- Total synthesis of uradl polyoxin c
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An improved synthesis of methyl (methyl 5-azido-5deoxy-2,3-O-isopropylidene-β-D-allofuranosid)uronate (7) from methyl 2,3-0-isopropylidene-β-D-rifro-pentodialdo-l,4-furanoside (6), using vinylmagnesium bromide in the key step, and its application to the total synthesis of uracil polyoxin C (1) are described.
- Kato, Keisuke,Chen, Cheng Yu,Akita, Hiroyuki
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- A new concept for the preparation of beta-L- and beta-D-2',3'-dideoxynucleoside analogues.
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[reaction: see text] A new method for the synthesis of 2',3'-dideoxynucleoside analogues has been developed. An electrochemical activation of 2-substituted furans is followed by the coupling with a pyrimidine or purine base. This gives planar furyl nucleosides as key intermediates, which are hydrogenated cis-selectively to give the corresponding beta-2',3'-dideoxynucleosides as racemic mixtures. An enzymatic kinetic resolution gives rise to beta-D- and beta-L-configured derivatives in high optical purity. This is exemplified by the synthesis of beta-D- and beta-L-3'-deoxythymidine.
- Albert, Martin,De Souza, Dominic,Feiertag, Petra,Hoenig, Helmut
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- Bicyclic nucleoside analogues from D-glucose: Synthesis of chiral as well as racemic 1,4-dioxepane ring-fused derivatives
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The dioxepanofuranose derivatives 4 and 12, obtained through the cyclization of the 3-(2-hydroxyethyl) ether of a d-xylo-pentodialdose derivative, were appropriately functionalized and elaborated to the first examples of the new class of 3′-O and 5′-O-bicyclic nucleoside analogues 9, 10, and 14 with a fused seven-membered ring. Reactions carried out through the intermediacy of the d-xylo-pentodialdose derivative 5 yielded racemic products, while prior protection of the 4-formyl group (as in 7) before deprotection of the 1,2-hydroxyl groups led to optically active analogues.
- Tripathi, Subhankar,Maity, Joy Krishna,Achari, Basudeb,Mandal, Sukhendu B.
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- Concise synthesis and antibacterial evaluation of novel 3-(1,4-disubstituted-1,2,3-triazolyl)uridine nucleosides
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We report herein a simple and efficient synthesis of a new series of antibacterial uridine nucleosides. The strategy involved a sequential silylation/N-glycosylation/N-propargylation procedure of uracil 1 for preparing the dipolarophile 5 in good yield. A series of novel uridine-[1,2,3]triazole nucleosides 6a–j were efficiently synthesized via the copper-catalyzed azide–alkyne cycloaddition (CuAAC) from dipolarophile 5 with different selected azides. The reactions were carried out under both conventional and ultrasonic irradiation conditions. In general, improvements were observed when reactions were carried out under sonication. Their antibacterial potential has been evaluated by means of a micro-dilution assay against either Gram-positive or Gram-negative bacteria. Compounds 6i and 6j have shown significant bactericidal activity against Staphylococcus aureus (MIC = 10 and 6 μM, respectively), and 6h against Escherichia coli (MIC = 8 μM). Moreover, antibacterial kinetic assays showed that 6i and 6j significantly reduced the S. aureus growth rate at the MIC concentration, after 6 h, compared to their deprotected analogs, 6k and 6l, respectively. Compound 6h also significantly reduced the growth of E. coli. These antibacterial effects may be related to the penetrating properties of these compounds, as revealed by the leakage of nucleic acids from the sensitive strains.
- Tachallait, Hamza,Bouyahya, Abdelhakim,Talha, Aicha,Bakri, Youssef,Dakka, Nadia,Demange, Luc,Benhida, Rachid,Bougrin, Khalid
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- Stereoselective synthesis of novel C-azanucleoside analogues by microwave-assisted nucleophilic addition of sugar-derived cyclic nitrones
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A series of C-azanucleoside analogues were synthesized by microwave-assisted nucleophilic addition of electron-rich hetero-aromatics to sugar-derived cyclic nitrones, and followed by reduction and deprotection. The nucleophilic addition afforded the 2′,3′-trans isomer as the dominant by the favorite exo attack and showed high stereoselectivity in polar solvent.
- Li, Xiaoliu,Qin, Zhanbin,Wang, Rui,Chen, Hua,Zhang, Pingzhu
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- Diastereoselective synthesis of some carbocyclic 2′-oxa-3′-aza- nucleosides
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Two strategies for the synthesis of isoxazolidinyl nucleosides as potential antiviral agents are reported: a one-step approach based on 1,3-dipolar cycloaddition of D-lyxosyl nitrone with N,N-dibenzyl-9-vinyl adenine, and a two-step methodology based on the Vorbrueggen nucleosidation of the 5-acetoxyisoxazolidine. The chiral D-lyxosyl nitrone undergoes regioselective 1,3-dipolar cycloadditions with N,N-dibenzyl-9-vinyl adenine and vinyl acetate giving 5-substituted isoxazolidines as a mixture of four diastereoisomers in good yields. The condensation of 5-acetoxyisoxazolidine with silylated uracil, thymine, and N-acetylcytosine proceeded with moderate to good stereoselectivity with the formation of the expected isoxazolidinyl β-and α-nucleosides.
- Hyrosova,Fisera,Jame,Pronayova,Medvecky,Koos
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- Synthesis of 3',4'-C-bishydroxymethyl-2',3',4'-trideoxy-β-L-threo- pentopyranosyl nucleosides as potential inhibitors of HIV
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The synthesis of 3',4'-bishydroxymethyl-2',3',4'-trideoxy pentopyranosyl derivatives of thymine, uracil, cytosine, and adenine is described. trans- (3S,4S)-Bis(methoxycarbonyl)cyclopentanone (3) was converted to 1-O-acetyl- 3,4-C-bis[(tert-butyldiphenylsiloxy)methyl]-2,3,4-trideoxy-α,β-L-threo- pentopyranose (6), which was subsequently condensed with the silylated purine and pyrimidine bases.
- Lundquist,Kvarnstrom,Svensson,Classon,Samuelsson
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- Experimental evidence for intramolecular attractive nonbonded C-F ··· H-C interactions in 2',3'-dideoxy-4'-(fluoromethyl)nucleosides - Through- space J(CF) and J(HF) NMR coupling constants, correlation with empirical parameters of solvent polarity and single-crystal X-ray structures
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A collection of 5'-O-benzyl-2',3'-dideoxy-4'-(fluoromethyl)nucleosides carrying both purinic and pyrimidinic nucleobases (uracil, 5-Br-uracil, 5- O2N-uracil, 6-Cl-purine and inosine) were synthesized in both the α and the β form. Through-space-transmitted 6J(CF) NMR coupling constants between F and C-6 (pyrimidinic base) or C-8 (purinic base) were observed for all of the α anomers of the compounds examined, whilst the corresponding 7J(HF) coupling constants were resolved only for the 5-substituted uracil derivatives. The absolute values of all the through-space couplings were found to decrease monotonically with increasing solvent polarity (CDCl3, MeOD, [D6]acetone, [D6]DMSO). This trend suggests that the through-space interaction is mediated by an intramolecular (sp3)C-F ··· H-C(sp2) hydrogen bond. The possibility of any relevant solvent-induced conformational change influencing the F/base mutual spatial relationship in the molecules investigated was ruled out by heteronuclear steady-state 1H{19F}-NOE experiments. A linear correlation was observed between 6J(CF) and 7J(HF) coupling constants and the Kamlet-Taft's hydrogen bond basicity parameter β. The crystal structures of the α and β anomers of the 5-nitrouracil nucleoside show evidence that the H-6 of the nucleobase forms hydrogen-bond- like interactions involving the O-benzyl oxygen atom in the β anomer, and that in the case of the α anomer this is replaced by the F atom of the fluoromethyl group.
- Mele, Andrea,Vergani, Barbara,Viani, Fiorenza,Meille, Stefano Valdo,Farina, Alessandra,Bravo, Pierfrancesco
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- β-Anomer selectivity in 2′-deoxynucleoside synthesis: A novel approach using an acyl carbamate directing group
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Glycosylation of silylated pyrimidines using a phenyl 2-deoxy-3-O-(N-benzoyl)carbamoyl-1-thio-D-erythro-pentofuranoside yielded 2-deoxy-β-ribonucleosides in good yields with excellent anomeric selectivity. This prototype 3-O-carbamate directing group was readily formed and removed in high yields.
