Novel aryl phosphate derivatives of the anti-HIV nucleoside analogue AZT have been prepared by phosphorochloridate chemistry. These materials were designed to act as membrane-soluble prodrugs of the bioactive free nucleotides. In vitro evaluation revealed the compounds to have a pronounced, selective anti-HIV activity in CEM cells; the magnitude of the biological effect varied considerably depending on the nature of the phosphate blocking group. Moreover, several of the compounds retain marked antiviral activity in TK- (thymidine kinase-deficient) mutant CEM cells in which AZT was virtually inactive. These data strongly support the hypothesis that the AZT phosphate derivatives exert their biological effects via intracellular release of AZT nucleotide forms and suggest that the potential of nucleoside drugs in antiviral chemotherapy may be enhanced by suitable nucleotide delivery strategies.

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On the basis of its favourable antiviral and pharmacokinetic properties, FV-100 is now being pursued as the clinical BCNA candidate for the treatment of VZV shingles.

A mutation is a sudden heritable change in the DNA in a living cell, not caused by genetic segregation or genetic recombination. Mutation breeding is the purposeful application of mutations in plant breeding. Unlike hybridization and selection, mutation breeding has the advantage of improving a defect in an otherwise elite cultivar, without losing its agronomic and quality characteristics. Mutation breeding is the only straightforward alternative for improving seedless crops. Since the first release of mutant cultivars that resulted from basic mutation research in Europe, mutation breeding has found a niche in plant breeding because of these advantages. Methodologies for mutation induction have been improved in main crops for both physical and chemical mutagens, and selection methodologies for mutant populations have been described. New mutagenic agents such as ion-beam radiation and cosmic rays are being investigated and a hitherto undescribed wide spectrum of mutations has been observed. Nevertheless, alkylating agents and ionizing radiation are still popular. The development of robust in vitro techniques for many crop species has contributed to improving the efficiency of mutation breeding. The ability to handle large mutagenized populations in a confined space, faster progeny turnover in vegetatively propagated species and the ability to screen for several biotic and abiotic stress factors in the culture environment make in vitro approaches very efficient. Mutant screening has undergone revolutionary changes in the past decade with reverse genetic approaches taking precedence. Therefore, integration of mutation techniques with molecular approaches is providing exciting opportunities for modern plant breeding.

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Bicyclic furano pyrimidine nucleosides have been found to be highly potent and selective inhibitors of varicella zoster virus (VZV). They are inactive against herpes simplex virus and have been known for several decades as (unwanted) synthetic by-products in the Pd-catalysed coupling of acetylenes to 5-iodo nucleosides. These fluorescent bicyclic nucleosides are now established as a new family of potent antivirals. They are unusual in that they exhibit complete specificity for VZV and require an alkyl (or alkylaryl) side-chain for biological activity. The latter requirement confers extremely high lipophilicities on these compounds, unknown amongst chemotherapeutic nucleosides, which may be of considerable importance in formulation, dosing and tissue distribution. The most potent compounds reported are p-alkylaryl compounds, with EC50 values below 1 nM versus VZV and selectivity index values of around 1,000,000. Here, we review the discovery, synthesis, characterization, antiviral profile, SAR, mechanism of action and development prospects for this new family of antivirals.

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