- Ester prodrugs of zidovudine
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Ten novel ester prodrugs of zidovudine (azidothymidine; AZT) were synthesized with aliphatic acids (acetic-stearic), and the enzymatic regeneration of AZT from the prodrugs was investigated both in vitro and in vivo. The enzymatic hydrolysis rates of the AZT esters in the presence of mouse enzyme systems (plasma, liver, and intestine, and kidney) were highly dependent on the lengths of the acyl chains of the prodrugs. The caprate or caprylate of AZT showed the highest reactivity to three of the four enzyme systems; either the decrease or the increase in the acyl chain length resulted in the decrease of the reactivity to the enzymes. Zidovudine (AZT) and three of the prodrugs (acetate, caprate, and stearate) were administered to mice intraperitoneally, and the plasma concentrations of AZT and a corresponding prodrug were measured. The AZT concentrations in plasma following the acetate administration rapidly decreased with a half-life of 14.5 min. This tendency is similar to that shown in direct AZT administration. On the other hand, the concentrations following the caprate or stearate administration decreased slowly and were maintained for as long as 4 h after dosing. The prodrug concentrations in plasma after the prodrug administration were under the detection limit (0.01 μg/mL), except for acetate. The absence of the caprate and stearate in plasma may be attributed to the high hydrophobicity or favorable tissue distribution of the ester derivatives.
- Kawaguchi,Ishikawa,Seki,Juni
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- AZT 5′-cholinephosphate as an anti-HIV agent: The study of biochemical properties and metabolic transformations using its 32P-labelled counterpart
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Biochemical and metabolic transformations of 3′-azido-3′- deoxythymidine 5′-choline phosphate (1) were studied using its 32P-labelled counterpart for the evaluation of possible reasons for its enhanced anti-HIV activity. An effective synthesis of 32P- labelled 1 with a specific activity >1,000 Ci/mmol was developed by esterification of 32P-phosphoric acid with choline in the presence of BrCN followed by the coupling of the resulting choline phosphate with 3′-azido-3′-deoxythymidine (AZT). Chemical and enzymatic stabilities of 1 as well as the dynamics of penetration through HL-60 cell membranes were studied at the concentrations comparable to its antiviral concentrations. The products of intracellular transformations of the studied nucleotide were identified. Copyright Taylor & Francis Group, LLC.
- Yanvarev, Dmitry V.,Shirokova, Elena A.,Astapova, Maria V.,Skoblov, Yury S.
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- 3'-Azido-3'-deoxy-5'-O-isonicotinoylthymidine: a novel antiretroviral analog of zidovudine. II. Stability in aqueous media and experimental and theoretical ionization constants.
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Degradation of 3'-azido-3'-deoxy-5'-O-isonicotinoylthymidine (AZT-Iso), an antiretroviral derivative of zidovudine, was investigated in buffer pH 7.4, mu = 300 mOsm at 37, 50 and 60 degrees C, and in water (pH 6.6, 37 degrees C), giving zidovudine (AZT) and isonicotinic acid (INA) as products. The rate constants were determined by reversed-phase HPLC showing pseudo-first-order kinetics related to the residual amount of AZT-Iso. In this way, the studied compound was demonstrated to be 153 times more stable in water than in buffer solution at 37 degrees C. The analytical method was conveniently validated demonstrating to be a rapid and accurate stability-indicating technique. In addition, experimental and theoretical values of pKa were determined.
- Teijeiro, Silvina A,Raviolo, Monica A,Motura, Marisa I,Brinon, Margarita C
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- 5-Halo-6-alkoxy-5,6-dihydro-pyrimidine nucleosides: Antiviral nucleosides or nucleoside prodrugs?
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5-Halo-6-alkoxy-5,6-dihydro derivatives of azidothymidine (AZT) and ethyldeoxyuridine (EDU) were developed and evaluated using in vitro and in vivo models. Although most of these 5,6-dihydro derivatives served as prodrugs in improving site-specific delivery and pharmacokinetic parameters, some unique characteristics were exhibited.
- Wiebe,Knaus,Cheraghali,Kumar,Morin,Wang
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- A novel synthesis of AZT
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A novel synthesis of AZT has been achieved from two commercial available products acetaldehyde and D-mannitol. The originality of the synthesis consists of using the powerful monovinylogation reagent, the 2-lithio-1-trimethylsiloxyethylene, and to introduce the thymine moiety and to build the furanose ring in the same and last step.
