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Optimized synthesis of 3′-O-aminothymidine and evaluation of its oxime derivative as an anti-HIV agent

  • Pavel N. Solyev EMAIL logo , Maxim V. Jasko , Tatiana A. Martynova , Ludmila B. Kalnina , Dmitry N. Nosik and Marina K. Kukhanova
Published/Copyright: September 12, 2015
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 21 Issue 5

Abstract

The synthesis and isolation of 3′-O-aminothymidine oximes have been optimized. Synthesized compounds were characterized by NMR and UV spectral and analytical data. A mixture of previously not reported syn and anti isomers of acetaldoximes was assessed for anti-HIV activity and the prevention of syncytia formation caused by HIV-1 infection.

Keywords: anti-HIV properties; Mitsunobu reaction; nucleoside analogues; oxime derivatives; syncytium formation

Introduction

3′-Modified nucleosides are used as inhibitors of HIV replication, and some of them have become efficient drugs. 3′-O-Aminothymidine is a nucleoside analogue of special interest as a cleavable primer extension terminator [1] and as a substrate for synthesis of antisense oligonucleotides [2, 3]. The reversible termination of oligonucleotides by 3′-O-aminothymidine takes place due to the -ONH2 fragment capable of deamination with sodium nitrite. This ability may be potentially extended to the termination of DNA synthesis catalyzed by reverse transcriptase if a suitable oxime protection is applied for the 3′-blockage, as in typical nucleoside analogue inhibitors. Our attention was focused on previously non-reported oxime derivatives of 3′-O-aminothymidine [4]. The goal of this study was the optimization of 3′-O-aminothymidine synthesis as well as evaluation of anti-HIV properties of its acetaldoximes.

Results and discussion

Synthesis

Synthesis of 3′-O-aminothymidine (TONH2) is usually conducted via the Mitsunobu reaction of xylothymidine with N-hydroxyphthalimide followed by the deblocking of the phthalimide moiety. Xylothymidine can be obtained either by 3′-keto-derivative reduction (non-selective for the resulting configuration) [3] or by the Mitsunobu procedure with reversible benzoic acid 3′-protection [1], but most frequently and successfully, xylothymidine is synthesized via 2,3′-anhydronucleoside formation [5]. Modifications usually take place after the introduction of the 5′-protecting group, but there is also a simplified ‘one-pot’ procedure [6] that was used here (Scheme 1). Thymidine was protected with trityl on the 5′-OH group and activated by mesylation at 3′-OH; at this point, the solvent was evaporated, and pure intermediate 5′-O-trityl-3′-O-mesylthymidine was crystallized from hexanes. Further treatment with aqueous KOH results in formation of a 2,3′-anhydrothymidine structure, and the use of excess of alkali causes ring opening into 5′-O-tritylxylothymidine 1. After chromatographic purification of 1 on silica gel, we performed the Mitsunobu procedure under typical conditions, which proceeded smoothly. It was found that cooling the reaction mixture is required only at the moment the reagents are mixed, and an increase in temperature until 80°C does not affect the reaction. At 80°C, the elimination becomes a competitive reaction and formation of a small amount of 5′-O-trityl-2′,3′-dideoxy-2′,3′-didehydrothymidine can be observed.

Scheme 1 Synthesis of target 3′-O-aminothymidine syn/anti-acetaldoximes 4.
Scheme 1

Synthesis of target 3′-O-aminothymidine syn/anti-acetaldoximes 4.

The target Mitsunobu product 2 poses some difficulties in purification on a silica gel column using the previously described procedures [1–3]. Nevertheless, the earlier proposed eluting system, hexane/dichloromethane/ethyl acetate in a 3:2:2 ratio, may be used for convenient TLC detection [3]. We developed two-step column chromatography purification instead. In the first step, silica gel column chromatography in chloroform/ethanol system (linear gradient of ethanol 0→5%) permitted separation of the target product contaminated with PPh3O. In the second step, re-purification using a fresh silica gel column in chloroform/hexane/ethanol system in a 7:3:1.5 ratio was conducted. This procedure allowed the isolation of pure 5′-O-trityl-3′-O-phthalimidothymidine. Removal of the phthalimidyl fragment of 2 was performed using excess hydrazine hydrate. The crude reaction mixture was then treated with acetaldehyde. Acetaldoxime structure 3 was the target product because it is more stable than formaldoxime and potentially less sterically hindered than acetoxime, hence more likely to be a substrate for enzymes. The trityl group was removed from the intermediate product 3 by treatment with acetic acid without any cleavage of the oxime bond. Both trityl-protected 3 and deprotected product 4 are mixtures of syn and anti isomers that could not be separated. Antiviral assays were carried out on a mixture of deprotected product 4 containing syn and anti isomers in a 1:1 ratio.

