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Fluorinated methylenecyclopropane analogues of nucleosides. Synthesis and antiviral activity of (Z)- and (E)-9-{[(2-fluoromethyl-2-hydroxymethyl)-cyclopropylidene]methyl}adenine and -guanine
- Source :
-
Bioorganic & Medicinal Chemistry . Mar2008, Vol. 16 Issue 5, p2148-2155. 8p. - Publication Year :
- 2008
-
Abstract
- Abstract: Synthesis and antiviral activity of the title fluoromethylenecyclopropane analogues 15a, 15b, 16a, and 16b is described. Methylenecyclopropane carboxylate was first transformed to 2,2-bis-hydroxymethylmethylenecyclopropane. Selective monoacetylation followed by introduction of fluorine gave 2-acetoxymethyl-2-fluoromethylmethylenecyclopropane as the key intermediate. The synthesis of analogues 15a, 15b, 16a, and 16b then followed alkylation–elimination procedure as described previously for other methylenecyclopropane analogues. The adenine Z-isomer 15a was found to be a potent inhibitor of Epstein–Barr virus (EBV) in vitro with EC50/CC50 (μM) 0.5/55.7. Compounds 15b, 16a, and 16b were also active but at higher concentrations, EC50/CC50 (μM) 3.2–7.5/53.6–64.1. Analogue 15a inhibited hepatitis C virus by virtue of its cytotoxicity and it moderately inhibited replication of the Towne strain of human cytomegalovirus (HCMV). The E-isomer 16a was a substrate for adenosine deaminase, whereas the Z-isomer 15a was not deaminated. [Copyright &y& Elsevier]
- Subjects :
- *NUCLEOSIDES
*FLUORINE
*CHEMICAL reactions
*ADENOSINE deaminase
Subjects
Details
- Language :
- English
- ISSN :
- 09680896
- Volume :
- 16
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31303490
- Full Text :
- https://doi.org/10.1016/j.bmc.2007.11.082