- Gauthier, Christine,Ramondenc, Yvan,Plé, Gérard
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- Synthesis method of (1 beta, 2 alpha, 4 beta) halogenated nucleoside compound
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The invention provides a synthesis method of a (1 beta, 2 alpha, 4 beta) halogenated nucleoside compound, and belongs to the field of organic synthesis. The synthesis method comprises the following steps of dissolving a compound 1 and a chiral phosphoric acid small-molecule catalyst in a solvent to obtain a mixed solution, adding an additive and a halogen source into the mixed solution, and carrying out an olefin asymmetric halogen cyclization reaction to prepare the (1 beta, 2 alpha, 4 beta) halogenated nucleoside compound as shown in a formula I. The synthesis method is simple and convenient in process, suitable for various reaction substrates and wide in application; and the synthesis method has high stereoselectivity on the beta-nucleoside compound and low cost, and the obtained beta-nucleoside compound has the advantages of high yield, high purity and very excellent effect. Meanwhile, the synthesis method is environment-friendly due to no use of a metal catalyst and the like. The synthesis method disclosed by the invention solves the technical problem of preparing the (1 beta, 4 beta) nucleoside compound in the prior art, can be used for efficiently preparing the (1 beta, 4 beta) nucleoside compound, and has a good application prospect.
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Paragraph 0094-0096
(2022/01/12)
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- A preparation method of zidovudine
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The invention relates to a preparation method of zidovudine. The method is a one kettle way, has characteristics of not separating intermediate products prepared in the separation and purification steps and continuously carrying out three-step reactions to directly prepare a reaction liquid containing zidovudine, and has advantages as follows: raw materials for reactions are cheap and easily available; there is no need to separate and purify reaction intermediate products; reactions are continuous; reaction operation steps are few; preparation period is short; preparation is simple; there are few three wastes (waste gas, waste water and industrial residue) and wastes are easy to recover and process; cost is low; reaction yield of zidovudine reaches up to more than 72%; and the method is easy for industrial production.
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Paragraph 0045-0071
(2019/05/15)
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- Modular click chemistry libraries for functional screens using a diazotizing reagent
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Click chemistry is a concept in which modular synthesis is used to rapidly find new molecules with desirable properties1. Copper(i)-catalysed azide–alkyne cycloaddition (CuAAC) triazole annulation and sulfur(vi) fluoride exchange (SuFEx) catalysis are widely regarded as click reactions2–4, providing rapid access to their products in yields approaching 100% while being largely orthogonal to other reactions. However, in the case of CuAAC reactions, the availability of azide reagents is limited owing to their potential toxicity and the risk of explosion involved in their preparation. Here we report another reaction to add to the click reaction family: the formation of azides from primary amines, one of the most abundant functional groups5. The reaction uses just one equivalent of a simple diazotizing species, fluorosulfuryl azide6–11 (FSO2N3), and enables the preparation of over 1,200 azides on 96-well plates in a safe and practical manner. This reliable transformation is a powerful tool for the CuAAC triazole annulation, the most widely used click reaction at present. This method greatly expands the number of accessible azides and 1,2,3-triazoles and, given the ubiquity of the CuAAC reaction, it should find application in organic synthesis, medicinal chemistry, chemical biology and materials science.
- Meng, Genyi,Guo, Taijie,Ma, Tiancheng,Zhang, Jiong,Shen, Yucheng,Sharpless, Karl Barry,Dong, Jiajia
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- Antimalarial naphthoquinones. Synthesis via click chemistry, in vitro activity, docking to PfDHODH and SAR of lapachol-based compounds
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Lapachol is an abundant prenyl naphthoquinone occurring in Brazilian Bignoniaceae that was clinically used, in former times, as an antimalarial drug, despite its moderate effect. Aiming to search for potentially better antimalarials, a series of 1,2,3-triazole derivatives was synthesized by chemical modification of lapachol. Alkylation of the hydroxyl group gave its propargyl ether which, via copper-catalyzed cycloaddition (CuAAC) click chemistry with different organic azides, afforded 17 naphthoquinonolyl triazole derivatives. All the synthetic compounds were evaluated for their in vitro activity against chloroquine resistant Plasmodium falciparum (W2) and for cytotoxicity to HepG2 cells. Compounds containing the naphthoquinolyl triazole moieties showed higher antimalarial activity than lapachol (IC50 123.5 μM) and selectivity index (SI) values in the range of 4.5–197.7. Molecular docking simulations of lapachol, atovaquone and all the newly synthesized compounds were carried out for interactions with PfDHODH, a mitochondrial enzyme of the parasite respiratory chain that is essential for de novo pyrimidine biosynthesis. Docking of the naphthoquinonolyl triazole derivatives to PfDHODH yielded scores between ?9.375 and ?14.55 units, compared to ?9.137 for lapachol and ?12.95 for atovaquone and disclosed the derivative 17 as a lead compound. Therefore, the study results show the enhancement of DHODH binding affinity correlated with improvement of SI values and in vitro activities of the lapachol derivatives.
