloudius R.,Akwi, Faith M.,Sagandira, Mellisa B.,Watts, Paul
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p. 13934 - 13942
(2021/06/28)
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- Methyl ketone derivative, and preparation method and applications thereof
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The invention discloses a methyl ketone derivative, and a preparation method and applications thereof. The preparation method comprises following steps: a ketone derivative and an organic peroxide are dissolved in a solvent, and reaction is carried out at 80 to 130 DEG C so as to obtain methyl pyrimidone and a methyl pyrimidone derivative. According to the preparation method, the ketone derivative is taken as a starting material; the raw materials are easily and widely available; products of different kinds can be obtained via the preparation method, and can be used directly or used in other further reaction. No metal is involved, so that the preparation method is suitable to be applied in pharmaceutical preparation technology. The preparation method is short in route, mild in reaction conditions, simple in reaction operation and postprocessing process, and high in yield, and is suitable for large-scale production.
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Paragraph 0043; 0044
(2017/08/28)
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- Method for synthesizing 2',3'-dehydrogenation-3'-deoxythymidine by using triacetyl 5-methyluridine
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The invention relates to a method for synthesizing 2',3'-dehydrogenation-3'-deoxythymidine by using triacetyl 5-methyluridine. The method is characterized in that eliminating reaction of palladium-catalyzed triacetyl 5-methyluridine is performed, and then dehydroxylation protection is performed to generate the 2',3'-dehydrogenation-3'-deoxythymidine. The method of a compound comprises the following preparation steps of adding the triacetyl 5-methyluridine, a palladium catalyst and lithium halide into an organic solvent, heating, reacting, and evaporating reaction liquid to dryness; adding sodium methoxide and a methanol solution, stirring at room temperature, reacting, filtering, and evaporating the methanol to dryness; recrystallizing the remained solid by acetone, filtering, and drying, so as to obtain a 2',3'-dehydrogenation-3'-deoxythymidine product. The method has the advantages that the 2',3'-dehydrogenation-3'-deoxythymidine compound is synthesized by two steps, the use of poisonous halogen and a large amount of strong acid is avoided, the operation is simple, the economic and high-efficiency effects are realized, the yield is high, and the application prospect is broad.
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Paragraph 0011; 0012; 0013; 0014; 0015; 0016; 0017; 0018
(2017/08/29)
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- Synthesis, nanosizing and in vitro drug release of a novel anti-HIV polymeric prodrug: Chitosan-O-isopropyl-5′-O-d4T monophosphate conjugate
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A novel approach to improve the antiviral efficacy of nucleoside reverse transcriptase inhibitors (NRTIs) and reduce their side effects was developed by constructing a nanosized NRTI monophosphate-polymer conjugate using d4T as a model NRTI. Firstly, a novel chitosan-O-isopropyl-5′-O-d4T monophosphate conjugate with a phosphoramidate linkage was efficiently synthesized through Atherton-Todd reaction under mild conditions. The anti-HIV activity and cytotoxicity of the polymeric conjugate were evaluated in MT4 cell line. Then the conjugate nanoparticles were prepared by the process of ionotropic gelation between TPP and chitosan-d4T conjugate to improve their delivery to viral reservoirs, and their physicochemical properties were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) techniques and X-ray diffraction (XRD). In vitro drug release studies in pH 1.1 and pH 7.4 suggested that both chitosan-d4T conjugate and its nanoparticles prefer to release d4T 5′-(O-isopropyl) monophosphate than free d4T for prolonged periods, which resulted in the enhancement of anti-HIV selectivity of the polymeric conjugate relative to free d4T due to bypassing the metabolic bottleneck of monophosphorylation. Additionally, the crosslinked conjugate nanoparticles can prevent the coupled drug from leaking out of the nanoparticles before entering the target viral reservoirs and provide a mild sustained release of d4T 5′-(O-isopropyl) monophosphate without the burst release. The results suggested that this kind of chitosan-O-isopropyl-5′-O-d4T monophosphate conjugate nano-prodrugs may be used as a targeting and sustained polymeric prodrugs for improving therapy efficacy and reducing side effects in antiretroviral treatment.