- Young, Robert J.,Shaw-Ponter, Sue,Hardy, George W.,Mills, Gail
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- Effective synthesis of nucleosides utilizing O-acetyl-glycosyl chlorides as glycosyl donors in the absence of catalyst: Mechanism revision and application to silyl-hilbert-johnson reaction
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An effective synthesis of nucleosides using glycosyl chlorides as glycosyl donors in the absence of Lewis acid has been developed. Glycosyl chlorides have been shown to be pivotal intermediates in the classical silyl-Hilbert-Johnson reaction. A possible mechanism that differs from the currently accepted mechanism advanced by Vorbrueggen has been proposed and verified by experiments. In practice, this catalyst-free method provides easy access to Capecitabine in high yield.
- Liang, Chengyuan,Ju, Weihui,Ding, Shunjun,Sun, Han,Mao, Gennian
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- Synthesis of 4′-substituted 2′-deoxy-4′-thiocytidines and its evaluation for antineoplastic and antiviral activities
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4′-Azido- (7), 4′-C-fluoromethyl- (8) 4′-C-ethynyl- (9) and 4′-C-cyano- (10) 2′-deoxy-4′-thiocytidines have been synthesized. In this study, it was found that the isolated yield of 4′-thiouracil nucleoside 13 in a Lewis acid-promoted Vorbrüggen-type glycosidation utilizing 12 was better than that of the electrophilic glycosidation reaction between silylated uracil and 11. This improved result prompted us to perform the glycosidation utilizing 36 and 43 for the synthesis of 37 and 44. Introduction of the azido group was carried out by nucleophilic substitution in the 4′-benzoyloxy derivative 22a. On the other hand, 9 and 10 were synthesized by way of the chemical manipulation of the hydroxymethyl group at the 4′-position of 46. Evaluation of the antineoplastic activity of 2 and 7–10 against human B-cell (CCRF-SB) and T-cell leukemia (Molt-4) cell lines revealed that 4′-azido- (7) and 4′-C-fluoromethyl- (8) derivatives exhibited cytotoxic activity whereas no cytotoxicity was observed in the 4′-C-ethynyl- (9) and 4′-C-cyano- (10) derivatives as well as the parent compound 2. Compound 7 was also found to possess promising antiviral activity against VZV and HSV-1 without any cytotoxity against HEL host cells. It is noteworthy that 7 exhibited potent inhibitory activities against the thymidine kinase-deficient (TK?) mutant of VZV and HSV-1.
- Haraguchi, Kazuhiro,Kumamoto, Hiroki,Konno, Kiju,Yagi, Hideki,Tatano, Yutaka,Odanaka, Yuki,Shimbara Matsubayashi, Satoko,Snoeck, Robert,Andrei, Graciela
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- SYNTHESIS OF 1-(3-HALOTETRAHYDRO-2-FURYL) DERIVATIVES OF URACIL, 5-SUBSTITUTED URACILS, AND CYTOSINE
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The cis and trans isomers of 1-(3-halotetrahydro-2-furyl) derivatives of uracil, 5-substituted uracils, and cytosine were obtained by alkylation of 2,4-bis(trimethylsilyl) derivatives of uracil, 5-substituted uracils, and cytosine with 2,3-dihalotetrahydrofurans . 2,3'-Anhydro compounds are also formed in the alkylation of 5-halouracil derivatives.The physicochemical properties of the compounds obtained and the antineoplastic activities of the 5-fluorouracil derivatives were studied.
- Kaulinya, L. T.,Lidak, M. Yu.
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- Stereoselective synthesis of oxa-bowls by nucleophilic addition to oxonium ions: Observation of nucleophile-dependent hydride migration
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A simple and reliable platform was developed for the synthesis of symmetrical oxa-bowls through the Lewis acid mediated etherification of dimethyl acetals. An intramolecular hydride transfer was observed with the use of electron-rich aryl nucleophiles, which also gave access to unsymmetrical oxa-bowls. A general strategy is developed for the stereoselective synthesis of symmetrical oxa-bowls through the Lewis acid mediated generation of oxonium ions from bis-acetals and their subsequent trapping with a variety of nucleophiles. Hydride migration is observed with the use of trimethoxybenzene as a nucleophile with rigid acetal precursors. This method is extended to the synthesis of unsymmetrically substituted oxa-bowls. Copyright
- Gharpure, Santosh J.,Porwal, Suheel K.
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- HMDS/KI a simple, a cheap and efficient catalyst for the one-pot synthesis of N-functionalized pyrimidines
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The syntheses of N-Alkylpyrimidine derivatives by reacting pyrimidin-2,4-diones with appropriate alkyl halide under microwave irradiation at 400 W were compared to the conventional synthesis route. These methodologies are regioselective and compatible with numerous substrates and furnish the corresponding N-alkylpyrimidines in good yields using a cheap catalyst HMDS/KI in MeCN. A comparison study between these two different modes of heating was investigated.
- Mansouri, Az-Eddine El,Zahouily, Mohamed,Lazrek, Hassan B.
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- Synthesis of spiroacetal-nucleosides as privileged natural product-like scaffolds
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The elaboration of a 6,6-spiroacetal scaffold to incorporate a nucleoside unit at the anomeric position is described. The novel spiroacetal-nucleoside hybrids 11 were generated via nucleosidation of acetoxy-spiroacetal 10 with a series of silylated nucleobases under Vorbrueggen conditions.
- Choi, Ka Wai,Brimble, Margaret A.
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- Efficient and selective catalytic N-Alkylation of pyrimidine by ammonium Sulfate?Hydro-thermal carbone under eco-friendly conditions
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Abstract: An efficient and inexpensive method for the N-alkylation of pyrimidines using ammonium sulfate coated Hydro-Thermal-Carbone (HTC) (AS?HTC) as reused heterogeneous catalyst was developed. The catalyst was characterized by several analytical techniques such as SEM, XRD, and FTIR. The effect of various parameters was studied including catalyst loading, mole ratio, to achieve excellent selectivity and yields in 80–90%. Significantly, the present protocol offers the use of an inexpensive and environmentally friendly catalyst and simple workup. The simplicity of the procedure, excellent yield of the products, and the recyclability of the catalyst are the main advantages of this method. Graphic Abstract: Ammonium sulfate coated Hydro-Thermal-Carbone (HTC) (AS?HTC); an efficient and reused heterogeneous catalyst of the N-alkylation of pyrimidines was developed. Excellent selectivity and yields (80–90%) toward N1-alkylpyrimidines were achieved. Significantly, the present protocol offers the use of an inexpensive and environmentally friendly catalyst and simple workup.[Figure not available: see fulltext.]
- Ait Ali, Mustapha,Belkharchach, Soumia,Ighachane, Hana,Lachgar, Abdessadek,Lazrek, Hassan B
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- The synthesis of new acyclic analogs of 3-phenacyluridine and comparative evaluation of their in vivo biological activity
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[Figure not available: see fulltext.] New structural analogs of 3-phenacyluridine were obtained as a result of N(3)-alkylation of 1-(2-acetoxyethyl)- and 1-(2-acetoxyethoxymethyl) uracil. Biological studies of the title compounds in an acute in vivo experiment did not reveal their hypnotic properties and ability to enhance the effects of diazepam and chloral hydrate.
- Novakov, Ivan А.,Brunilina, Leila L.,Kirillov, Ivan А.,Nawrozkij, Maxim B.,Robinovich, Mariya D.,Titova, Evgeniya S.,Sheikin, Dmitry S.,Ruchko, Evsey А.,Pavlova, Alla V.,Kotlyarova, Anastasiya А.,Tolstikova, Tatyana G.
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- Er(OTf)3 as a valuable catalyst in a short synthesis of 2′,3′-dideoxy pyranosyl nucleosides via Ferrier rearrangement
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Er(OTf)3 is a useful catalyst for the Ferrier rearrangement furnishing 2′,3′-dideoxy pyranosyl nucleosides easily by means of cleaner reaction profiles, short reaction times, mild reaction conditions, good stereoselectivity, and good recoverability of the commercially available catalyst. Georg Thieme Verlag Stuttgart.