- Brand?o, Geraldo Célio,Rocha Missias, Franciele C.,Pereira, Guilherme Rocha,Arantes, Lucas Miquéias,Soares, Luciana Ferreira,Braga de Oliveira, Alaide,Roy, Kuldeep K.,Doerksen, Robert J.
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p. 191 - 205
(2018/05/02)
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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 0039; 0041
(2017/08/28)
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- Intermediate preparation zidovudines and method
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Disclosed is a method for preparing zidovudine (B). The method comprises the following steps: 1) 2'-halothymidine (A) is used as the raw material to obtain a compound of formula (I) by protecting the hydroxyl group thereof in the 5'-position; 2) the compound of formula (I) is subjected to the acylation of the hydroxyl group in the 3'-position to obtain a compound of formula (VI); 3) the compound of formula (VI) is dehalogenated to obtain a compound of formula (111); 4) the compound of formula (III) is subjected to an elimination reaction to obtain a compound of formula (IV); 5) the compound of formula (IV) is subjected to an azidation reaction to obtain a compound of formula (V); and 6) the compound of formula (V) is deprotected to obtain zidovudine (B); the specific reaction formula being shown in (C)below. In the formulae: X is a halogen, P1 is a protecting group for hydroxyl; and P2 is C1-C4 alkylsulfonyl, fluoro-C1-C4 alkylsulfonyl, arylsulfonyl or -CS-R, wherein R is C1-C4 alkyl.
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- BIOCATALYTIC PRODUCTION OF NUCLEOSIDE ANALOGUES AS ACTIVE PHARMACEUTICAL INGREDIENTS
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A biocatalytic process for producing active pharmaceutical ingredients (APIs) or intermediates thereof, wherein those APIs or their intermediates are nucleoside analogues (NAs) of formula I and wherein said NAs are active as pharmaceutically relevant antivirals and anticancer medicaments, intermediates or prodrugs thereof.
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Paragraph 0234
(2016/04/09)
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- Investigation of reactions postulated to occur during inhibition of ribonucleotide reductases by 2′-azido-2′-deoxynucleotides
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Model 3′-azido-3′-deoxynucleosides with thiol or vicinal dithiol substituents at C2′ or C5′ were synthesized to study reactions postulated to occur during inhibition of ribonucleotide reductases by 2′-azido-2′-deoxynucleotides. Esterification of 5′-(tert-
- Dang, Thao P.,Sobczak, Adam J.,Mebel, Alexander M.,Chatgilialoglu, Chryssostomos,Wnuk, Stanislaw F.
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experimental part
p. 5655 - 5667
(2012/09/25)
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- Serendipitous discovery of a zidovudine guanidine complex: A superior process for the production of zidovudine
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A superior process for the commercial production of zidovudine (AZT) has been developed. It was discovered that an AZT-guanidine complex formed when a crude zidovudine solution was treated with guanidine. This readily precipitated from protic solvents resulting in the exclusion of impurities and permitted the development of a superior isolation and purification of AZT.
- Radatus, Bruno K.
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experimental part
p. 1281 - 1286
(2012/01/13)
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- Synthesis and anticancer activity of 5'-chloromethylphosphonates of 3'-azido-3'-deoxythymidine (AZT)
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A series of novel N-alkyl 5'-chloromethylphosphonates of 3'-azido-3'-deoxythymidine (6-15) was synthesized by means of phosphonylation of 3'-azido-3'-deoxythymidine (4) with P-chloromethylphosphonic ditriazolide (3) followed by a reaction with the appropriate amine. The synthesized phosphonamidates 6-15 were evaluated for their cytotoxic activity in two human cancer cell lines: oral (KB) and breast (MCF-7) using the sulforhodamine B (SRB) assay. The highest activity in KB human cancer cells was displayed by phosphonamidate 8 (IC50 = 5.8 μg/mL), however, this compound was less potent than the parent AZT (IC50 = 3.1 μg/mL). Phosphonamidate 10 showed only moderate activity (IC50 = 12.1 μg/mL) whereas the other phosphonamidates proved inactive. Similarly, the highest activity in MCF-7 human cancer cells was displayed by phosphonamidate 8 (IC50 = 3.7 μg/mL) but it proved somewhat less active than AZT (IC50 = 2.6 μg/mL). Some activity was also displayed by phosphonamidate 10 (IC50 = 12.8 μg/mL) but the other phosphonamidates were found inactive. Hydrolysis studies indicate that the synthesized phosphonamidates are likely to act as prodrugs of the parent nucleoside (AZT). Transport measurements showed that the most active phosphonamidates (8 and 10) were able to permeate across the intestinal epithelium in vitro. The apparent permeability coefficients determined in Caco-2 cell monolayers indicated that these compounds could be moderately absorbed in humans.