- Yang, Lin,Chen, Liqiang,Zeng, Rong,Li, Chao,Qiao, Renzhong,Hu, Liming,Li, Zelin
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experimental part
p. 117 - 123
(2010/04/06)
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- Synthesis of nucleoside-based antiviral drugs in ionic liquids
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Nucleoside-based antiviral drugs have been synthesized using imidazolium-based ionic liquids as reaction medium. The ionic liquids were proved to be better solvents for all the nucleoside in terms of solubility and reaction medium as compared to conventional molecular solvents.
- Kumar, Vineet,Malhotra, Sanjay V.
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supporting information; experimental part
p. 5640 - 5642
(2009/06/18)
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- New telluride-mediated elimination for novel synthesis of 2′,3′-didehydro-2′,3′-dideoxynucleosides
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(Chemical Equation Presented) Several 2′,3′-dideoxynucleosides (ddNs) and 2′,3′-didehydro-2′,3′-dideoxynucleosides (d4Ns) are FDA-approved anti-HIV drugs. Via conveniently synthesized 2,2′-anhydronucleosides, we have developed a novel synthesis of d4Ns by discovering and applying a new telluride-mediated elimination reaction. Our experiment results show that after substitution of 2,2′-anhydronucleosides with a telluride monoanion, a telluride intermediate is formed, and its elimination leads to formation of the olefin products (d4Ns). Our mechanistic study indicates that this telluride-assisted reaction consists of two steps: substitution (or addition) and elimination. By using dimethyl ditelluride (0.1 equiv) as the reagent, d4Ns can be synthesized with yields up to 90% via this telluride-mediated elimination. Our novel strategy has great potential to simplify synthesis of these drugs and to further reduce cost of AIDS treatment and will also facilitate development of novel d4N and ddN analogues.
- Sheng, Jia,Hassan, Abdalla E. A.,Huang, Zhen
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p. 3725 - 3729
(2008/09/20)
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- Process for the Large Scale Production of Stavudine
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The present invention provides a method for preparing pure Stavudine having purity more than 99.5% comprises: i) Converting 3′,5′-anhydrothymidine to crude Stavudine, ii) Converting crude Stavudine to stable solvates of Stavudine, iii) Desolvation of the solvates to give pure Stavudine. The present invention also disclosed novel solvates of Stavudine and conversion of novel Stavudine solvates to Stavudine.
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(2009/01/24)
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- Synthesis and anti-HIV-1 activities of novel podophyllotoxin derivatives
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In order to explore the range of biological activities of the podophyllotoxin compound class, a novel series of derivatives of podophyllotoxin, which were conjugates containing stavudine and different structural podophyllotoxin analogues, were designed, synthesized, and evaluated for their anti-HIV-1 activities in vitro. Among these compounds, 19d and 19c showed the highest anti-HIV-1 activities with EC50 values of 0.17 and 0.29 μM and TI values of 466.9 and 354.5, respectively.
- Chen, Shi-Wu,Wang, Yun-Hua,Jin, Yan,Tian, Xuan,Zheng, Yong-Tang,Luo, Du-Qiang,Tu, Yong-Qiang
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p. 2091 - 2095
(2008/02/02)
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- NOVEL METHOD FOR THE PREPARATION OF STAVUDINE POLYMORPHIC FORM I AND FORM II
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A novel method for the preparation of stavudine polymorphic form I and form II is described; it's prepared starting from 5'-acetate-2',3'-diacetyl-5-methyluridine. The 5' -acetate-2',3'-diacetyl-5-methyluridine, by reaction with catalytic amounts of sodium methoxide in a C1-C4 alcholic solvent, gives crude stavudine form II. Crude stavudine form II, which doesn't need to be isolated or purified, can be converted into polymorphic form I by slurry at reflux in isopropanol.
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(2008/06/13)
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- A NEW IMPROVED PROCESS FOR THE PREPARATION OF STAVUDINE FORM I
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The present invention relates to an improved process for obtaining Stavudine Polymorphic Form I useful in the treatment of retroviral infections.