- Procopio, Antonio,Dalpozzo, Renato,De Nino, Antonio,Nardi, Monica,Oliverio, Manuela,Russo, Beatrice
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- 5-Methylcytosine is Oxidized to the Natural Metabolites of TET Enzymes by a Biomimetic Iron(IV)-Oxo Complex
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Ten-eleven-translocation (TET) methyl cytosine dioxygenases play a key role in epigenetics by oxidizing the epigenetic marker 5-methyl cytosine (5mC) to 5-hydroxymethyl cytosine (5hmC), 5-formyl cytosine (5fC), and 5-carboxy cytosine (5cC). Although much of the metabolism of 5mC has been studied closely, certain aspects—such as discrepancies among the observed catalytic activity of TET enzymes and calculated bond dissociation energies of the different cytosine substrates—remain elusive. Here, it is reported that the DNA base 5mC is oxidized to 5hmC, 5fC, and 5cC by a biomimetic iron(IV)-oxo complex, reminiscent of the activity of TET enzymes. Studies show that 5hmC is preferentially turned over compared with 5mC and 5fC and that this is in line with the calculated bond dissociation energies. The optimized syntheses of d3-5mC and d2-5hmC are also reported and in the reaction with the biomimetic iron(IV)-oxo complex these deuterated substrates showed large kinetic isotope effects, confirming the hydrogen abstraction as the rate-limiting step. Taken together, these results shed light on the intrinsic reactivity of the C?H bonds of epigenetic markers and the contribution of the second coordination sphere in TET enzymes.
- Jonasson, Niko S. W.,Daumann, Lena J.
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- 1-Ethyluracil, a New Scaffold for Preparing Multicomponent Forms: Synthesis, Characterization, and Computational Studies
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In this work, we describe the successful preparation of a series of cocrystals of the modified nucleobase 1-ethyluracil with different coformers in a 1:1 or 2:1 (nucleobase:coformer) ratio including urea (URE) or some compounds containing carboxylic and hydroxyl groups such as l-malic acid (MAL), l-tartaric acid (TAR), 2-hydroxybenzoic acid (SAL), 4-hydroxybenzoic acid (4HB), and 2,4-dihydroxybenzoic acid (DHB). The influence of the hydroxyl substituent on the alkyl chain for 1·TAR and 1·SAL cocrystals or the phenyl ring for 1·SAL, 1·4HB, and 1·DHB multicomponent solids was studied. All of the compounds were characterized by powder X-ray diffraction, FT-IR, and thermal methods. Moreover, for those whose single-crystal structures could be determined, computational studies were also performed to investigate the factors that may affect the cocrystal formation, the recurrent motifs, and the energies associated with the H-bonding interactions using DFT calculations and a combination of the quantum theory of atoms in molecules (QTAIM) and the noncovalent interaction index (NCIplot) computational tools.
- Barceló-Oliver, Miquel,Benito, Mónica,Frontera, Antonio,Molins, Elies,Rosselló, Yannick
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- A complex of 5-hydroxypyrrolidin-2-one and pyrimidine-2,4-dione isolated from Jatropha curcas
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A complex of 5-hydroxypyrrolidin-2-one and pyrimidine-2,4-dione was isolated from the leaves of Jatropha curcas L. by extraction with ethyl acetate and subsequent fractionation of the extract by column chromatography on Sephadex LH20, silica gel and fractogel TSK HW 40. Final purification was carried out by HPLC on a preparative RP-18 column and the structure was proposed mainly by mass spectrometry, 1H- and 13C-NMR.
- Staubmann, Ruth,Schubert-Zsilavecz, Manfred,Hiermann, Alois,Kartnig, Theodor
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- Synthesis of ABBV-168, a 2′-Bromouridine for the Treatment of Hepatitis C
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ABBV-168 is a dihalogenated nucleotide under investigation for the treatment of hepatitis C virus. Three synthetic routes aimed at achieving the stereoselective installation of the C2′ gem-Br,F substitution and subsequent Vorbruggen glycosylation were explored to prepare the penultimate nucleoside intermediate. Development culminated in a route to ABBV-168 featuring a de novo chromatography-free furanose synthesis, protecting group-directed Vorbruggen glycosylation, and highly selective phosphoramidation to furnish the API.
- Voight, Eric A.,Brown, Brian S.,Greszler, Stephen N.,Halvorsen, Geoff T.,Zhao, Gang,Kruger, Albert W.,Hartung, John,Lukin, Kirill A.,Martinez, Steven R.,Moschetta, Eric G.,Tudesco, Michael T.,Ide, Nathan D.
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- Practical and reliable synthesis of 2′,3′,5′,5″-tetradeuterated uridine derivatives
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Deuterated drugs are valuable in the fields of drug discovery and medicinal chemistry. 2′,3′,5′,5″-tetradeuterated uridine derivatives were synthesised from 2,3,5,5′-selectively tetradeuterated ribose using Sajiki’s H–D exchanged Ru/C–H2–D2O–NaOH system and silyl–Hilbert–Johnson methods. The total deuterium content of the tetradeuterated uridines was over 92% using either basic or acidic reaction conditions. These derivatives would be expected as building blocks for the synthesis of deuterium-substituted nucleic acid probes for tracking the pharmacokinetics of nucleic acid drugs.
- Miyamoto, Noriko,Ohno, Hiroki,Kitamura, Yoshiaki,Park, Kwihwan,Sawama, Yoshinari,Sajiki, Hironao,Kitade, Yukio
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- Methanesulfonic-acid-catalysed ring opening and glycosylation of 1,2-(Acetylcyclopropane)-annulated d -lyxofuranose
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A mild and effective method for the synthesis of 2-C-branched disaccharides, glycoconjugates, and nucleoside analogues is described. 1,2-(acetylcyclopropane)-annulated D-lyxofuranose underwent ring opening catalysed by CH3SO3H to act as an efficient glycosyl donor and give the glycosylation products in good yields and with high diastereoselectivities. Copyright
- Wang, Cong,Ma, Xiaofeng,Zhang, Jichao,Tang, Qin,Jiao, Wei,Shao, Huawu
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- 1-cyclopentyluracils: Synthesis and conformational analysis by X-ray crystallography and AM1 theoretical calculations
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A series of 1-cyclopentyl 5-substituted pyrimidines was synthesized and their energy-minimized structures were determined by AM1 and compared with the crystal structure of the parent compound, 1-cyclopentyluracil (2). As has been reported for other nucleoside analogues, the energy-minimized conformations were similar for all the compounds, but were not fully in agreement with the X-ray crystal structure obtained for 2.
- Teran,Teijeira,Santana,Uriarte,Castineiras
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- One-pot synthesis of antiviral acyclovir and other nucleosides derivatives using doped natural phosphate as Lewis acid catalyst
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Natural phosphate doped with iodine or potassium iodide is an active catalyst for the one-pot synthesis of acyclonucleosides. To demonstrate the utility of the new catalyst system, the highly important antiviral drug acyclovir was directly and regioselectively obtained from NAcG with no byproducts. Copyright Taylor & Francis Group, LLC.
- Lazrek, Hassan B.,Baddi, Laila,Smietana, Michael,Vasseur, Jean-Jacques,Sebti, Said,Zahouily, Mohamed
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- Synthesis and biological evaluation of novel thioapio dideoxynucleosides.
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On the basis of the bioisosteric rationale to apio dideoxynucleosides, novel thioapio dideoxynucleosides have been synthesized, starting from 1,3-dihydroxyacetone via thioapio sugar acetate as a key intermediate. The intermediate was condensed with silylated pyrimidine bases such as N(4)-benzoylcytosine, uracil or thymine in the presence of TMSOTf to give the beta-anomers and alpha-anomers, respectively. The intermediate was also condensed with silylated 6-chloropurine to give the 6-chloropurine derivatives and which were converted to adenine derivatives and, N(6)-methyladenine derivatives and, and hypoxanthine derivatives and, respectively. The guanine analogues and were also synthesized from the condensation of sugar acetate with 2-acetamido-6-chloropurine. All synthesized final compounds were tested against HIV-1. Most of the synthesized compounds exhibited toxicity-dependent anti-HIV-1 activity, among which 6-chloropurine derivative was found to be the most cytotoxic and showed good cytotoxicity against colon cancer cell lines. Although we could not find good anti-HIV agents in this study, findings of some anticancer activity in this series will allow this class of nucleosides to be the new template for the development of new anticancer agents (Fig. 1).