- Celewicz, Lech,Jó?wiak, Agnieszka,Ruszkowski, Piotr,Laskowska, Halina,Olejnik, Anna,Czarnecka, Anna,Hoffmann, Marcin,Hladoń, Boguslaw
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p. 6375 - 6382
(2011/12/14)
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- Multifunctional Forms of Polyoxazoline Copolymers and Drug Compositions Comprising the Same
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The present disclosure provides copolymers of 2-substituted-2-oxazolines possessing two or three reactive functional groups which are also chemically orthogonal. The copolymers described may be random copolymers, block copolymers or a mixture of random and block copolymer configurations. Furthermore, the present disclosure provides novel methods for synthesizing the above polymers and for conjugating to molecules such as targeting, diagnostic and therapeutic agents.
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- Floating pharmaceutical composition comprising an active phase and a non-active phase
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The invention concerns a floating pharmaceutical composition consisting of at least a first phase comprising at least a high dose active principle combined with one or several carriers and at least a second phase comprising at least a gas-generating system. The invention also concerns tablets comprising such a pharmaceutical composition and a method for preparing such tablets.
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- Foldamers derived from nucleoside β-amino acids: PNA or DNA? Can we have both in one place?
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The synthesis of a modified thymidine (nucleoside β-amino acid) monomer and preliminary investigations into the solid phase peptide synthesis of PNA/DNA chimeras containing a neutral, internucleoside amide linkage are described. Copyright Taylor & Francis Group, LLC.
- Threlfall, Richard,Davies, Andrew,Howarth, Nicola,Cosstick, Richard
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p. 611 - 614
(2008/09/17)
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- An efficient F-18 labeling method for PET study: Huisgen 1,3-dipolar cycloaddition of bioactive substances and F-18-labeled compounds
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The Cu(I)-catalyzed, 1,3-dipolar cycloaddition reaction was applied successfully to the synthesis of small, F-18-labeled biomolecules, and an optimal condition was developed for one-pot, two-step reaction without any interim purifications. This technique was employed in various F-18-labeled, 1,2,3-triazole syntheses with high radiochemical yield.
- Sirion, Uthaiwan,Kim, Hee Jun,Lee, Jae Hak,Seo, Jai Woong,Lee, Byoung Se,Lee, Sang Ju,Oh, Seung Jun,Chi, Dae Yoon
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p. 3953 - 3957
(2008/02/04)
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- Metabolic properties of phosphonate esters
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The object of the present work was to investigate the difference in the metabolism of the phosphonate derivatives of primary or secondary hydroxyl groups. To study the phosphorolytic cleavage of such P-O bonds, zidovudine (AZT) hexanoyloxymethyl-methylphosphonate (HOM-AZT-P), an ester of a primary OH functionality, and methyl-pivaloyloxymethyl-testosterylphosphonate (POM-T-P), an ester of a secondary OH functionality, were prepared. The actions of pure enzymes such as alkaline phosphatase and phosphodiesterase on the corresponding phosphonate compounds (AZT-P and T-P) were investigated at various pH values. The phosphonate derivative of the secondary hydroxyl group of testosterone proved completely resistant to such phosphorolytic attacks, and release of free testosterone could not be detected. The phosphonate derivative of the primary hydroxyl group of zidovudine proved resistant to phosphodiesterase, but not to alkaline phosphatase, and in this second case, release of free zidovudine could be detected.
- Somogyi, Gabor,Buchwald,Bodor
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p. 378 - 381
(2007/10/03)
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- New lipophilic derivatives of AZT and d4T 5′-phosphonates
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5′-Aminocarbonylphosphonyl and aminocarbonylmethylphosphonyl diesters of AZT and d4T were synthesized as potential anti-HIV agents.