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(2008/06/13)
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- PROCESS FOR THE LARGE SCALE PRODUCTION OF STAVUDINE
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The present invention provides a method for preparing pure Stavudine having purity more than 99.5% comprises: i) Converting 3’,5’-anhydrothymidine to crude Stavudine, ii) Converting crude Stavudine to stable solvates of Stavudine, iii) Desolvation of the solvates to give pure Stavudine. The present invention also disclosed novel solvates of Stavudine and conversion of novel Stavudine solvates to Stavudine.
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Page/Page column 6-7
(2008/06/13)
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- Synthesis and metabolism of naphthyl substituted phosphoramidate derivatives of stavudine
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The synthesis of naphthylphosphoramidate derivatives of stavudine was achieved using a four-step procedure. The derivatives were subjected to several different enzymes including lipase, esterase, Subtilisin Carlsberg, and Carica papaya, and their hydrolysis rates were determined. Based on the rates of hydrolysis, we were able to differentiate between the chiralities at the phosphorus center of the phosphoramidate compounds. In addition, lipase was found to distinguish between both α and β forms of the compounds. The superior chiral selectivity shown by lipase toward the naphthyl substituted phosphoramidate derivatives is attributed to the restrictive binding pocket of the lipase.
- Venkatachalam,Qazi,Uckun
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p. 5161 - 5177
(2008/02/05)
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- Site-specific enzymatic activation of the anti-HIV agent stampidine
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Stampidine (STAMP, DDE-113, HI-113, N-[p-(4-bromophenyl)-2',3'-didehydro- 3'-deoxy-5'-thymidylyl]-L-alanine methyl ester, CAS 217178-62-6) and two stampidine analogs containing ethyl or t-butyl groups were synthesized and their rates of enzymatic activation were compared side-by-side. Enzymes such as lipase, esterase and protease did not hydrolyze the butyl substituted STAMP analog. These experimental results show that the site of attack for the enzymatic hydrolysis of STAMP is the ester side chain of the molecule. ECV · Editto Cantor Verlag.
- Venkatachalam, Taracad K.,Qazi, Sanjive,Uckun, Fatih M.
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p. 167 - 175
(2007/10/03)
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- A comparative study of the hydrolysis pathways of substituted aryl phosphoramidate versus aryl thiophosphoramidate derivatives of stavudine
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A comparative study of aryl phosphoramidate and aryl thiophosphoramidate derivatives of 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T) was performed. The study focused on the nature of the substituents and the influence of a thiophosphoramidate in the structure of these derivatives. The rate of alkaline hydrolysis of these two types of d4T derivatives indicated that replacement of oxygen with sulfur decreases the rate of hydrolysis by twofold. Additionally, the activation energy (Ea) for the sulfur analogs is comparatively higher than that of the oxygen analogs. Notably, an intermediate was formed in the hydrolysis reaction of the sulfur analogs of d4T that was absent in the case of the oxygen analog, and the tentative structure of the intermediate was proposed based on LC/mass spectroscopy data. Using both HPLC and 31P-NMR techniques, we identified the hydrolysis product of the phosphoramidate derivatives and were able to show in in vitro studies that porcine liver esterase can hydrolyze the methyl ester portion of the phosphoramidate derivatives. Aryl phosphoramidate derivatives of d4T were 1000-fold more active than the corresponding aryl thiophosphoramidate derivatives, indicating that the energy of activation of hydrolysis of these phosphoramidate derivatives plays a significant role in their biological potency.
- Venkatachalam,Yu,Samuel,Qazi,Pendergrass,Uckun
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p. 665 - 683
(2007/10/03)
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- 3,5-Di-(tert-Butyl)-6-fluoro-cycloSal-d4TMP - A Pronucleotide with a Considerably Improved Masking Group
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A new, considerably improved cycloSal masking group has been developed. This new group combines four desirable properties and has been attached to the anti-HIV drug 2′,3′-dideoxy-2′,3′-didehydrothymidine (d4T, 1) to give 3,5-(di-tert-butyl)-6-fluoro-cycloSal-d4TMP (2i). This phosphate triester has a reasonable chemical half-life, highly selectively released d4TMP, has poor - if any - inhibitory effect on butyrylcholinesterase (BChE), and achieved the TK-bypass. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).
