Fluorinated methylenecyclopropane analogues of nucleosides. Synthesis and antiviral activity of (Z)- and (E)-9-{[(2-fluoromethyl-2-hydroxymethyl)-cyclopropylidene]methyl}adenine and -guanine.
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 [corrected] Compounds 15a, 15b, 16a and 16b were not active against Epstein-Barr virus (EBV) [corrected] 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.
Li
Chengwei
C
Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201-1379, USA.
Prichard
Mark N
MN
Korba
Brent E
BE
Drach
John C
JC
Zemlicka
Jiri
J
D000225:Adenine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003521:Cyclopropanes / Q000737:chemistry*; D017611:Fluorine Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006147:Guanine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects; D006900:Hydroxylation; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry
D000998:Antiviral Agents; D003521:Cyclopropanes; D017611:Fluorine Compounds; D009705:Nucleosides; C508672:methylenecyclopropane; D006147:Guanine; D000225:Adenine