- Moon, Hyung Ryong,Kim, Hea Ok,Lee, Sang Kook,Choi, Won Jun,Chun, Moon Woo,Jeong, Lak Shin
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- A convenient one-pot synthesis of acyclonucleosides
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Bis(trimethylsilyl)pyrimidine bases were treated directly with 1,3-dioxolane (or 2-methyl-1,3-dioxolane), chlorotrimethylsilane and a metal iodide, such as KI or NaI, in acetonitrile at room temperature to afford acyclopyrimidine derivatives, including 2-thiopyrimidine derivatives, in good yields. Introduction of an acyclic chain into 2-thiopyrimidine bases, however, necessitated the use of 2 eq of the reagents.
- Ubasawa,Takashima,Sekiya
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- Synthesis and RT inhibitory activity evaluation of new pyrimidine-based Seco-nucleosides
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Eleven new 3 ′,4 ′- seco acyclic nucleosides (4-14) were prepared by nucleophilic substitution of protected pyrimidine bases on ethyl 3,3-diethoxypropanoate (3). Structures were characterized spectroscopically and a brief analysis of their conformation in solution was performed by the vicinal coupling constants 3 J H 2′ aH 3′ and 3 J H 2′ bH 3′. In solid state, compound 6 forms a homodimer linked by hydrogen bonding. In preliminary tests all compounds show low toxicity and gentle activity against HIV-1 RT in vitro. Copyright Taylor & Francis Group, LLC.
- Vargas, Genaro,Escalona, Iker,Salas, Magali,Gordillo, Barbara,Sierra, Adolfo
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- A convenient method for the synthesis of N-vinyl derivatives of nucleobases
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Trimethylsilyl trifluoromethanesulfonate (TMSOTf) reveals, one more time, its enormous flexibility as Lewis acid catalyst, transforming the well known, but drastic, exchange of the acetyl group of vinyl acetate with pyrimidine and purine derivatives in a very gentle and quick method to obtain a whole set of vinyl nucleobases.
- Dalpozzo, Renato,De Nino, Antonio,Maiuolo, Loredana,Procopio, Antonio,Romeo, Roberto,Sindona, Giovanni
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- Total synthesis of carbocyclic nikkomycin C
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The carbocyclic analogue 11 of nikkomycin C1 is prepared by a sequence involving allylic rearrangement of the imino ester adduct 3, palladium-mediated substitution of the allylic lactone 4c with uracil bis(trimethylsilyl)ether 6, and osmylation of the double bond.
- Ward, Simon E.,Holmes, Andrew B.,McCague, Ray
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- ANALOGS OF PYRIMIDINE NUCLEOSIDES. 17. SYNTHESIS OF 1-URACILS
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The synthesis of 2-fluoromethyltetrahydrofuran is described, and it is shown that chlorination of the latter gives 2-chloro-5- and 2-chloro-2-fluoromethyltetrahydrofurans in a ratio of 5:1. 2,4-Bis(trimethylsilyl) derivatives of uracil were alkylated by means of the mixture of α-chloro ethers without separation, and a mixture of the cis and trans isomers of 1-(5-fluoromethyltetrahydro-2-furyl)uracils and 1-(2-fluoromethyltetrahydro-2-furyl)uracils were obtained.The reaction products were identified on the basis of the PMR spectra.
- Kaulinya, L. T.,Yagupol'skii, L. M.,Kondratenko, N. V.,Vechirko, E. P.,Berzinya, A. E.,et. al.
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- Nucleoside synthesis from 3-alkylated sugars: Role of 3β-oxy substituents in directing nucleoside formation
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Using Vorbrueggen's protocol, reaction of persilylated uracil with xylofuranose derivatives having 3β-oxy-3α-alkyl substitution produced both α- and β-nucleosides. Only the β-nucleosides were formed from substrates having the reverse stereochemistry at C-3 or lacking the 3-alkyl substituent. Participation of the 3β-oxy substituent in stabilizing the incipient C-1 carbonium ion (or oxonium ion) intermediate has been suggested from analysis of energy-minimized conformations. The Royal Society of Chemistry 2006.
- Sahabuddin, Sk.,Ghosh, Ramprasad,Achari, Basudeb,Mandal, Sukhendu B.
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- ANN-QSAR model for selection of anticancer leads from structurally heterogeneous series of compounds
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Developing a model for predicting anticancer activity of any classes of organic compounds based on molecular structure is very important goal for medicinal chemist. Different molecular descriptors can be used to solve this problem. Stochastic molecular descriptors so-called the MARCH-INSIDE approach, shown to be very successful in drug design. Nevertheless, the structural diversity of compounds is so vast that we may need non-linear models such as artificial neural networks (ANN) instead of linear ones. SmartMLP-ANN analysis used to model the anticancer activity of organic compounds has shown high average accuracy of 93.79% (train performance) and predictability of 90.88% (validation performance) for the 8:3-MLP topology with different training and predicting series. This ANN model favourably compares with respect to a previous linear discriminant analysis (LDA) model [H. Gonzalez-Diaz et al., J. Mol. Model 9 (2003) 395] that showed only 80.49% of accuracy and 79.34% of predictability. The present SmartMLP approach employed shorter training times of only 10 h while previous models give accuracies of 70-89% only after 25-46 h of training. In order to illustrate the practical use of the model in bioorganic medicinal chemistry, we report the in silico prediction, and in vitro evaluation of six new synthetic tegafur analogues having IC50 values in a broad range between 37.1 and 138 μg mL-1 for leukemia (L1210/0) and human T-lymphocyte (Molt4/C8, CEM/0) cells. Theoretical predictions coincide very well with experimental results.
- Gonzalez-Diaz, Humberto,Bonet, Isis,Teran, Carmen,De Clercq, Erik,Bello, Rafael,Garcia, Maria M.,Santana, Lourdes,Uriarte, Eugenio
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- Synthesis of 2,3-dideoxy-2-fluoro-2,3-endo-methylene-and 2,3-dideoxy-2-fluoro-3-c-hydroxymethyl-2,3-endo-methylene-pentofuranoses and their use in the preparation of conformationally locked bicyclic nucleosides
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Construction of protected 2,3-dideoxy-2-fluoro-2,3-endo-methylene-pentofuranoses from d-glyceraldehyde and 2,3-dideoxy-2-fluoro-3-C-hydroxymethyl-2,3-endo-methylene-pentofuranoses from d-isoascorbic acid, via Simmons-Smith-type stereoselective cyclopropanations on the respective fluoroallyl alcohols, is described. Synthesis of the corresponding conformationally locked sugar modified uridine and guanosine nucleosides was achieved via Vorbrüggen or Mitsunobu methodologies. Stereochemical confirmation of the novel nucleosides was performed on the basis of 2D NOESY NMR experiments. Analysis of 2',3'-dideoxy-2'-fluoro-3'-C-hydroxymethyl-2',3'-endo-methylene-uridine by X-ray crystallography yielded the principal conformational parameters and indicated that the furanoid ring adopted an oE/oT1, East pucker. The uridine and guanosine nucleosides were found to be inactive in the hepatitis C virus (HCV) cell-based replicon assay, which was corroborated on examination of the corresponding nucleoside triphosphates against the HCV NS5B polymerase.
- Clarkson, Rob,Komsta, Zofia,Mayes, Benjamin A.,Moussa, Adel,Shelbourne, Montserrat,Stewart, Alistair,Tyrrell, Andrew J.,Wallis, Laura L.,Weymouth-Wilson, Alexander C.
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- Stereoselective cyclopropanation in the synthesis of 3'-deoxy-3'-C-hydroxymethyl-2',3'-methylene-uridine
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The synthesis of the novel 2',3'-cyclopropane nucleoside 3'-deoxy-3'-C-hydroxymethyl-2',3'-methylene-uridine is described. Stereoselective construction of the cyclopropane ring was achieved via Simmons-Smith cyclopropanation of a benzyl protected silyl enol ether, which was itself derived from 1,2-O-isopropylidene-α-D-xylofuranose.