- Ducho, Christian,Wendicke, Silke,Goerbig, Ulf,Balzarini, Jan,Meier, Chris
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p. 4786 - 4791
(2007/10/03)
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- ARYL PHOSPHATE DERIVATIVES WITH SELECTIVE ACTIVITY AGAINST ADENOVIRUS AND HIV
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Methods and compositions for treating ADV infections and HIV/ADV co-infections by administering an aryl phosphate derivative of d4T having an electron withdrawing substituent on the aryl group and an amino acid substituent on the phosphate group are described. Preferred aryl phosphate derivatives of d4T are d4T-5’-[p-bromophenyl methodyalaninyl phosphate] and d4T-5’-[p-chlorophenyl methoxyalaninyl phosphate].
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- Synthesis of acyclic bis-vinyl pyrimidines: A general route to d4T via metathesis
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Unsaturated acyclic pyrimidine analogues, 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}uracil, 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}thymine and 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}cytosine having two asymmetric carbon atoms have been prepared in good yield starting from uridine and 5-methyluridine. The bis-vinyl thymine derivative underwent ring closure metathesis to give d4T, thus providing a novel synthesis of this compound.
- Ewing,Gla?on,Mackenzie,Postel,Len
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p. 941 - 945
(2007/10/03)
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- Process for the preparation of substantially pure stavudine and related intermediates useful in the preparation thereof
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There are disclosed novel Stavudine solvates as follows: Stavudine NN-dimethyllacetamide solvates; Stavudine NN-dimethylacrylamide solvates and Stavudine NN-dimethylpropionamide solvates and processes for producing Stavudine NN-dimethylacetamide solvates, Stavudine NN dimethylacrylamide solvates and Stavudine NN dimethylpropionamide solvates which results in pure Stavudine.
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(2008/06/13)
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- Compositions for treating viral infections, and methods therefor
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Methods and combinations of an agent that promotes DNA synthesis in a virally-targeted cell and a nucleoside analogue having antiviral activity are provided for treating a viral infection in a subject in need thereof. Such compositions are particularly effective where the subject has resistance to a nucleoside analogue, where the subject has resting cellular reservoirs of such a virus, or to induce a post-treatment period of replication incompetence of such a virus.
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- A novel approach to unsaturated acyclic nucleoside analogues and the first synthesis of d4T by ring closure metathesis
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Novel unsaturated acyclic nucleoside analogues, 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}uracil, 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}thymine and 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}cytosine have been prepared in good yield from uridine and 5-methyluridine by periodate cleavage followed by a double Wittig reaction which introduces two vinyl groups. The thymine derivative underwent ring closure metathesis to give a novel synthesis of d4T.
- Ewing, David,Gla?on, Virginie,Mackenzie, Grahame,Postel, Denis,Len, Christophe
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p. 3503 - 3505
(2007/10/03)
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- An improved synthesis of 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) and the fate of the precursor, 2,3'-anhydro-5'-O-(4,4'-dimethoxytrityl)-thymidine
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The fate of the precursor, 2,3'-anhydro-5'-O-(4,4'-dimethoxytrityl)-thymidine was investigated during the synthesis of [18F]FLT with the aim of improving the radiochemical yield. This precursor was shown to undergo a rapid base catalysed elimination reaction and to be consumed within 5-10 min. The by-product was identified. Modification of the syntheis has produced between 1.85-3.70 GBq (50-199 mCi) of [18F]FLT in 60 min using an automated synthesis system.
- Cleij, M. C.,Steel, C. J.,Brady, F.,Ell, P. J.,Pike, V. W.,Luthra, S. K.
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p. S871 - S873
(2007/10/03)
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- Synthesis of new homo and heterodinucleosides containing the 2′,3′-dideoxynucleosides AZT and D4T
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The synthesis of new dinucleosides of AZT and D4T is described.
- Taourirte,Lazrek,Vasseur,Ferrero,Fernandez,Gotor
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p. 959 - 962
(2007/10/03)
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- Synthesis of 2',3'-dideoxy-2',3'-didehydro nucleosides via a serendipitous route.
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This paper describes a "green" synthesis of 2',3'-unsaturated 2',3'-dideoxynucleosides via an electrochemical reaction. Using this approach d4T, d4U, ddA and ddI can be synthesized in high yields.