Antiviral activity and toxicity

Antiviral activity was determined in MT-4 cells infected with HIV-1 (899A strain) at the multiplicity of infection 0.2–0.5 units/cell according to the previously published procedure [7]. Antiviral activity and toxicity were determined in the presence of the tested compounds (0.01–300 μm, three replicates for each dose) and were assessed in 4 days. The cell concentration and viability were measured by the trypan blue dye exclusion calorimetric assay, and the EC50 and CC50 values were calculated. 3′-Azido-3′-deoxythymidine (AZT or zidovudine, Retrovir® from ViiV Healthcare) was used as a control. Cytotoxicity was assessed in MT-4 cells, cultured in the presence of various doses of the compounds (0.01–1000 μm) for 4 days. The data in Table 1 show that the oxime product 4 possesses moderate activity against HIV-1.

Table 1

Antiviral activity and cytotoxicity syn+anti acetaldoximes of 3′-O-aminothymidine.

CompoundCC50a (μm)EC50b (μm)
415042
AZT>1000.04

aCompound concentration required to reduce cell viability by 50%.

bCompound concentration required to inhibit HIV replication by 50%.

Syncytia formation

Infection of cell culture with HIV-1 results in the formation of multinucleated giant cells or syncytia. The ability to form syncytia may be a major contribution to the virulence of HIV and may play a role in the disease progression [8, 9]. It has been shown that exposure to AZT has a significant impact on syncytium formation and cell killing in an in vitro assay [10]. We compared the effects of AZT and compound 4 on syncytium development in lymphoblastoid cell culture MT-4 (Figure 1) according to the described procedure [10]. Figure 1B shows cells 3 days after infection with HIV-1, and Figure 1A shows uninfected control cells. One can see that the presence of AZT (Figure 1C) or compound 4 (Figure 1D) in the assays results in a significant reduction in syncytia size. The action of both compounds is similar, although the effective concentration of 4 was 1–1.5 orders of magnitude higher. The effects were time (1–5 days) and dose dependent for AZT (0.01–1 μm) and for 4 (1–150 μm) (data not shown). These data correlate with anti-HIV activity of AZT and compound 4.

Figure 1 Effects of compound 4 and AZT on syncytia formation (in 3 days after infection). (A) Control uninfected cells; (B) MT-4 cell culture after HIV-1 infection; (C) infected cell culture growing in the presence of 0.1 μm AZT; (D) infected cell culture growing in the presence of 10 μm4.
Figure 1

Effects of compound 4 and AZT on syncytia formation (in 3 days after infection). (A) Control uninfected cells; (B) MT-4 cell culture after HIV-1 infection; (C) infected cell culture growing in the presence of 0.1 μm AZT; (D) infected cell culture growing in the presence of 10 μm4.

Conclusion

An optimized procedure for 3′-O-aminothymidine oximes synthesis and isolation of the intermediate products was developed. The synthesized syn-/anti-oximes possess anti-HIV activity and prevent cells from syncytia formation caused by HIV-1 infection.

Experimental

Diethyl azodicarboxylate (Fluka), methanesulfonyl chloride (Acros), trityl chloride (Acros), hydrazine hydrate (Fluka), and thymidine (Fluka) were purchased from the indicated suppliers. THF was distilled over sodium before use. The reaction process was monitored using TLC on precoated Kieselgel 60F254 plates (Merck, Germany), and column chromatography was performed on silica gel (40–63 μm; Merck, Germany). 1H and 13C NMR spectra were registered in DMSO-d6 on a Bruker AMX III 400 spectrometer with the working frequency of 400 MHz for 1H NMR (Me4Si as an internal standard) and 100.6 MHz for 13C NMR (with carbon-proton decoupling, Me4Si as an internal standard). UV spectra were registered on a Shimadzu UV-2401PC spectrophotometer in CH3OH in the range of 220–300 nm. High-resolution mass spectra (HR-ESI-MS) were acquired in a positive ion mode on a Bruker maXis™ instrument; syringe injection was used for solutions in acetonitrile (flow rate 3 μL/min), nitrogen was applied as an inert gas, interface temperature was set at 180°C.