- Shirokova, Elena A.,Jasko, Maxim V.,Khandazhinskaya, Anastasiya L.,Yanvarev, Dmitry V.,Skoblov, Yury S.,Pronayeva, Tatyana R.,Fedyuk, Nina V.,Pokrovsky, Andrey G.,Kukhanova, Marina K.
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p. 981 - 985
(2007/10/03)
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- Specific lipid conjugates to nucleoside diphosphates and their use as drugs
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The present invention concerns new phospholipid derivatives of nucleosides of the general formula (I) in which R1represents a straight-chained or branched, saturated or unsaturated aliphatic residue with 9-14 carbon atoms which can optionally be substituted once or several times; R2can represent a straight-chained or branched, saturated or unsaturated aliphatic residue with 8-12 carbon atoms which can optionally be substituted once or several times; m is 2 or 3; A can represent a methylene group or an oxygen; Nuc can be a nucleoside or a residue derived from a nucleoside derivative; and tautomers thereof and their physiologically tolerated salts of inorganic and organic acids and bases as well as pharmaceutical preparations containing these compounds.
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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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- Selective cleavage of O-(dimethoxytrityl) protecting group with sodium periodate
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Sodium periodate in aqueous organic solvents selectively removes, under mild reaction conditions, the O-(dimethoxytrityl) protecting group. Selectivity of the cleavage was studied using the nucleoside derivatives protected by various types of groups commonly used in nucleoside and nucleotide chemistry.
- Rejman, Dominik,Kralikova, Sarka,Tocik, Zdenek,Liboska, Radek,Rosenberg, Ivan
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p. 502 - 508
(2007/10/03)
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- Design, synthesis, and biological evaluation of anti-HIV double-drugsconjugates of HIV protease inhibitors with a reverse transcriptase inhibitor through spontaneously cleavable linkers
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Based o the prodrug concept as well as the combination of two different classes of anti-HIV agents, we designed and synthesized a series of anti-HIV double-drugs consisitng of HIV protease inhibitors conjugated with a nucleoside reverse transcriptase inhibitor in an effort to enhance the antiviral activity. For the conjugation, a series of linkers that conjoins the two different classes of inhibitors has been investigted. Double-drugs using a succinyl amino acid linker were shown to release the parent drugs via spontaneous imide formation at a faster rate compared ring. Among the double-drugs, KNI-1039 (3B) with a glutaryl-glycine linker exhibited extremely potent anti-HIV activity compared with that of the individual components. Double-drug 3b was relatively stable in culture medium, whereas it regenerated active species in cell homogenate. These results suggested that the synergistic enhancement of anti-HIV activities of 3b may be due to their ability to penetrate into the target cell and subsequent regeneration of two diferent classes of anti-HIV agents in the cytoplasm. Copyright
- Matsumoto, Hikaru,Kimura, Tooru,Hamawaki, Tomonori,Kumagai, Akira,Goto, Toshiyuki,Sano, Kouichi,Hayashi, Yoshio,Kiso, Yoshiaki
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p. 1589 - 1600
(2007/10/03)
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- A simple and efficient synthesis of 3prime;-azido-3′-deoxythymidine (AZT) employing a convergent route
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The syn-homoallyl alcohol 2a has been prepared with absolute stereoselectivity following PDC oxidation of the mixture of diastereomers 2a, 2b and subsequent K-selectride reduction of the resulting ketone 3. Compound 2a has been efficiently utilized for a simple synthesis of AZT I in a convergent manner.
- Dhotare,Chattopadhyay
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p. 1337 - 1340
(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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- A facile method for deprotection of trityl ethers using column chromatography
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A mild, efficient and inexpensive detritylation method is reported that uses trifluoroacetic acid on a silica gel column to obtain pure, detritylated compounds in one-step. This method is applicable to acid stable as well as acid sensitive compounds with only slight alterations in the procedure. Nineteen examples are given.
- Pathak, Ashish K.,Pathak, Vibha,Seitz, Lainne E.,Tiwari, Kamal N.,Akhtar, Mohammad S.,Reynolds, Robert C
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p. 7755 - 7757
(2007/10/03)
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- P-(Alkyl)-nucleoside 5′-hydrogenphosphonates as depot forms of antiviral nucleotide analogues
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P-(Alkyl)esters of AZT 5′-hydrogenphosphonate were synthesized and their stabilities in the phosphate buffer and human serum were evaluated. The esters bearing residues of primary and secondary alcohols were degraded to give AZT, whereas those containing tertiary alkyl groups yielded AZT 5′-hydrogenphosphonate. The corresponding derivatives of d2A and d2T showed the same properties.