- Guo,Sanghvi,Brammer Jr.,Hudlicky
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p. 1263 - 1266
(2007/10/03)
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- The Phospholipase-Induced Degradation of Phosphatidylnucleosides
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Hydrolysis of phosphatidylnucleosides, 5'-(rac-1-hexadecyl-2-palmitoyl-sn-glycero-3-phosphoryl)-3'-azido-3'-deoxythymidine and -2',3'-didehydro-3'-deoxythymidine, effected by phospholipases (PL) A2, C, and D was studied to reveal the metabolism of these derivatives. It was shown that PLA2 deacetylates the glycerol residue at position 2, PLC is inactive, and PLD hydrolyzes the phosphatidylnucleosides to give free nucleosides.
- Novozhilova, T. I.,Malekin, S. I.,Kozhukhov, V. I.,Kruglyak, Yu. L.,Kurochkin, V. K.
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p. 213 - 215
(2007/10/03)
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- Process for the production of asymmetrical phosphoric acid diesters
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The present invention concerns a process for the production of asymmetrical phosphoric acid diesters. The process is characterized in that a phosphoric acid ester is condensed with a compound containing hydroxy groups in the presence of an arylsulfonic acid chloride and an organic base, the residue of evaporation is stirred out with an organic solvent after the hydrolysis, the arylsulfonic acid pyridine salt which forms is nearly completely crystallized and recycled, the lipid derivative that is formed is precipitated as a sparingly soluble salt by addition of a solution containing alkaline-earth ions and isolated, the sparingly soluble salt is isolated as the free acid in an organic solvent by suspension in a water-immiscible organic solvent and a dilute aqueous mineral acid, the crude product is purified if desired, by means of preparative chromatography on a RP phase and subsequently the free acid is converted if desired into any desired salt.
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- A new thymine free synthesis of the anti-AIDS drug d4T via regio/stereo controlled β-elimination of bromoacetates
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The anti-AIDS drug d4T was prepared without contamination of the nucleoside bond cleaved by-product thymine from the readily available ribonucleoside 5-methyluridine (1). This was accomplished by using a new strategy which involved a regio/stereo controlled β-elimination of trans-bromoacetates 6.
- Chen, Bang-Chi,Quinlan, Sandra L.,Reid, J. Gregory,Spector, Richard H.
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p. 729 - 732
(2007/10/03)
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- Independent synthesis and fate studies of impurities in process intermediates of the anti-AIDS drug d4T
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Impurities in isolated intermediates in a process to prepare d4T were identified, independently synthesized, and then taken through the process to determine their ultimate fate. Some of the products from these fate studies were also independently synthesized and used in the validation of impurity assay methods.
- Reddy, Jayachandra P.
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p. 203 - 207
(2013/09/08)
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- Preparation of d4T from 5-methyluridine
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The present invention concerns an improved process of making d4T from 5-MU. Another aspect of the invention relates to useful intermediates produced during the process.
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- A new protocol for the removal of dimethoxytrityl ether groups derived from primary alcohols
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A range of primary alcohol dimethoxytrityl ethers were deprotected by using ultrasound at ambient temperature (yields 69-100%). The new procedure may find utility in the synthesis of materials of biological interest, such as oligonucleotides.
- Wang, Yikang,McGuigan, Christopher
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p. 3829 - 3833
(2007/10/03)
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- Facile synthesis of 2',3'-unsaturated nucleosides from 2-deoxyribose
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A straightforward approach for the synthesis of 2',3'-unsaturated nucleosides starting from 2-deoxyribose is described. This novel route involves two new methods; (1) preparation of 2-deoxy-1-thioribofuranoside by direct condensation of 2-deoxyribose and thiophenol, (2) formation of the nucleoside skeleton by the direct coupling of 2,3-unsaturated 1-thiopentofuranoside with pyrimidine bases.
