Synthesis and antiviral activity of (S)-9-[4-hydroxy-3-(phosphonomethoxy)butyl]guanine.
The synthesis of (S)-9-[4-hydroxy-3-(phosphonomethoxy)butyl]guanine (3), starting from (S)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (4), is described. Alkylation of trityl derivative 7 with (diethylphosphono)methyl triflate provided phosphonate 8, which was readily converted to mesylate 12 in three steps. Nucleophilic substitution of the mesylate group of 12 by 2-amino-6-chloropurine sodium salt led to (S)-2-amino-6-chloro-9-[3-[(diethyl-phosphono)methoxy]-4-(tetrahydro- 2H-pyran-2-yloxy)butyl]purine (13). Sequential treatment of 13 with trimethylsilyl bromide and then with 2 N HCl furnished 3. Preliminary in vitro screening indicated that 3 exhibited a potent activity against human cytomegalovirus (HCMV) but was not active against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). The adenine and cytosine derivatives (14 and 15) did not exhibit activity against HSV-1 and -2 and HCMV.
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Bristol-Meyers Squibb Company, Pharmaceutical Research and Development Division, Wallingford, Connecticut 06492.
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Martin
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D000225:Adenine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000077404:Cidofovir; D003587:Cytomegalovirus / Q000187:drug effects / Q000254:growth & development; D003596:Cytosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D018139:Simplexvirus / Q000187:drug effects / Q000254:growth & development; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C058654:9-(3-hydroxy-2-phosphonomethoxypropyl)guanine; D006147:Guanine; D003596:Cytosine; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine; D000077404:Cidofovir