Synthesis of 5′-O-trityl-xylothymidine (1)

The procedure was carried out with chromatographic purification of only small samples of the intermediate products for characterization. A solution of thymidine (5 g, 0.02 mol) in pyridine (30 mL) was stirred at room temperature and treated with trityl chloride (7.4 g, 0.024 mol). The mixture was stirred at 40°C for 16 h, then cooled, and the resulting intermediate product, 5′-O-tritylthymidine,1 was treated with mesyl chloride (3.2 mL, 0.045 mol). The mixture was stirred for 8 h, then quenched with 5 mL of distilled water, concentrated, and extracted with chloroform and aqueous solution of NaHCO3. The organic layer was dried with Na2SO4, concentrated, and the residue was crystallized at 0°C from a mixture of hexanes-chloroform. Crystals of pure 5′-O-trityl-3′-O-mesylthymidine2 were separated and dissolved in dioxane, and the residual solvent was evaporated in vacuo. To a solution of 5′-O-trityl-3′-O-mesylthymidine in dioxane, a 1-m KOH aqueous solution (30 mL) was added in three portions, which resulted in a change of the color of the mixture from yellow to red, referring to the 5′-O-trityl-2,3′-anhydrothymidine3 structure formation. The color turned back to yellow in 12 h, after which time the mixture was neutralized with aqueous acetic acid. The reaction mixture was concentrated and purified on a silica gel column eluting with ethanol (0→12%)/chloroform system. Target fractions were concentrated to give 8.98 g (82.5%) of pure compound 1 as a white powder; mp 231–232°C; UV: λmax 266.3 nm; 1H NMR: δ 11.24 (s, 1H, 3-NH), 7.61 (q, 1H, 4J6, 5-Me = 1.0 Hz, H-6) 7.22–7.38 (m, 15H, Tr), 6.12 (dd, 1H, 3J1′, 2′a = 8.2 Hz, 3J1′, 2′b = 2.2 Hz, H-1′), 5.19 (d, 1H, 3J3′-OH, 3′ = 3.4 Hz, 3′-OH), 4.21 (m, 1H, H-3′), 4.09 (m, 1H, H-4′), 3.38–3.43 (dd, 1H, 2J5′a, 5′b = 10.3 Hz, 3J5′a, 4′ = 8.0 Hz, H-5′a), 3.20–3.24 (dd, 1H 2J5′a, 5′b = 10.3 Hz, 3J5′b, 4′ = 2.9 Hz, H-5′b), 2.50–2.58 (m, 1H, H-2′a), 1.84–1.88 (dd, 1H, 2J2′a, 2′b = 14.6 Hz, 3J2′b, 1′ = 2.2 Hz, H-2′b), 1.65 (d, 3H, 4J5-Me, 6 = 1.0 Hz, 5-Me); 13C NMR: δ 163.7 (C-4), 150.4 (C-2), 143.6 (i-C [Tr]), 136.7 (C-6), 128.3 (m-C [Tr]), 127.8 (o-C [Tr]), 126.9 (p-C [Tr]), 108.3 (C-5), 86.1 (C [Tr]), 84.1 (s, C-4′), 83.2 (C-1′), 68.9 (C-3′), 63.0 (C-5′), 40.7 (C-2′), 12.4 (5-Me).

Synthesis of 5′-O-trityl-3′-phthalimidyloxythymidine (2)