- Komsta, Zofia,Mayes, Benjamin A.,Moussa, Adel,Shelbourne, Montserrat,Stewart, Alistair,Tyrrell, Andrew J.,Wallis, Laura L.,Weymouth-Wilson, Alexander C.,Yurek-George, Alexander
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- The silyl method for the synthesis of 1[-2(phenoxy)ethyl]uracils
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A modification of the method for the synthesis of N(1)- substituted derivatives of uracil is proposed using the Gilbert-Johnson reaction, which consists of the alkylation of 5-substituted 2,4- bis(trimethylsiloxy)pyrimidines with 1-bromo-2-(phenoxy)ethanes of low reactivity at 180-185° without solvent. The corresponding 1-[2-(phenoxy)ethyl]uracils, which were obtained in 55-74% yield, contained no impurities of the N(1), N(3)-disubstituted compounds. 2005 Springer Science+Business Media, Inc.
- Novikov,Ozerov
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- Synthesis of 1,2,3-triazolyl nucleoside analogues and their antiviral activity
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Abstract: Based on the fact that a search for influenza antivirals among nucleoside analogues has drawn very little attention of chemists, the present study reports the synthesis of a series of 1,2,3-triazolyl nucleoside analogues in which a pyrimidine fragment is attached to the ribofuranosyl-1,2,3-triazol-4-yl moiety by a polymethylene linker of variable length. Target compounds were prepared by the Cu alkyne-azide cycloaddition (CuAAC) reaction. Derivatives of uracil, 6-methyluracil, 3,6-dimethyluracil, thymine and quinazolin-2,4-dione with ω-alkyne substituent at the N1 (or N5) atom and azido 2,3,5-tri-O-acetyl-D-β-ribofuranoside were used as components of the CuAAC reaction. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. The best values of IC50 (inhibiting concentration) and SI (selectivity index) were demonstrated by the lead compound 4i in which the 1,2,3-triazolylribofuranosyl fragment is attached to the N1 atom of the quinazoline-2,4-dione moiety via a butylene linker (IC50 = 30?μM, SI = 24) and compound 8n in which the 1,2,3-triazolylribofuranosyl fragment is attached directly to the N5 atom of the 6-methyluracil moiety (IC50 = 15?μM, SI = 5). According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 4i and 8n against H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRP). Graphic abstract: [Figure not available: see fulltext.]
- Andreeva, Olga V.,Garifullin, Bulat F.,Zarubaev, Vladimir V.,Slita, Alexander V.,Yesaulkova, Iana L.,Saifina, Liliya F.,Shulaeva, Marina M.,Belenok, Maya G.,Semenov, Vyacheslav E.,Kataev, Vladimir E.
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- SYNTHESIS, ANTITUMORIGENIC ACTIVITY, AND ELECTROCHEMICAL PROPERTIES OF URACIL DERIVATIVES OF THE FURAN SERIES
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1-(Tetrahydrofuryl) derivatives of 5-trimethylgermyl(silyl)uracil and uracil derivatives of 3-(5-nitro-2-furyl)acrylic acid, as well as 1-(γ-triethylgermyl)- and 1-(γ-triethoxysilyl)propylcarbamoyl-5-fluorouracils, were synthesized.Six of the 14 new investigated compounds have high cytotoxic activity in a culture of melanoma B16 cells. 5-Fluorouracil derivatives of 3-(5-nitro-2-furyl)acrylic acid display antitumorigenic activity with respect to lympholeucosis P388 that is comparable to the activity of ftorafur.It was demonstrated by electrochemical studies that the antitumorigenic activity is not determined by the redox properties of the investigated compounds.
- Trushule, M.,Kupche, E.,Augustane, I.,Verovskii, N. V.,Lukevits, E.,et al.
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- Triplet Energy Transfer versus Excited State Cyclization as the Controlling Step in Photosensitized Bipyrimidine Dimerization
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Polymethylene-linked bipyrimidine models have been designed with different C5 substitutions and bridge lengths. Selective irradiation of 2′-methoxyacetophenone (2M) with the bipyrimidine models affords cyclobutane pyrimidine dimers, even in the presence of bulky substituents. Substitution at C5 affects both the relative triplet energies (ET(rel)) of the pyrimidines (Pyr) and the steric hindrance toward intermolecular energy transfer and intramolecular triplet Pyr? quenching. Photophysical studies showed that alkyl substitution resulted in a significant decrease in the ET(rel) value. Quenching of the triplet excited state of 2M by the Pyr derivatives was proven and established their quenching rate constants (kq). As a general trend, the thymine-containing compounds showed kq values higher than 109 M-1 s-1, while in the uracil and tert-butyluracil analogues, kq was markedly lower. These data are explained considering three different scenarios: (a) triplet energy transfer is the rate controlling step, (b) excited state cyclization is the rate controlling step, and (c) the rate controlling step switches along the reaction. Thus, by introducing variations in the substitution at C5, the length of the linking bridge, or the substrate concentration, it is possible to switch from a process governed by the intrinsic dimerization step to an energy transfer-controlled process.
- Alzueta, Ofelia R.,Cuquerella, M. Consuelo,Miranda, Miguel A.
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- Natural phosphate as Lewis acid catalyst: A simple and convenient method for acyclonucleoside synthesis
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A new and efficient method for the synthesis of N-1/N-9-[(2-acetoxyethoxy)methyl]pyrimidine/purine using natural phosphate as Lewis acid catalyst was developed.
- Alahiane,Rochdi,Taourirte,Redwane,Sebti,Lazrek
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- Chitosan–silica sulfate nanohybrid: a highly efficient and green heterogeneous nanocatalyst for the regioselective synthesis of N-alkyl purine, pyrimidine and related N-heterocycles via presilylated method
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Abstract: The presilylation of purine and pyrimidine nucleobases as well as other related N-heterocycles with HMDS utilizing chitosan–silica sulfate nanohybrid (CSSNH) is described. CSSNH is proved to be a useful, highly efficient and eco-friendly heterogeneous nanohybrid catalyst for silylation of nucleobases. The presilylated nucleobases then underwent the reaction with different sources of carbon electrophiles to afford the desired N-alkyl-substituted derivatives in good-to-excellent yields. CSSNH exhibits several advantageous involving ease of handling and preparation, low cost, reusability and environmental benignity. These unique properties render the CSSNH to be an ideal candidate for use in green industrial processes. Graphic abstract: [Figure not available: see fulltext.].
- Behrouz, Somayeh,Soltani Rad, Mohammad Navid,Piltan, Mohammad Amin
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p. 113 - 124
(2019/07/30)
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- Β-selective D-psicofuranosylation of pyrimidine bases and thiols
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N-Glycosidation of D-psicofuranosyl donor 1 with pyrimidine bases took place β-selectively in a β/α-ratio of 8:1 ~ 7:1. For S-glycosidation, 3,4-O-(3-pentylidene)-protected D-psicofuranosyl donor 15 was effective to increase β-selectivity up to 7:1.
- Ueda, Atsushi,Nishimura, Yuri,Makura, Yui,Tanaka, Masakazu,Uenishi, Junichi
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p. 729 - 743
(2019/04/26)
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- COMPOSITIONS AND METHODS FOR TREATING HCV INFECTION
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The present invention features compositions and methods for the treatment of HCV infection. In one embodiment, the compositions of the invention comprise (1) Compound 1 or a pharmaceutically acceptable salt thereof, and (2) Compound 2a or a pharmaceutically acceptable salt thereof. In another embodiment, the compositions of the invention comprise (1) Compound 1 or a pharmaceutically acceptable salt thereof, and (2) a prodrug of Compound 2a (e.g., one of Compounds 2b-2k or Examples 3-1 to 3-10) or a pharmaceutically acceptable salt of said prodrug.
