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Novel syntheses of 4'-modified cyclopentenyl pyrimidine C-nucleosides were performed via C-C bond formation using S(N)2 alkylation via the key intermediate mesylates 6 and 16, which were prepared from acyclic ketone derivatives. When antiviral evaluation of synthesized compound was performed against various viruses such as HIV-1, HSV-1 and HSV-2, isocytidine analogue 20 showed moderate anti-HIV activity in CEM cell line (EC(50) = 13.1 micromol).

The synthesis and antiviral evaluation of new 3′-O-phosphonoethyl modified phosphonate nucleosides related to PMDTA and PMDTT is described. The reaction scheme starts from protected L-threose and the phosphonate group is introduced by the Arbuzov reaction. The 2′-OH as well as the 2′-deoxygenated nucleosides have been obtained. Unfortunately, none of these synthesized compounds shows activity against HIV and HCV.

A new series of acyclic C-nucleosides 1′,2′-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4] triazolo[3,4-b][1,3,4]thiadiazoles bearing arylsulfonamide (5–8) and arylcarboxamide (9–12) residues have been synthesized under microwave irradiation. Thiadiazines 13–15 have been analogously prepared, and upon acid hydrolysis, afforded the free nucleosides 16–18. The new synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compound 7 was also screened against a panel of tumor cell lines consisting of CD4 human T-cells.

This article describes an efficient route for synthesizing novel cyclopropyl homologous PMEA analogues. The condensation of the bromide 8 with nucleosidic bases (A, U, T, C, 5-FU, G) under standard nucleophilic substitution and deprotection conditions, afforded the target phosphonic acid analogues 14 approximately 18 and 21. These compounds were evaluated for their potential antiviral properties against various viruses. Guanine derivative 21 showed significant antiviral activity.

In these study, novel acyclic (E)-bromovinyl nucleosides were synthesized as potential antiviral agents. The coupling of the allylic bromide 9 with bases (thymine, uracil, 5-fluorouracul, 5-iodouracil, cytosine, adenine) afforded a series of novel acyclic nucleosides. The synthesized compounds were evaluated for their antiviral activity against various viruses such as HIV-1, HSV-1, HSV-2, and HCMV. 5-Iodouracil analogue 19 showed weak anti-HIV-1 activity.

Novel vinyl branched apiosyl nucleosides were synthesized in this study. Apiosyl sugar moiety was constructed by sequential ozonolysis and reductions. The bases (uracil and thymine) were efficiently coupled by glycosyl condensation procedure (persilyated base and TMSOTf). The antiviral activities of the synthesized compounds were evaluated against the HIV-1, HSV-1, HSV-2, and HCMV. Compound 10beta displayed moderate anti-HIV activity (EC50 = 17.3 microg/mL) without exhibiting any cytotoxicity up to 100 microM.

A very simple synthetic route for novel cyclopentene phosphonate nucleosides is described. The characteristic cyclopentene moiety 6 was constructed via a ring-closing metathesis of divinyl 5 , which could be readily prepared from diethylmalonate. The condensation of the mesylate 11 with nucleobases (A,C,T,U) under nucleophilic substitution conditions (K 2 CO 3 , 18-Crown-6, DMF) afforded the target nucleosides 12 , 13 , 14 , and 15 . In addition, the antiviral evaluations against various viruses were performed.

Since the discovery of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-didehydro-2',3'-dideoxythymidine (d4T) as potent and selective inhibitors of the replication of human immunodeficiency virus (HIV), there has been a growing interest for the synthesis of 2',3'-didehydro-2',3'dideoxynucleosides with electron withdrawing groups on the sugar moiety. Here we described an efficient method for the synthesis of such nucleoside analogs bearing structural features of both AZT and d4T The key intermediate, 3-azido-1,2-bis-O-acetyl-5-O-benzoyl-3-deoxy-D-ribofuranose, 5 was synthesized from commercially available D-xylose in five steps, from which a series of pyrimidine and purine nucleosides were synthesized in high yields. The resultant protected nucleosides were converted to target nucleosides using appropriate chemical modifications. The final nucleosides were evaluated as potential anti-HIV agents.

The synthesis of (±)-4′-ethynyl (8) and 4′-cyano (9) carbocyclic analogues of the anti-HIV agent stavudine (5, d4T) is reported. The carbocyclic unit (16) was constructed from readily available β-keto ester 10. The ethynyl or cyano group of 8 and 9 were prepared, after the introduction of thymine base to 16, by manipulation of the ester function. Evaluation of the anti-HIV activity of 8 and 9 was also carried out. This work was financially supported in part by grants from the Japan Health Sciences Foundation (SA14718 to H. T.), Japan Society for the Promotion of Science (KAKENHI No. 15790075 to H. K., No. 15590100 to K. H., and No. 15590020 to H. T.), and NIH USA (RO1 AI 38204 to Y.-C. C.).

A new anti‐HIV agent 4′‐cyano‐2′,3′‐didehydro‐3′‐deoxythymidine (9) was synthesized by allylic substitution of the 3′,4′‐unsaturated nucleoside 14, having a leaving group at the 2′‐position, with cyanotrimethylsilane in the presence of SnCl4. Evaluation of the anti‐HIV activity of 9 showed that this compound is much less potent than the recently reported 2′,3′‐didehydro‐3′‐deoxy‐4′‐(ethynyl)thymidine (1).

Homo‐ and heterodimers of AZT and d4T, possessing carbonate and carbamate linkers, have been synthesized with the aim to enhance the antiviral activity of their components. Homo‐ and heterodimer carbamates showed weak anti‐HIV activity. On the other hand, dinucleoside carbonates showed marked antiviral activity.

A new 32‐mer 2′,5′‐oligoribonucleotide of 1‐methyl‐6‐thioinosinic acid (10) has been synthesized. The design of this unique oligoribonucleotide is based on the reported HIV inhibitory activities of both 2′,5′‐oligonucleotides and the 3′,5′‐oligoribonucleotides containing the 1‐methyl‐6‐mercaptopurine base. Tm and CD studies of 10 revealed that it has no organized secondary structure, presumably due to the rigidity of the molecule. The synthesized oligomer, 10, showed a potent inhibitory effect on HIV‐1RF and significantly inhibited HIV‐1 reverse transcriptase. †In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.

The synthesis of 1,2,3-triazole acyclonucleosides 7a-h via 1,3-dipolar cycloaddition of N-9/N-1-propargylpurine/pyrimidine 2a-h with azido-pseudo-sugar 4 is described and none of them had anti-HIV activity.

Anti-HIV activity and cytotoxicity were tested for novel phosphonate derivatives of AZT, d4T and ddA. For d4T phosphonate derivatives the most active was 2',3'-Dideoxy-2',3'-didehydrothymidine 5'-isopropylphosphite and among the AZT phosphonate derivatives highest activity was shown by 2',3'-Dideoxy-3'-azidothymidine 5'-cyclohexylphosphite.