- Khandazhinskaya,Shirokova,Karpenko,Zakirova,Tarussova,Krayevsky
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p. 1795 - 1804
(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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- Transformations of β-D-xylofuranosyl nucleosides. Synthesis of 3′-azido-3′-deoxythymidine
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A modified synthesis of 3′-azido-3′-deoxythymidine starting from D-xylose is proposed.
- Mustafin,Gataullin,Abdrakhmanov,Spirikhin,Tolstikov
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p. 2007 - 2008
(2007/10/03)
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- Synthesis and application of 3′-amino-dye-terminators for dna sequencing
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The synthesis of 3′-aminomodified nucleoside 5′-triphosphates and their coupling with oligoaminoacid-linked dyes is described. Application for DNA dye-terminator sequencing was investigated. Copyright 1997 by Marcel Dekker, Inc.
- Wojczcwski,Faulstich,Engels
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p. 751 - 754
(2007/10/03)
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- Pyrimidine nucleoside derivatives and methods for producing them
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Nucleoside derivatives such as 2'-deoxy-2'-bromo-5'-O-acetyl-5-methyluridine, etc., are important intermediates which can be converted into nucleoside derivatives, such as 3'-azido-3'-deoxythymidine, etc., which are useful as medicines.
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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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- Treatment of human viral infections
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Treatment of AIDS or humans carrying or infected with the AIDS virus or having antibodies to the AIDS virus is disclosed using the compound 3'-azido-3'-deoxythymidine or a pharmaceutically acceptable basic salt thereof. Also disclosed is the use of the 5'-mono-, di- and triphosphate of 3'-azido-3'-deoxythymidine or a pharmaceutically acceptable basic salt thereof for the same purpose. Additionally, there is disclosed the treatment of Kaposi's sarcoma with 3'-azido-3'-deoxythymidine (AZT) and the synergistic activity in the treatment of humans infected with HTLV-III of AZT and interferon as well as AZT and acyclovir and AZT and 2-amino-9-(2-hydroxyethoxymethyl)purine or an ester thereof.
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- An improved synthesis of azidothymidine
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A convenient and high yielding procedure is described for a direct conversion of thymidine (1) into 2,3'-anhydrothymidine (2) using the Mitsunobu reaction. Isolation and characterization of two new compounds, 3 and 4, are discussed. AZT has been synthesized from 1 in two steps, in 62% overall yield, by heating 2 with NaN3 in DMF.
- Balagopala, Meher I.,Ollapally, Abraham P.,Lee, Henry J.
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p. 899 - 906
(2007/10/03)
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- 38. Nucleotides: Part XLVI. The synthesis of phospholipid conjugates of antivirally active nucleosides by the improved phosphoramidite methodology
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The application of the improved phosphoramidite strategy for the synthesis of oligonucleotides using β-eliminating protecting groups to phospholipid chemistry offers the possibility to synthesize phospholipid conjugates of AZT (6) and cordycepin. The synthesis of 3′-azido-3′-deoxythymidine (6) was achieved by a new isolation procedure without chromatographic purification steps in an overall yield of 50%. Protected cordycepin (=3′-deoxyadenosine) derivatives, the N6,2′-bis[2-(4-nitrophenyl)ethoxycarbonyl]cordycepin (12) and the N6,5′-bis[2-(4-nitrophenyl)ethoxycarbonyl]cordycepin (13) were prepared by known methods and direct acylation of N6-[2-(4-nitrophenyl)ethoxycarbonyl]cordycepin (9), respectively. These protected nucleosides and the 3′-azido-3′-deoxythymidine (6) reacted with newly synthesized and properly characterized lipid-phosphoramidites 21-25, catalyzed by 1H-tetrazole, to the corresponding nucleoside-phospholipid conjugates 26-38 in high yield. The deprotection was accomplished via β-elimination with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in aprotic solvents to give analytically pure nucleoside-phospholipid diesters 39-51 as triethylammonium or sodium salts. The newly synthesized compounds were characterized by elemental analyses and UV and 1H-NMR spectra.
