30516-87-1Relevant articles and documents
Ester prodrugs of zidovudine
Kawaguchi,Ishikawa,Seki,Juni
, p. 531 - 533 (1990)
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.
AZT 5′-cholinephosphate as an anti-HIV agent: The study of biochemical properties and metabolic transformations using its 32P-labelled counterpart
Yanvarev, Dmitry V.,Shirokova, Elena A.,Astapova, Maria V.,Skoblov, Yury S.
, p. 23 - 36 (2007)
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.
3'-Azido-3'-deoxy-5'-O-isonicotinoylthymidine: a novel antiretroviral analog of zidovudine. II. Stability in aqueous media and experimental and theoretical ionization constants.
Teijeiro, Silvina A,Raviolo, Monica A,Motura, Marisa I,Brinon, Margarita C
, p. 1789 - 1803 (2003)
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.
5-Halo-6-alkoxy-5,6-dihydro-pyrimidine nucleosides: Antiviral nucleosides or nucleoside prodrugs?
Wiebe,Knaus,Cheraghali,Kumar,Morin,Wang
, p. 501 - 505 (1995)
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.
A novel synthesis of AZT
Gauthier, Christine,Ramondenc, Yvan,Plé, Gérard
, p. 7513 - 7517 (2001)
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.
Synthesis method of (1 beta, 2 alpha, 4 beta) halogenated nucleoside compound
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Paragraph 0094-0096, (2022/01/12)
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.
A preparation method of zidovudine
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Paragraph 0045-0071, (2019/05/15)
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.
Modular click chemistry libraries for functional screens using a diazotizing reagent
Meng, Genyi,Guo, Taijie,Ma, Tiancheng,Zhang, Jiong,Shen, Yucheng,Sharpless, Karl Barry,Dong, Jiajia
, p. 86 - 89 (2019/11/13)
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.
Antimalarial naphthoquinones. Synthesis via click chemistry, in vitro activity, docking to PfDHODH and SAR of lapachol-based compounds
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.
, p. 191 - 205 (2018/05/02)
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.
Methyl ketone derivative, and preparation method and applications thereof
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Paragraph 0039; 0041, (2017/08/28)
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.