A solution of 5′-O-trityl-xylothymidine (0.5 g, 1.04 mmol) in THF (15 mL) was cooled to 0°C and treated with N-hydroxyphthalimide (0.5 g, 1.56 mmol), triphenylphosphine (0.411 g, 1.23 mmol), and diisopropyl azodicarboxylate (0.244 mL, 1.23 mmol). After 6 h, the reaction mixture was concentrated in vacuo and partitioned between chloroform and water. Organic layer was dried with Na2SO4 and then concentrated. Chromatographic purification was performed in two steps using silica gel: first, eluting with chloroform/ethanol (95:5) to separate a mixture of the target product and triphenylphosphine oxide from other by-products, and second, using a new column and eluting with chloroform/hexane/ethyl acetate (7:3:1.5). Target fractions were concentrated in vacuo, resulting in 0.43 g (43.4%) of pure compound 2 as white powder; mp 109–110°C; UV: λmax 270.9 nm; 1H NMR: δ 11.36 (s, 1H, 3-NH), 7.88 (m, 4H, Phth), 7.48 (q, 1H, 4J6, 5-Me = 1.0 Hz, H-6) 7.23–7.35 (m, 15H, Tr), 6.34 (dd, 1H, 3J1′, 2′b = 6.0 Hz, 3J1′, 2′a = 6.1 Hz, H-1′), 5.15 (m, 1H, H-3′), 4.31 (m, 1H, H-4′), 3.30–3.34 (dd, 1H, 2J5′a, 5′b = 10.7 Hz, 3J5′a, 4′ = 4.2 Hz, H-5′a), 3.24–3.28 (dd, 1H, 2J5′a, 5′b = 10.7 Hz, 3J5′b, 4′ = 4.3 Hz, H-5′b), 2.13–2.28 (m, 2H, H-2′), 1.46 (d, 3H, 4J5-Me, 6 = 1.0 Hz, 5-Me); 13C NMR: δ 163.4 (C-4), 163.4 (CO [Phth]), 150.2 (C-2), 143.1 (i-C [Tr]), 135.3 (C-6), 134. 7 (4+5 [Phth]), 128.4 (1+2 [Phth]), 128.1 (m-C [Tr]), 127.8 (s, o-C [Tr]), 127.1 (p-C [Tr]), 123.3 (3+6 [Phth]), 109.8 (C-5), 87.5 (C [Tr]), 86.6 (C-4′), 83.6 (C-1′), 81.1 (C-3′), 63.6 (C-5′), 35.6 (C-2′), 11.6 (5-Me).

Synthesis of 5′-O-trityl-3′-O-aminothymidine syn/anti-acetaldoximes (3)

A solution of 5′-O-trityl-3′-phthalimidyloxythymidine (56 mg, 0.088 mmol) in dichloromethane (2 mL) was cooled to 0°C and treated dropwise with a solution of hydrazine hydrate (0.03 mL) in dichloromethane (5 mL). The reaction mixture became cloudy as the phthalic hydrazide formed and precipitated. After 2 h, the solvent was evaporated, and the residue was treated with dichloromethane (5 mL) and acetaldehyde (0.04 mL). After stirring for 16 h, the mixture was filtered and the solution was applied to a silica gel column and eluted with ethanol (0→7%)/chloroform system. Target fractions were concentrated in vacuo to give 0.033 g (71.4%) of a mixture of syn/anti isomers of 3 as a white powder; UV: λmax 265.2 nm; 1H NMR: δ 11.34 (2s, 2H, 3-NH), 7.56 and 7.54 (2q, 2×1H, 4J6, 5-Me = 1.0 Hz, H-6), 7.49 (q, 1H, 3JCH, Me = 5.8 Hz, CH [anti]), 7.26–7.41 (m, 30H, 2Tr), 6.95 (q, 1H, 3JCH, Me = 5.5 Hz, CH [syn]), 6.17–6.23 (m, 2H, 2H-1′), 4.79–4.86 (m, 2H, 2H-3′), 4.08–4.14 (m, 2H, 2H-4′), 3.24–3.34 (m, 4H, 2H-5′), 2.37–2.43 (m, 4H, 2H-2′), 1.77 (d, 3H, 3JMe, CH = 5.5 Hz, Me [syn]), 1.76 (d, 3H, 3JMe, CH = 5.8 Hz, Me [anti]), 1.46 (br.s, 6H, 5-Me); 13C NMR: δ 163.5 (C-4), 150.3 (C-2), 149.1 and 148.8 (2s, 2CH), 143.3 (i-C [Tr]), 135.5 (C-6), 128.2 (m-C [Tr]), 127.94 (o-C [Tr]), 127.2 (p-C [Tr]), 109.8 (C-5), 86.5 (C [Tr]), 83.9 and 83.8 (2s, C-4′), 82.4 and 82.2 (2s, C-1′), 82.0 and 81.6 (2s, C-3′), 64.2 and 64.1 (2s, C-5′), 36.3 and 36.0 (2s, C-2′), 14.9 (Me [anti]), 11.8 (Me [syn]), 11.6 (5-Me). HRMS (ESI). Calcd for C31H31N3O5 [M+H]+, [M+Na]+): m/z 526.2336 and 548.2156. Found: m/z 526.2332 and 548.2156.