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Paragraph 0057
(2018/06/06)
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- Pyrimidine derivatives of n-acetylguanidine: Novel inhibitors of sodium-hydrogen exchanger 1
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Sodium-hydrogen exchanger (Na+/H+) type 1 (NHE-1) inhibitors have been shown to protect the heart during ischaemia and early reperfusion. As such, NHE-1 inhibitors are of special interest for clinical development for the attenuation of both acute and chronic post-myocardial infarction responses. New pyrimidine derivatives of N-acetylguanidine containing fragments of uracil, thymine, and their 3-benzyl derivatives were synthesised. These compounds showed in vitro inhibitory effects on NHE-1 that were significantly higher than those of zoniporide in platelet swelling assays.
- Ozerov, Alexander,Novikov, Mikhail,Spasov, Alexander,Iezhitsa, Igor,Gurova, Natalia,Gurova, Valeria
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p. 1101 - 1107
(2018/08/28)
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- A deuterium generation of sophie cloth wei and use thereof
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The invention discloses deuterated Sofosbuvir and application thereof. Deuterated Sofosbuvir is a nucleoside phosphoramidate compound shown in the formula I or II, or stereisomer, salt, hydrate, solvate or crystal of the nucleoside phosphoramidate compound. The compound and the composition are used for treating flaviviridae viruses, and particularly used for treating infection of hepatitis c virus (HCV); and the deuterated Sofosbuvir has good HCV resistance.
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Paragraph 0125; 0126; 0128; 0129
(2017/11/23)
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- PSI - 7977 intermediate compound preparation method (by machine translation)
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The invention belongs to the field of medical technology, in particular to a process for the synthesis of PSI - 7977 intermediate compound preparation method. The method has simple operation, mild reaction conditions, easy after treatment, the reaction cycle is short, high yield, the advantages of the safety-controllable, the resulting intermediate compound I with high optical purity, the advantage of stable nature, more suitable for large scale industrial production. (by machine translation)
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Paragraph 0041-0044
(2017/07/01)
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- Bridged ring fluoroester, and preparation method and application thereof
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The invention discloses fire-new bridged ring fluoroester (1R,4R,5R,6R)-6-fluoro-6-methyl-2,7-dioxygen bicyclo [2.2.1] heptyl-5-formic ether (the structural formula is shown as a formula V), a preparation method of the bridged ring fluoroester, and application of the bridged ring fluoroester to synthesis of PSI-6130 by using the compound V for further synthesis of sofosbuvir. The structure is in the specification. The fire-new bridged ring fluoroester has the advantages that the synthesis path is simple and short; the three-dimensional configuration selectivity is excellent and controllable; heavy metal and virulent raw materials are not used in the reaction process; few three wastes are generated; the environment-friendly effect is achieved; the obvious economic benefits are realized; the fire-new bridged ring fluoroester is suitable for industrial mass production.
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Paragraph 0081
(2017/10/13)
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- A general method for N-glycosylation of nucleobases promoted by (p-Tol)2SO/Tf2O with thioglycoside as donor
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Based on a preactivation strategy using the (p-Tol)2SO/Tf2O system, a series of nucleosides were synthesized by coupling various thioglycosides with pyrimidines and purines under mild conditions. High yields and excellent β-stereoselectivities were obtained with either armed or disarmed N-glycosylation donors by tuning the amount of (p-Tol)2SO additive.
- Liu, Guang-Jian,Zhang, Xiao-Tai,Xing, Guo-Wen
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supporting information
p. 12803 - 12806
(2015/08/06)
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- Scaffold hopping: Exploration of acetanilide-containing uracil analogues as potential NNRTIs
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In order to identify novel nonnucleoside inhibitors of HIV-1 reverse transcriptase two series of amide-containing uracil derivatives were designed as hybrids of two scaffolds of previously reported inhibitors. Subsequent biological evaluation confirmed acetamide uracil derivatives 15a-k as selective micromolar NNRTIs with a first generation-like resistance profile. Molecular modeling of the most active compounds 15c and 15i was employed to provide insight on their inhibitory properties and direct future design efforts.
- Babkov, Denis A.,Valuev-Elliston, Vladimir T.,Paramonova, Maria P.,Ozerov, Alexander A.,Ivanov, Alexander V.,Chizhov, Alexander O.,Khandazhinskaya, Anastasia L.,Kochetkov, Sergey N.,Balzarini, Jan,Daelemans, Dirk,Pannecouque, Christophe,Seley-Radtke, Katherine L.,Novikov, Mikhail S.
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p. 1069 - 1081
(2015/03/04)
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- 2'-CHLOROACETYLENYL SUBSTITUTED NUCLEOSIDE DERIVATIVES
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The present invention relates to 2′-chloroacetylenyl-substituted nucleoside derivatives of the general formula (I): As well as pharmaceutical compositions comprising such compounds and methods to treat or prevent an HIV infection, HBV infection, HCV infection or abnormal cellular proliferation, comprising administering said compounds or compositions. In addition, the present invention includes processes for the preparation of such compounds, and the related β-D and β-L-nucleoside derivatives.
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Paragraph 0217
(2013/04/10)
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- N1,N3-disubstituted uracils as nonnucleoside inhibitors of HIV-1 reverse transcriptase
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A series of phenyloxyethyl and cinnamyl derivatives of substituted uracils were synthesized and found to exhibit potent activity against HIV-RT and HIV replication in cell culture. In general, the cinnamyl derivatives proved superior to the phenyloxyethyl derivatives, however 1-[2-(4-methylphenoxy)ethyl] -3-(3,5-dimethylbenzyl)uracil (19) exhibited the highest activity (EC 50 = 0.27 μM) thus confirming that the 3-benzyluracil fragment in the NNRTI structure can be regarded as a functional analogue of the benzophenone pharmacophore typically found in NNRTIs.
- Novikov, Mikhail S.,Valuev-Elliston, Vladimir T.,Babkov, Denis A.,Paramonova, Maria P.,Ivanov, Alexander V.,Gavryushov, Sergey A,Khandazhinskaya, Anastasia L.,Kochetkov, Sergey N.,Pannecouque, Christophe,Andrei, Graciela,Snoeck, Robert,Balzarini, Jan,Seley-Radtke, Katherine L.
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p. 1150 - 1158
(2013/03/29)
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- Synthesis and anti-HCMV activity of 1-[ω-(phenoxy)alkyl]uracil derivatives and analogues thereof
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HCMV infection represents a life-threatening condition for immunocompromised patients and newborn infants and novel anti-HCMV agents are clearly needed. In this regard, a series of 1-[ω-(phenoxy)alkyl]uracil derivatives were synthesized and examined for antiviral properties. Compounds 17, 20, 24 and 28 were found to exhibit highly specific and promising inhibitory activity against HCMV replication in HEL cell cultures with EC50 values within 5.5-12 μM range. Further studies should be undertaken to elucidate the mechanism of action of these compounds and the structure-activity relationship for the linker region.
- Novikov, Mikhail S.,Babkov, Denis A.,Paramonova, Maria P.,Khandazhinskaya, Anastasia L.,Ozerov, Alexander A.,Chizhov, Alexander O.,Andrei, Graciela,Snoeck, Robert,Balzarini, Jan,Seley-Radtke, Katherine L.
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p. 4151 - 4157
(2013/07/27)
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- NOVEL 3′-DEOXY-3′-METHYLIDENE- -L-NUCLEOSIDES
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The present invention includes novel 3′-deoxy-3′-methylidene-β-L-nucleosides, pharmaceutical composition comprising such compounds, as well as the methods to treat or to prevent viral infections and in particular HBV and/or HIV infections. In accordance with the present invention, there are provided compounds represented by Formula (I), wherein B is selected from A1 and A2;
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Page/Page column 50
(2011/07/07)
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- 1-[2-(2-Benzoyl- and 2-benzylphenoxy)ethyluracils as potent anti-HIV-1 agents
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Non-nucleoside reverse transcriptase inhibitors (NNRTI) are key components in highly active antiretroviral therapy for treating HIV-1. Herein we present the synthesis for a series of N1-alkylated uracil derivatives bearing ω-(2-benzyl- and 2-benzoylphenoxy)alkyl substituents as novel NNRTIs. These compounds displayed anti-HIV activity similar to that of nevirapine and several of them exhibited activity against the K103N/Y181C RT mutant HIV-1 strain. Further evaluation revealed that the inhibitors were active against most nevirapine-resistant mono- and di-substituted RTs with the exception of the V106A RT. Thus, the candidate compounds can be regarded as potential lead compounds against the wild-type virus and drug-resistant forms.