- Sujino, Keiko,Yoshida, Tomoyasu,Sugimura, Hideyuki
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p. 6133 - 6136
(2007/10/03)
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- Asymmetric synthesis of nucleosides via molybdenum-catalyzed alkynol cycloisomerization coupled with stereoselective glycosylations of deoxyfuranose glycals and 3-amidofuranose glycals
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Deoxygenated furanose glycals were efficiently prepared by molybdenum pentacarbonyl-catalyzed cycloisomerization of alkynyl alcohols, which were easily prepared in chiral nonracemic form by short synthetic sequences featuring asymmetric epoxidations of commercially available allylic alcohols. The cycloisomerization reaction was demonstrated to be compatible with ester and amide functional groups. A 2,3-dideoxyfuranose glycal was stereoselectively converted into the anti-AIDS β-nucleoside stavudine (2',3'-didehydro-2',3'-dideoxythymidine, d4T) and the antiviral 3'-deoxy-β-nucleoside cordycepin. The anchimeric and hydrogen-bond-directing effects of 3-amido-2,3-dideoxyfuranose glycals were exploited in a novel and highly stereoselective synthesis strategy for a variety of biologically active 3'-amino-2',3'-dideoxy- and 3'-amino-3'-deoxy-β-nucleosides, including puromycin aminonucleoside. In addition, the mechanism of the molybdenum-catalyzed alkynol cycloisomerization reaction has been studied. Evidence is presented which indicates that cyclic molybdenum carbene anions are catalytic intermediates in these cyclizations.
- McDonald, Frank E.,Gleason, Mark M.
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p. 6648 - 6659
(2007/10/03)
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- Synthesis of 1-(2,3-dideoxy-β-D-glycero-pent-2-enofuranosyl(thymine (d4T; stavudine) from 5-methyluridine
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A practical synthetic method of d4T (3) from 5-methyluridine (2a) was developed. The Marumoto-Mansuri method was modified using 2',3'-O-methoxyethylidene-5-methyluridine (10) as an intermediate to afford 1-(3,5-di-O-acetyl-2-bromo-2-deoxy-β-D-ribofuranosyl)thymine (6a) in high yield with less formation of byproducts. The reaction mechanism was also discussed.
- Shiragami,Ineyama,Uchida,Izawa
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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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- Efficient transformation of thymidine into 2',3'-didehydro-2',3'-dideoxy- thymidine (D4T) involving opening of a 2,3'-anhydro derivative by phenylselenol
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A new, high-yielding method for introduction of the selenophenyl residue at the 3'- position of thymidine is reported. This reaction avoided any strongly basic or reductive reagent, thus allowing the use of benzoate ester as a protective group at O-5'. Further oxidation-elimination sequence followed by basic deprotection afforded 2',3'-didehydro-2',3'- dideoxythymidine (D4T) in 67.5% overall yield from thymidine.
- Becouarn,Czernecki,Valery
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p. 1227 - 1232
(2007/10/02)
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- Synthesis of 2,3'-anhydro-2'-deoxyuridines and 2,3'-didehydro-2',3'-dideoxyuridines using polymer supported fluoride
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Reaction of methyl 5-O-tert-butyldiphenylsilyl-2-deoxy-3-O-p-toluenesulfonyl-α,β-D-eryt hro-pentofuranoside (2) with silylated uracils 3 using trimethylsilyl trifluoromethanesulfonate (TMS triflate) as catalyst afforded after crystallization in Et2O the corresponding β-nucleosides 4. Reaction of 4 with tetrabutylammonium fluoride (TBAF) or Amberlyst A-26 resin (F--form) in THF at room temperature or at reflux gave the corresponding deprotected 2,3'-anhydro-2'-deoxyuridines 6 and 2',3'-didehydro-2',3'-dideoxyuridines 7, respectively.
- Larsen,Kofoed,Pedersen
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p. 1121 - 1125
(2007/10/02)
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- Synthesis of 2',3'-didehydro-2',3'-dideoxy nucleosides from 2',2'-bis(phenylthio) nucleoside analogs
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2',3'-Didehydro-2',3'-dideoxy nucleosides were synthesized from 2',2'-bis(phenylthio) nucleoside analogs via five-step reactions. The sulfonyl group of the intermediate was removed by a treatment with sodium amalgam.
- Niihata,Kuno,Ebata,Matsushita
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p. 2327 - 2329
(2007/10/03)
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- 5'-Benzoyl-2'α'-bromo-3'-O-methanesulfonylthymidine: A Superior Nucleoside for the Synthesis of the Anti-Aids Drug D4T (Stavudine).