Synthesis of 3′-O-aminothymidine syn/anti-acetaldoximes (4)

A solution of 5′-O-trityl-3′-O-aminothymidine syn/anti-acetaldoximes (0.033 g, 0.063 mmol) in 80% aqueous acetic acid (3 mL) was allowed to stand at 37°C for 16 h, then concentrated in vacuo. The residue was dissolved in toluene and the solution was concentrated to azeotropically remove water. The crude product 4 was purified on a silica gel column eluting with ethanol (0→20%)/chloroform system. Concentration of the target fractions gave 0.015 g (81.2%) of a mixture of syn/anti-isomers of 4 as white powder; UV: λmax 265.2 nm; 1H NMR: δ 11.28 (2s, 2H, 3-NH), 7.74 (q, 1H, 4J6, 5-Me = 1.0 Hz, H-6 [anti]), 7.73 (q, 1H, 4J6, 5-Me = 1.0 Hz, H-6 [syn]), 7.52 (q, 1H, 3JCH, Me = 5.8 Hz, CH [anti]), 6.97 (q, 1H, 3JCH, Me = 5.5 Hz, CH [syn]), 6.12–6.18 (m, 2H, 2H-1′), 5.13 (m, 2H, 2OH), 4.76 (m, 1H, H-3′ [syn]), 4.70 (m, 1H, H-3′ [anti]), 4.04 (m, 1H, H-4′ (syn]), 4.01 (m, 1H, H-4′ [anti]), 3.57–3.68 (m, 4H, H-5′), 2.16–2.33 (m, 2×2H, 2×H-2′), 1.80 (2d, 6H, 3JMe, CH = 5.5 Hz, 3JMe, CH = 5.8 Hz, 2Me), 1.78 (d, 3H, 4J5-Me, 6 = 1.0 Hz, 5-Me); 13C NMR: δ 163.6 (C-4), 150.4 (C-2), 148.9 (CH [anti]), 148.6 (CH [syn]), 135.9 (C-6), 109.6 (C-5 [syn]), 109.5 (C-5 [anti]), 84.1 (C-4′ [syn]), 83.9 (bs, C-4′ [anti]+C-1′ [syn]), 83.8 (C-1′ [anti]), 82.5 (C-3′ [syn]), 82.1 (C-3′ [anti]), 61.7 (C-5′ [syn]), 61.7 (C-5′ [anti]), 36.3 (C-2′ [syn]), 36.1 (C-2′ [anti]), 15.0 (Me [anti]), 12.2 (5-Me), 11.8 (Me [syn]). HRMS (ESI). Calcd for C12H17N3O5 [M+H]+ and [M+Na]+): m/z 284.1241 and 306.1060. Found: m/z 284.1241 and 306.1055.

Dedicated to the memory of the late Professor Kyoichi A. Watanabe, a great medicinal chemist and our best friend.

Corresponding author: Pavel N. Solyev, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia, e-mail:

Acknowledgments

This work was supported by the Russian Foundation for Basic Research (grants 13-04-40307-H and 14-04-31163-mol_a).

References

[1] Chen, F.; Gaucher, E. A.; Leal, N. A.; Hutter, D.; Havemann, S. A.; Govindarajan, S.; Ortlund, E. A.; Benner, S. A. Reconstructed evolutionary adaptive paths give polymerases accepting reversible terminators for sequencing and SNP detection. Proc. Natl. Acad. Sci. USA2010, 107, 1948–1953.10.1073/pnas.0908463107Search in Google Scholar

[2] Burgess, K.; Gibbs, R.; Metzker, M.; Raghavachari, R. Synthesis of an oxyamide linked nucleotide dimer and incorporation into antisense oligonucleotide sequences. J. Chem. Soc. 1994, 915–916.10.1039/c39940000915Search in Google Scholar

[3] Yang, T.; Chien, F.; Chung, F. Synthesis of thymidine dimer containing novel (N-acetyl)imino linkage. J. Chin. Chem. Soc.2001, 48, 949–952.10.1002/jccs.200100139Search in Google Scholar

[4] De Clercq, E.; Inoue, I.; Kondo, K. EP Patent 0381335A1. Date of publication of application: August 8, 1990.Search in Google Scholar

[5] Horwitz, J. P.; Chua, J.; Da Rooge, M. A.; Noel, M.; Klundt, I. L. Nucleosides. III. 1-(2′-Deoxy-3′,5′-epoxy-β-d-threo-pentofuranosyl) thymine. J. Am. Chem. Soc. 1963, 28, 942–944.10.1021/jo01039a015Search in Google Scholar