- Novikov, Mikhail S.,Ivanova, Olga N.,Ivanov, Alexander V.,Ozerov, Alexander A.,Valuev-Elliston, Vladimir T.,Temburnikar, Kartik,Gurskaya, Galina V.,Kochetkov, Sergey N.,Pannecouque, Christophe,Balzarini, Jan,Seley-Radtke, Katherine L.
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body text
p. 5794 - 5802
(2011/11/04)
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- Computationally-guided optimization of a docking hit to yield catechol diethers as potent anti-HIV agents
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A 5-μM docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use of free energy perturbation (FEP) calculations to predict relative free energies of binding aided the optimizations by identifying optimal substitution patterns for phenyl rings and a linker. The most potent resultant catechol diethers feature terminal uracil and cyanovinylphenyl groups. A halogen bond with Pro95 likely contributes to the extreme potency of compound 42. In addition, several examples are provided illustrating failures of attempted grafting of a substructure from a very active compound onto a seemingly related scaffold to improve its activity. (Figure presented)
- Bollini, Mariela,Domaoal, Robert A.,Thakur, Vinay V.,Gallardo-Macias, Ricardo,Spasov, Krasimir A.,Anderson, Karen S.,Jorgensen, William L.
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supporting information; experimental part
p. 8582 - 8591
(2012/02/02)
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- Synthesis and antiviral evaluation of α-l-2′- deoxythreofuranosyl nucleosides
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The synthesis of a series of α-l-2′-deoxythreofuranosyl nucleosides featuring the nucleobases A, T, C and U is described in seven steps from 1,2-O-isopropyledene-α-l-threose, involving a Vorbru?ggen coupling and a Barton-McCombie deoxygenation protocol as the key steps. All analogues, including a phosphoramidate nucleoside phosphate prodrug of the T analogue, were evaluated against a broad panel of different viruses but found inactive, while also lacking notable cellular toxicity. The thymidine analogue showed inhibition to mitochondrial thymidine kinase-2 (TK-2), herpes simplex virus type 1 (HSV-1) TK, varicella-zoster virus (VZV) TK and Mycobacterium tuberculosis thymidylate kinase.
- Toti, Kiran S.,Derudas, Marco,McGuigan, Christopher,Balzarini, Jan,Van Calenbergh, Serge
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experimental part
p. 3704 - 3713
(2011/11/07)
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- One-flow, multistep synthesis of nucleosides by Bronsted acid-catalyzed glycosylation
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Nucleosides in flow: A general, scalable method of Bronsted acid-catalyzed nucleoside formation is described. Because of the high reaction temperatures readily available to the flow reaction format, mild Bronsted acids, particularly pyridinium triflates, can be used. A one-flow multistep synthesis of unprotected nucleosides is also reported (see scheme).
- Sniady, Adam,Bedore, Matthew W.,Jamison, Timothy F.
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supporting information; body text
p. 2155 - 2158
(2011/04/23)
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- A short stereoselective synthesis of the protected uracil 3′-epi-polyoxin C
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A short synthetic approach to the protected uracil 3′-epi-polyoxin C 20 has been developed. The stereoselective [3,3]-sigmatropic rearrangement of the corresponding 7-thiocyanato-α-d-xylo-hept-5-enfuranose 6 was employed as the key step to construct the C-5 stereocentre in 5-isothiocyanato-α-d- gluco-hept-6-enfuranose 8 and the formal synthesis of uracil 3′-epi-polyoxin C has been accomplished for the first time. This synthesis provides a facile method for multigram scale preparation and thus is useful for the research into the polyoxins' structure-activity relationship and to search for more potent and effective anticandidal agents.
- Gonda, Jozef,Martinkova, Miroslava,Baur, Andrea
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experimental part
p. 207 - 214
(2011/05/02)
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- Electrophilic glycosidation employing 3,5-O-(di-tert-butylsilylene)-erythro-furanoid glycal leads to exclusive formation of the β-anomer: synthesis of 2′-deoxynucleosides and its 1′-branched analogues
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Stereoselectivity in N-iodosuccimide (NIS)-mediated electrophilic glycosidation was examined by employing 2,4-bis-O-(trimethylsilyl)thymine and three different silyl-protected erythro-furanoid glycals 12, 16, and 18. As a result, it was found that 3,5-O-(di-t-butylsilylene)-protected 18 gave only the β-anomer (21). The remarkable stereoselectivity observed by employing 18 is discussed on the basis of its X-ray crystallographic analysis. 1-Substituted glycals gave the corresponding β-anomer, again exclusively, to provide access to 1′-branched 2′-deoxynucleosides.
- Haraguchi, Kazuhiro,Konno, Kiju,Yamada, Kaori,Kitagawa, Yasuyuki,Nakamura, Kazuo T.,Tanaka, Hiromichi
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body text
p. 4587 - 4600
(2010/07/05)
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- 2-C-Methyluridine modified hammerhead ribozyme against the estrogen receptor
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A new synthesis of 2′-C-methyluridine phosphoramidite is presented. Special emphasis is dedicated to the improvement of the protection of the tertiary 2′-hydroxyl group. Comparison to previous protecting strategies and analysis of stability under 5′-DMTr removing conditions are discussed. The synthetic incorporation of this modified nucleoside into the catalytic core of a hammerhead ribozyme against the estrogen receptor α protein (ER-α), and transfection experiments in MCF-7 cell line are also presented.
- Pontiggia, Rodrigo,Pontiggia, Osvaldo,Simian, Marina,Montserrat, Javier M.,Engels, Joachim W.,Iribarren, Adolfo M.
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supporting information; experimental part
p. 2806 - 2808
(2010/08/04)
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- One-pot synthesis of azanucleosides from proline derivatives stereoselectivity in sequential processes
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Common amino acid derivatives can be transformed in onestep fashion into N-azanucleosides. The method is a sequential process initiated, by a domino radical decarboxylation/ oxidation reaction; an acyliminium ion is formed as an intermediate and can be trapped by nitrogen bases (purines, pyrimidines, and benzotriazole). The mildness of the reaction conditions and the good, yields obtained make this procedure an interesting alternative to the conventional processes. Good stereoselectivities were obtained with 4-(silyloxy)proline derivatives as substrates.
- Boto, Alicia,Hernandez, Dacil,Hernandez, Rosendo
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experimental part
p. 3847 - 3857
(2010/09/05)
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- A procedure for facile synthesis of nucleosides using N, O-Bistrimethyl- silylacetamide in the presence of natural phosphate coated with potassium iodide
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Several α-D/L-arabino and β-D/L- xylonucleosides were synthesized in good yields under mild conditions by N-glycosylation of 1-O-acetyl D/L- arabino, and xylofuranose, with silylated nucleobases (uracil, thymine and 6- azauracil) in acetonitrile using natural phosphate (NP) coated with potassium iodide in BSA as catalyst.
- Baddi, Laila,Smietana, Michael,Sebti, Said,Vasseur, Jean-Jacques,Lazrek, Hassan B.
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experimental part
p. 196 - 199
(2011/07/08)
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- Synthesis and anti-HIV activity of 2′-deoxy-2′-fluoro-4′-C-ethynyl nucleoside analogs
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Based on the favorable antiviral profiles of 4′-substituted nucleosides, novel 1-(2′-deoxy-2′-fluoro-4′-C-ethynyl-β-d-arabinofuranosyl)-uracil (1a), -thymine (1b), and -cytosine (2) analogs were synthesized. Compounds 1b and 2 exhibited potent anti-HIV-1 activity with IC50 values of 86 and 1.34 nM, respectively, without significant cytotoxicity. Compound 2 was 35-fold more potent than AZT against wild-type virus, and also retained nanomolar antiviral activity against resistant strains, NL4-3 (K101E) and RTMDR. Thus, 2 merits further development as a novel NRTI drug.
