title: Nucleotides and pronucleotides of 2,2-bis(hydroxymethyl)methylenecyclopropane analogues of purine nucleosides: synthesis and antiviral activity.
abstract: Phenylmethylphosphor-L-alaninate pronucleotides 7a, 7b, 8a, and 8b, cyclic phosphates 10a and 10b, and phosphates 11a and 11b derived from 2,2-bis(hydroxymethyl)methylenecyclopropane analogues 1a, 1b, 2a, and 2b were synthesized and evaluated for their antiviral activity. An improved protocol for the synthesis of analogues 1a, 1b, 2a, and 2b is also described. Phosphate 11a was the most effective agent against human and murine cytomegalovirus (EC(50) 0.25-1.1 microM). The Z-pronucleotides 7a and 7b had EC(50) 3.6-25.2 and 3-18.4 microM, respectively. The EC(50) of cyclic phosphate 10a was 6.0-20 microM. The activity against Epstein-Barr (EBV) was assay-dependent. Pronucleotides 7a and 7b and phosphate 11a had EC(50) 2.3-3.4 microM against EBV/H-1, but 7b was cytotoxic (CC(50) 3.8 microM). Cyclic phosphate 10a was the only compound effective against EBV/Daudi (EC(50) 0.96 microM), but it was inactive in H-1 cells. Pronucleotide 7a was active against varicella zoster virus with EC(50) 6.3 and 7.3 microM, respectively, and hepatitis B virus (HBV, EC(50) 4.1 microM). Cyclic phosphate 10a was the most effective analogue against HBV (EC(50) 0.8 microM).
authors.affiliation: Department of Chemistry, Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201-1379, USA.
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Yan
authors.forename: Earl R
authors.initials: ER
authors.lastname: Kern
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gullen
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Cheng
authors.forename: John C
authors.initials: JC
authors.lastname: Drach
authors.forename: Jiri
authors.initials: J
authors.lastname: Zemlicka
mesh_terms: D000225:Adenine / Q000737:chemistry; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001671:Biochemistry / Q000379:methods; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D009711:Nucleotides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011684:Purine Nucleosides / Q000737:chemistry*
chemical_list: D000998:Antiviral Agents; D009711:Nucleotides; D011684:Purine Nucleosides; D000225:Adenine