- Sigmund, Harald,Pfleiderer, Wolfgang
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p. 426 - 438
(2007/10/03)
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- Synergistic antiviral nucleoside combinations
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An antiviral composition comprising in combination an effective antiviral amount of 3'-fluoro-2',3'-dideoxy nucleoside compound I of the formula STR1 wherein B is adenine, thymine, guanine, cytosine, inosine, uracil, 5-ethyluracil, 2,6-diaminopurine; and an effective antiviral amount of 2',3'-dideoxy nucleoside compound II of the formula STR2 wherein X is N3 or H or together with Y forms an additional carbon-carbon bond, Y and Z are independently H, OH or F, and B is adenine, thymine, guanine, cytosine, inosine, uracil, 5-ethyluracil, 2,6-diaminopurine, and a physiologically acceptable carrier.
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- A New Synthesis f the Anti-AIDS Drug AZT from 5-Methyluridine
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The anti-AIDS drug AZT is prepared in six steps in 44percent overall yield starting from the readily available ribonucleoside 5-methyluridine.
- Chen, Bang-Chi,Quinlan, Sandra L.,Reid, J. Gregory
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p. 7961 - 7964
(2007/10/02)
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- Recovery of AZT by guanidine precipitation
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A process for recovering 3'-azido-3'-deoxythymidine (AZT) or a salt thereof from a mixture of chemicals involving the reaction of the AZT with guanidine to form a salt precipitate. The salt precipitate is then acidified to pH of less than about 9 to yield free AZT, which can then be crystallized from solution. 3'-Azido-3'-deoxythymidine and its salts, also known as AZT and Zidovudine, is used in the treatment of AIDS patients.
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- Process for preparing AZT
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A process for preparing AZT and comprising the steps of: a) reacting a 2'-halo-5'-protected pyrimidinyl 2'-deoxyribonucleoside having a 3'-sulfonyl group with tributyl tin hydride and catalytic amount of azobisisobutyronitrile in an ether, ester, or ketone solvent to yield a dehalogenated pyrimidinyl 2'-deoxyribonucleoside; followed by b) reacting said dehalogentated pyrimidinyl 2'-deoxynucleoside formed in step (a) with a base, a lithium salt, and an azide salt to yield a 5'-protected pyrimidinyl 3'-dideoxy-3'-azido-ribonucleoside; and c) deprotecting the nucleoside derivative of step (b) to yield 3'-dideoxy-3'-azidothymidine.
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- Mononucleoside Phosphotriester Derivatives with S-Acyl-2-thioethyl Bioreversible Phospate-Protecting Groups: Interacellular Delivery of 3'-Azido-2',3'-dideoxythymidine 5'-Monophosphate
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The synthesis, in vitro anti-HIV-1 activity, and decomposition pathways of several mononucleoside phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) incorporating a new kind of carboxylate esterase-labile transient phosphate-protecting group, namely S-acyl-2-thioethyl, are reported.All the described compounds showed marked antiviral activity in thymidine kinase-deficient CEM cells in which AZT was virtually inactive.The results strongly support the hypothesis that such pronucleotides exert their biological effects via intracellular delivery of the 5'-mononucleotide of AZT.This point was corroborated by decomposition studies in cell extracts and culture medium.
- Lefebvre, Isabelle,Perigaud, Christian,Pompon, Alain,Aubertin, Anne-Marie,Girardet, Jean-Luc,et al.
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p. 3941 - 3950
(2007/10/03)
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- Lipophilic &α-Hydroxybenzylphosphonates as Prodrugs of 3'-Azido-2',3'-dideoxythymidine (AZT)
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The α-hydroxybenzylphosphonates 1a-1j of the antiviral drug 3'-azido-2',3'-dideoxythymidine 5 (AZT) as potential lipophilic prodrugs were readily accessible in 49percent to 87percent yield via a four-step synthetic pathway introducing the modifications in the aromatic ring system in the last step by making use of intermediate 6.All compounds 1a-1j exhibited higher partition coefficients in 1-octanol/water than AZT (5).In hydrolysis studies at pH 7.5 we observed that precursors to bioactive compounds were delivered by simple hydrolysis of the lipophilic precursors 1a-1j via two different mechanisms: the phosphonate-phosphate rearrangement leading to the benzylphosphotriesters 2 and/or the direct cleavage into the di-AZT phosphonate 6.Both compounds 2 and 6 were further degraded yielding the potentially antiviral active compounds 4 and 8, respectively.The hydrolysis pathway could be controlled by the substitution pattern in the benzylic moiety.Identical hydrolytic behavior of 1 was detected in "biological" hydrolysis kinetics by using a RPMI culture medium containing 10percent heat-inactivated fetal calf serum (FCS).The title compounds 1a-1j exhibited considerable HIV-1 and HIV-2 activity in wild-type CEM/O cells. - Keywords: AZT; Nucleoside α-hydroxybenzylphosphonates; Phosphonate-phosphate rearrangement; Prodrugs; HIV chemotherapy
- Meier, Chris,Habel, Lothar W.,Balzarini, Jan,Clercq, Eric De
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p. 2195 - 2202
(2007/10/03)
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- Synthesis, bioactivation and anti-HIV activity of 4-acyloxybenzyl bis(nucleosid-5'-yl) phosphates
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4-Acyloxybenzyl bis(nucleosid-5'-yl) phosphates 7a-c and 9a-c were prepared as potential prodrugs of the anti-HIV nucleosides 3'-azido-3'- deoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI) or their 5'- monophosphates. The anti-HIV activities of these triesters were determined in two T-cell lines. In a C8166 cell line they displayed activities comparable to and in some cases superior to AZT, but they also exhibited an increase in cytotoxicity. In a thymidine kinase deficient JM T-cell line the activity was reduced but was still superior to AZT. In the presence of porcine liver carboxyesterase (PLCE), triester 7b biodegrades to the diester 10 which, with phosphodiesterase, gives initially AZT monophosphate 3 and AZT.