- Wang, Qiang,Li, Yanfeng,Song, Chuanjun,Qian, Keduo,Chen, Chin-Ho,Lee, Kuo-Hsiung,Chang, Junbiao
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supporting information; experimental part
p. 4053 - 4056
(2010/08/19)
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- Synthesis and antitumor activity of novel 2′,3′-diethanethio- 2′,3′,5′-trideoxy-5′-triazolonucleoside analogues
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A series of novel 2′,3′-diethanethio-2′,3′, 5′-trideoxy-5′-triazoloribonucleosides was synthesized in excellent yields and their antitumor activity was evaluated. These nucleoside analogues with aromatic substituted triazole rings showed significantly improved activity towards a broad range of tumor cell lines and those without arene substitutes were inactive.
- Yu, Jin-Lan,Wu, Qin-Pei,Zhang, Qing-Shan,Xi, Xiao-Dong,Liu, Ning-Ning,Li, Yun-Zheng,Liu, Yan-Hong,Yin, Hong-Quan
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supporting information; experimental part
p. 3219 - 3222
(2010/08/20)
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- Silica sulfuric acid (SSA) as a highly efficient heterogeneous catalyst for persilylation of purine and pyrimidine nucleobases and other N-heterocycles using HMDS
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Purine and pyrimidine nucleobases and other N-heterocycles have been silylated with HMDS in excellent yields in the presence of a catalytic amount of silica sulfuric acid (SSA) as a heterogeneous catalyst. SSA utilizes a shorter reaction time and higher yields of silylated nucleobases. SSA is reusable for several times without a decrease in reactivity or yield of silylated adducts. Copyright
- Rad, Mohammad Navid Soltani,Khalafi-Nezhad, Ali,Divar, Masoumeh,Behrouz, Somayeh
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experimental part
p. 1943 - 1954
(2010/11/16)
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- Synthesis and antitumor activity of 5′-deoxy-4′-thio-l- nucleosides
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A series of novel 5′-deoxy-4′-thio-l-nucleosides was designed and synthesized. The absolute configuration of the target compound 23α was confirmed by X-ray crystallography. The antitumor activities of the target compounds were tested against the growth of human carcinoma of colon (LOVO), human leukemia cell line (CEM) and human breast cancer cell line (MDA-MB-435) cells in vitro. 6-cyclopentylamino and 6-cyclohexylamino purine compounds 26 and 27, both in α-configuration and in β-form, exhibited strong inhibition to CEM.
- Cong, Liqing,Zhou, Weicheng,Jin, Dongzhe,Wang, Juan,Chen, Xiuhua
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experimental part
p. 619 - 627
(2011/04/22)
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- Synthesis of a carbohydrate-derived 1-oxaspiro[4.4]nonane skeleton and its conversion into spironucleosides
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An easy entry to the 1-oxaspiro[4.4]nonane skeleton has been developed starting from a d-glucose-derived substrate. The key steps involve (a) installation of olefin moieties at the appropriate places through simple transformations and (b) construction of spiro rings by utilizing ring-closing metathesis reactions between these olefin functionalities. Subsequent deprotection of the acetonide functionality, peracetylation, nucleosidaton under Vorbrggen reaction conditions, and final deprotections result in the formation of the spironucleosides. The involvement of an interesting intra/intermolecular acetyl migration has been used to rationalize the product distribution during desilylation. Various 1D and 2D NMR techniques and X-ray analyses of some important intermediates were used for assigning the structures and stereochemistry of the products. Georg Thieme Verlag Stuttgart New York.
- Maity, Joy Krishna,Achari, Basudeb,Drew, Michael G. B.,Mandal, Sukhendu B.
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experimental part
p. 2533 - 2542
(2010/09/08)
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- Additive pummerer reaction of 3,5-O-(Di-tert-butyl)silylene-4-thiofuranoid glycal: A high-yield and β-selective entry to 4-thioribonucleosides
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Upon reacting 3,5-O-(di-tert-butyl)silylene-4-thiofuranoid glycal S-oxide (6) with Ac2O/TMSOAc/BF3·OEt2 in CH 2Cl2, the additive Pummerer reaction proceeded to furnish the corresponding 1,2-di-O-acetyl-4-thioribofuranose 7. Compound 7 serves as a highly β-selective glycosyl donor in the Vorbrueggen condensation carried out in the presence of TMSOTf. Thus, the 4-thio-β-D-ribofuranosyl derivatives of uracil, thymine, N4-acetylcytosine, 6-chloropurine, and 2-amino-6-chloropurine were synthesized. The use of 7 can be extended to the β-selectivesynthesis of 4-thio-C-ribonucleosides.
- Haraguchi, Kazuhiro,Matsui, Hiromitsu,Takami, Shin,Tanaka, Hiromichi
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supporting information; experimental part
p. 2616 - 2619
(2009/07/25)
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- Synthesis of a novel, optically active uridine analog containing a 1,4-dioxane sugar moiety. Synthesis of the corresponding dinucleotide
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A new optically active uridine nucleoside analogue in which a substituted 1,4-dioxane ring functioned as the sugar analogue was prepared from L-tartaric acid. The nucleoside analogue was further converted into the corresponding protected dinucleotide.
- Yu, Qiang,Carlsen, Per
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experimental part
p. 220 - 237
(2009/12/24)
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- Synthesis and antiviral evaluation of 4'-C-azidomethyl -β-D- ribofuranosyl purine and pyrimidine nucleosides
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In the search for inhibitors of the replication of RNA viruses, including hepatitis C virus (HCV), the hitherto unknown 4'-C-azidomethyl - D-ribofuranosyl nucleosides of the five naturally occurring nucleic acid bases have been synthesized and their antiviral properties examined. These 4'-C-branched nucleosides were stereospecifically prepared by glycosylation of purine and pyrimidine aglycons with a suitable peracylated 4-C-azidomethyl-D-pentofuranose sugar, followed by removal of the protecting groups. The prepared compounds were tested for their activity against several viruses, but they did not show an antiviral effect.
- Griffon, Jean-Francois,Dumas, Audrey,Storer, Richard,Sommadossi, Jean-Pierre,Gosselin, Gilles
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experimental part
p. 435 - 449
(2010/07/14)
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- Synthesis and molecular modelling of unsaturated exomethylene pyranonucleoside analogues with antitumor and antiviral activities
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This report describes the total and facile synthesis of the unsaturated keto and exomethylene pyranonucleoside analogues, 1-(2,3,4-trideoxy-4-methylene-6-O-trityl-α-d-glycero-hex-2-enopyranosyl)uracil (10), 1-(2,3-dideoxy-α-d-glycero-hex-2-enopyranosyl-4-ulose)uracil (17) and 1-(2,3,4-trideoxy-4-methylene-α-d-glycero-hex-2-enopyranosyl)uracil (18). Commercially available 1,2,3,4,6-penta-O-acetyl-α-d-mannopyranose (1) was condensed with silylated uracil, deacetylated and acetalated to afford 1-(2,3-O-isopropylidene-α-d-mannopyranosyl)uracil (4). Two different synthetic routes were investigated for the conversion of 4 into the olefinic derivative 1-(2,3,4-trideoxy-4-methylene-6-O-trityl-α-d-glycero-hex-2-enopyranosyl)uracil (10). Although the two procedures are quite similar with respect to yields and final products, the second also leads to the keto-2′,3′-unsaturated analogue (17). The new analogues were evaluated for their anticancer and antiviral activities using several tumor cell lines and gastrointestinal rotavirus. All of the compounds showed direct antiviral effect against rotavirus infectivity in Caco-2 cell line. Moreover, 1-(2,3,4-trideoxy-4-methylene-6-O-trityl-α-d-glycero-hex-2-enopyranosyl)uracil (10) was found to be potent in MCF-7 breast carcinoma cell line.
- Agelis, George,Tzioumaki, Niki,Tselios, Theodore,Botic, Tanja,Cencic, Avrelija,Komiotis, Dimitri
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p. 1366 - 1375
(2008/09/21)
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- Studies directed toward the development of amide-linked RNA mimics: Synthesis of the monomeric building blocks
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(Chemical Equation Presented) A general approach toward the synthesis of all four monomeric building blocks of the ribonucleoside amino acids 3′-amino-5′-carboxymethyl-3′,5′-dideoxy nucleosides in their protected forms is described that will facilitate the development of amide-linked RNA mimics.
- Chakraborty, Tushar Kanti,Gajula, Praveen Kumar,Koley, Dipankar
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p. 6916 - 6919
(2008/12/22)
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