[6] Jung, M. E.; Toyota, A. Preparation of 4′-substituted thymidines by substitution of the thymidine 5′-esters. J. Org. Chem. 2001, 66, 2624–2635.10.1021/jo001223aSearch in Google Scholar

[7] Solyev, P. N.; Shipitsin, A. V.; Karpenko, I. L.; Nosik, D. N.; Kalnina, L. B.; Kochetkov, S. N.; Kukhanova, M. K.; Jasko, M. V. Synthesis and anti-HIV properties of new carbamate prodrugs of AZT. Chem. Biol. Drug. Des. 2012, 80, 947–952.10.1111/cbdd.12047Search in Google Scholar

[8] Taleno, M.; Levy, J. A. MT-4 plaque formation can distinguish cytopathic subtypes of the human immunodeficiency virus (HIV). Virology1988, 167, 299–301.10.1016/0042-6822(88)90084-0Search in Google Scholar

[9] Tersmette, M.; De Goede, R. E. Y.; Al, B. J. M.; Winkel, I. N.; Gruters, R. A.; Cuypers, H. T.; Huisman, H. G.; Miedema, F. Differential syncytium-inducing capacity of human immunodeficiency virus isolates: frequent detection of syncytium-inducing isolates in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. J. Virol. 1988, 62, 2026–2032.10.1128/jvi.62.6.2026-2032.1988Search in Google Scholar

[10] Buckheit, R. W., Jr.; Germany-Decker, J.; Qualls-Goodwin, K.; Bowdon, B. J.; Shannon, W. M. 3′-Azido-3′-deoxythymidine-induced reduction in the ability of uninfected CD4-expressing cells to participate in syncytium formation. Proc. Natl. Acad. Sci. USA1992, 89, 8361–8365.10.1073/pnas.89.17.8361Search in Google Scholar

Supplemental Material:

The online version of this article (DOI: 10.1515/hc-2015-0150) offers supplementary material, available to authorized users.

Received: 2015-7-20
Accepted: 2015-8-14
Published Online: 2015-9-12
Published in Print: 2015-10-1

©2015 by De Gruyter

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  2. Guest Editorial
  3. Dedication to Kyoichi A. Watanabe
  4. Review
  5. From ribavirin to NAD analogues and back to ribavirin in search for anticancer agents
  6. Preliminary Communications
  7. 5′-Norcarbocyclic analogues of furano[2,3-d]pyrimidine nucleosides
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https://doi.org/10.1515/hc-2015-0150
Keywords for this article
anti-HIV properties; Mitsunobu reaction; nucleoside analogues; oxime derivatives; syncytium formation
Creative Commons
BY-NC-ND 3.0

Articles in the same Issue

  1. Frontmatter
  2. Guest Editorial
  3. Dedication to Kyoichi A. Watanabe
  4. Review
  5. From ribavirin to NAD analogues and back to ribavirin in search for anticancer agents
  6. Preliminary Communications
  7. 5′-Norcarbocyclic analogues of furano[2,3-d]pyrimidine nucleosides
  8. Fluorescent 1,2,3-triazole derivative of 3′-deoxy-3-azidothymidine: synthesis and absorption/emission spectra
  9. Research Articles
  10. Synthesis and characterization of N-glucosylated dithiadiazepine derivatives through carbon-sulfur bond formation
  11. Synthesis of 8-alkoxy-1,3-dimethyl-2, 6-dioxopurin-7-yl-substituted acetohydrazides and butanehydrazides as analgesic and anti-inflammatory agents
  12. 13C NMR spectroscopy of heterocycles: 3,5-diaryl-4-bromoisoxazoles
  13. Synthesis and anti-proliferative activity of pyridine O-galactosides and 4-fluorobenzoyl analogues
  14. Optimized synthesis of 3′-O-aminothymidine and evaluation of its oxime derivative as an anti-HIV agent
  15. Synthesis and antimicrobial properties of 5,5′-modified 2′,5′-dideoxyuridines
  16. Acyclic analogs of nucleosides based on tris(hydroxymethyl)phosphine oxide: synthesis and incorporation into short DNA oligomers
  17. Synthesis and antiviral evaluation of 2′,3′-dideoxy-2′,3′-difluoro-D-arabinofuranosyl 2,6-disubstituted purine nucleosides
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