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The anti-AIDS drug d4T is prepared in 75percent overall yiled starting from the readily available ribonucleoside 5-methyluridine (1).The key step in this new synthesis is the zinc-induced reductive elimination of the bromomesylate 4, which affords d4T without nucleoside bond cleavage.A facile procedure for the deprotection/isolation of this highly water soluble product is also described.
- Chen, Bang-Chi,Quinlan, Sandra L.,Stark, Derron R.,Reid, J. Gregory,Audia, Vicki H.,et al.
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p. 7957 - 7960
(2007/10/02)
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- Nitrogen glycosylation reactions involving pyrimidine and purine nucleoside bases with furanoside sugars
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Different approaches for the synthesis of nucleoside analogs (potential HIV inhibitors) are described. Starting from a suitably substituted furanose ring, it is demonstrated that a high facial stereocontrol of the glycosylation reaction can be effected. Different reaction conditions including Lewis acid promoted, S(N)2 displacement and some enzymatic methodologies for the stereoselective synthesis of these compounds are reviewed.
- Wilson,Hager,El-Kattan,Liotta
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p. 1465 - 1479
(2007/10/02)
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- Synthesis of Some 2',3'-Didehydro-2',3'-didepxynucleosodes Derived from Modified Pyrimidine Bases
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3',5'-Bis-O-(4-tolylsulfonyl)-thymidine and 2'-deoxyuridine (13a and 13b) reacted with sodium ethoxide in boiling ethanol to give the corresponding ethoxy-oxetanes 12a and 12b in 67 and 66percent overal yield for the two-step processes starting from thymidine 4a and 2'-deoxyuridine 4b, respectively.Treatment of the ethoxy-oxetanes 12a and 12b with hydrogen sulfide and N1,N1,N3,N3-tetramethylguanidine in dry pyridine solution gave the 2-thiothymine- and 2-thiouracyl-derived oxetanes 19a and 19b in 62 and 68.5percent yield, respectively.When the latter compounds were treated with potassium tert-butoxide in dimethyl sulfoxide, the corresponding 2',3'-didehydro-2',3'-dideoxynucleosides (d4 nucleosides) 10a and 10b were obtained in 66 and 60percent yield, respectively.The 2-thiothymine-derived oxetane 19a was converted via the 5-methyl-2-thiocytosine-derived oxetane 21a into the 5-methyl-2-thiocytosine-derived d4 nucleoside 11a in 59.5percent overall yield; the 2-thiouracil-derived oxetane 19b was similarly converted into the 2-thiocytosine- and 4-N-methyl-2-thiocytosine-derived d4 nucleosides 11b and 23 in 51 and 50percent overall yield, respectively.Finally, the ethoxy-oxetane 12b was converted into the corresponding amino- and methylamino-oxetanes 25a and 25b in 74 and 83percent yield, respectively.The latter compound, 25b, was succesively converted into the 2-N-methylisocytosine-derived d4 nucleoside 26b in 62percent yield.
- Reese, Colin B.,Varaprasad, Chamakura V. N. S.
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p. 189 - 196
(2007/10/02)
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- A Facile Route to Pyrimidine-Based Nucleoside Olefins: Application to the Synthesis of d4T (Stavudine)
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An efficient synthetic route to nucleoside olefins in the uridine, cytidine, and thymidine series is described which utilizes the Garegg-Samuelsson iodine/triphenylphosphine/imidazole-promoted deoxygenation of the 2',3'-hydroxyl groups as the key step.Cyclopentadiene ketal protection was employed for all the nucleoside 2',3'-hydroxyls to facilitate blocking of the 5'-hydroxyl and the pyrimidine nitrogens with the benzyl or 4-methoxybenzyl (PMB) groups.Deblocking of the cyclopentylidene group followed by olefination of the resulting diols provided protected nucleoside olefins 18-20.Starting with 5-methyluridine 4 and utilizing the 4-methoxybenzyl group for 5',N3 protection, the overall scheme provided the anti-HIV compound d4T (1) after deprotection of the PMB groups.The dibenzylhypoxanthine nucleoside diol 17 derived from inosine gave either unreacted starting material or decomposition products under several sets of conditions.
- Luzzio, Frederick A.,Menes, Michael E.
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p. 7267 - 7272
(2007/10/02)
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