- Routledge,Walker,Freeman,Hay,Mahmood
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p. 1545 - 1558
(2007/10/02)
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- Synthesis of nucleotide lipophilic prodrugs containing two inhibitors targeted against different phases of the HIV replication cycle
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We describe the preparation of nucleoside acyl 5'-di or 5'-triphosphates, containing a nucleoside analog moiety and 13-oxa-myristic acid as lipophilic chain. At physiological pH these products liberated exclusively the corresponding nucleotides.
- Bonnaffe,Dupraz,Ughetto-Monfrin,Namane,Dinh
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p. 783 - 787
(2007/10/02)
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- Synthesis, decomposition pathways and 'in vitro' evaluation of bioreversible phosphotriesters of AZT
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The synthesis, pharmacokinetic data and biological evaluation of a series of phosphotriesters containing S-acyl-2-thioethyl groups as enzyme-labile phosphate protecting groups and AZT as a model are described. A comparison of pharmacokinetic data and 'in vitro' experiments show that such bioreversible phosphotriesters of AZT are able to cross cell membranes and deliver the corresponding nucleoside monophosphate inside the cell. Moreover, kinetic data show that modification of the protecting groups can allow to modulate both the extracellular stability of the parent compond and the delivery of nucleoside monophosphate inside the cell.
- Lefebvre,Pompon,Perigaud,Girardet,Gosselin,Aubertin -,Kirn,Imbach
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p. 763 - 766
(2007/10/02)
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- Process for the deoxygenation of nucleosides
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An efficient process for the deoxygenation of 2'- and or 3'-hydroxyl groups of a nucleoside that includes reacting the hydroxyl group with 3-halopropionitrile or 2-nitroethylhalide and carbon disulfide in base to form a 2'- or 3'-(cyanoethylthio or nitroethylthio)thiocarbonyl, that is reductively eliminated and replaced with hydrogen. The deoxygenation process can be used in a wide variety of nucleoside syntheses that require the elimination of the 2'- or 3'-hydroxyl groups, including the preparation of 3'-substituted-2',3'-dideoxynucleosides such as 3'-azido-3'-deoxythymidine and 3'-azido-2',3'-dideoxyuridine.
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- Preparation of 3'-substituted-2',3'-dideoxynucleosides and 2'-deoxynucleosides from acyclic, achiral precursors
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A process for the preparation of 3'-substituted-2',3'-dideoxynucleosides is provided that utilizes inexpensive, non-carbohydrate, acyclic, achiral starting materials and that proceeds with high enantiomeric and stereochemical control. The method can be used to prepare the pharmaceutically important compounds 3'-azido-3'-deoxythymidine, 3'-azido-2',3'-dideoxyuridine, 3'-fluoro-3'-deoxythymidine, and 3'-fluoro-3'-deoxyuridine.
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- Stereocontrolled synthesis of pyrimidine 2',3'-dideoxy-β-nucleosides by intramolecular glycosylation
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β-2',3'-Dideoxynucleosides and their 3'-azido and 3'-fluoro substituted derivatives were synthesized in a stereocontrolled manner by the dimethyl(methylthio)sulfonium tetrafluoroborate promoted intramolecular glycosylation of phenyl 2,3-dideoxy-5-O-(2-pyrimidyl)-1-thioglycosides followed by hydrolysis or ammonolysis.
- Sujino,Sugimura
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p. 1883 - 1886
(2007/10/02)
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