title: Synthesis and antiviral activity of phosphoralaninate derivatives of methylenecyclopropane analogues of nucleosides.
abstract: Phenylmethylphosphoro-L-alaninate prodrugs of antiviral Z-methylenecyclopropane nucleoside analogues and their inactive E-isomers were synthesized and evaluated for their antiviral activity against HCMV, HSV-1, HSV-2, HHV-6, EBV, VZV, HIV-1 and HBV. The adenine Z-analogue was a potent inhibitor of all these viruses but it displayed cellular toxicity. The guanine Z-derivative was active against HCMV, HBV, EBV and VZV and it was not cytotoxic. The 2,6-diaminopurine analogue was the most potent against HIV-1 and HBV and somewhat less against HHV-6, HCMV, EBV and VZV in a non-cytotoxic concentration range. The 2-amino-6-cyclopropylamino and 2-amino-6-methoxypurine prodrugs were also more active than parent analogues against several viruses but with a less favorable cytotoxicity profile. In the E-series of analogues, adenine derivative was active against HIV-1, HBV and EBV, and it was non-cytotoxic. The guanine analogue exhibited a significant effect only against HBV. The 2,6-diaminopurine E-analogue was inactive with the exception of a single EBV assay. The 2-amino-6-methoxypurine Z-methylenecyclopropane nucleoside analogue was an effective inhibitor of HCMV, MCMV and EBV. The 2,6-diaminopurine Z-prodrug seems to be the best candidate for further development.
authors.affiliation: Department of Chemistry, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201-1379, USA.
authors.forename: Y L
authors.initials: YL
authors.lastname: Qiu
authors.forename: R G
authors.initials: RG
authors.lastname: Ptak
authors.forename: J M
authors.initials: JM
authors.lastname: Breitenbach
authors.forename: J S
authors.initials: JS
authors.lastname: Lin
authors.forename: Y C
authors.initials: YC
authors.lastname: Cheng
authors.forename: J C
authors.initials: JC
authors.lastname: Drach
authors.forename: E R
authors.initials: ER
authors.lastname: Kern
authors.forename: J
authors.initials: J
authors.lastname: Zemlicka
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D019380:Anti-HIV Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects; D006564:Herpesviridae / Q000187:drug effects; D006801:Humans; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D003521:Cyclopropanes; D011355:Prodrugs; D000409:Alanine