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On the hypothesis that one carbon homologation of 4′-selenonucleosides might relieve the steric repulsion between cellular kinases and bulky selenium, 5′-homo-4′-Se-d4Ns, 3 a–e, as anti-HIV agents were designed and synthesized stereoselectively from d-gulonic γ-lactone, with the conversion of 2′,3′-diol into the olefin as the key step. The anti-HIV activity of all synthesized compounds, 5′-homo-4′-Se-d4Ns, was toxicity-dependent, unlike normal 4′-Se-d4Ns, which were inactive against HIV-1. This result indicates that 5′-homo-4′-Se-d4Ns might be phosphorylated by cellular kinases as per the hypothesis.

Stereo- and regio-selective synthesis of 3′-C-substituted-(N)-methanocarba adenosines 3a–c as potential anticancer agents was achieved by employing stereoselective cyclopropanation, stereoselective nucleophilic addition, regioselective isopropylidene cleavage and regioselective base condensation of cyclic sulfate as key steps.

(−)-6′-β-Fluoro-aristeromycin (2), a potent inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase, has been synthesized via stereoselective electrophilic fluorination followed by a purine base build-up approach. Interestingly, purine base condensation using a cyclic sulfate resulted in a synthesis of (+)-5′-β-fluoro-isoaristeromycin (2a). Computational analysis indicates that the fluorine atom controlled the regioselectivity of the purine base substitution.

A series of acyclic selenopurine nucleosides 3a-f and 4a-g were synthesized based on the bioisosteric rationale between oxygen and selenium, and then evaluated for antiviral activity. Among the compounds tested, seleno-acyclovir (4a) exhibited the most potent anti-herpes simplex virus (HSV)-1 (EC50 = 1.47 µM) and HSV-2 (EC50 = 6.34 µM) activities without cytotoxicity up to 100 µM, while 2,6-diaminopurine derivatives 4e-g exhibited significant anti-human cytomegalovirus (HCMV) activity, which is slightly more potent than the guanine derivative 4d, indicating that they might act as prodrugs of seleno-ganciclovir (4d).