Treatment of 5-azacytosine sodium salt with diisopropyl [(2-chloroethoxy)methyl]phosphonate followed by removal of ester groups with BrSi(CH3)3 afforded 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (3). Reaction of 5-azacytosine with [(trityloxy)methyl]-(2S)-oxirane followed by etherification with diisopropyl (bromomethyl)phosphonate and removal of ester groups gave 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (1). The synthesis of 6-azacytosine congener 2 was analogous using N4-benzoylated intermediates. Compound 1 was shown to exert strong activity against a broad spectrum of DNA viruses including adenoviruses, poxviruses, and herpesviruses (i.e., herpes simplex viruses, varicella zoster virus, and human cytomegalovirus). Decomposition of 1 in alkaline solutions resulted in products 17 and 18. While the N-formylguanidine derivative 17 proved active, the carbamyolguanidine derivative 18 was devoid of antiviral activity.

Gilead Sciences and IOCB Research Centre Centre for New Antivirals and Antineoplastics Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic

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