Fluoroanalogues of anti-cytomegalovirus agent cyclopropavir: synthesis and antiviral activity of (E)- and (Z)-9-{[2,2-bis(hydroxymethyl)-3-fluorocyclopropylidene]methyl}-adenines and guanines.
Synthesis of fluorinated cyclopropavir analogues 13a, 13b, 14a, and 14b is described starting from alkene 15. Addition of carbene derived from dibromofluoromethane gave bromofluoro cyclopropane 16. Reduction (compound 17) followed by desilylation gave intermediate 18, which was transformed to 2-nitrophenylselenenyl derivative 19. Oxidation to selenoxide 20 was followed by beta-elimination to afford methylenecyclopropane 21. Addition of bromine provided compound 22 for alkylation-elimination of adenine and 2-amino-6-chloropurine. The resultant E,Z isomeric mixtures of methylenecyclopropanes 23a + 24a and 23c + 24c were resolved and the individual isomers were deprotected to give adenine analogues 13a and 14a as well as compounds 13c and 14c. Hydrolytic dechlorination of 13c and 14c furnished guanine analogues 13b and 14b. The only significant antiviral effects were observed with analogue 13a against HCMV and 14a against VZV in cytopathic inhibition assays.
Zhou
Shaoman
S
Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201-1379, USA.
Zemlicka
Jiri
J
Kern
Earl R
ER
Drach
John C
JC
D000225:Adenine / Q000737:chemistry*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001966:Bromine / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000378:metabolism*; D003586:Cytomegalovirus Infections / Q000188:drug therapy*; D015195:Drug Design; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D009696:Nucleic Acids / Q000737:chemistry; D009705:Nucleosides / Q000737:chemistry; D014466:Ultraviolet Rays
D000998:Antiviral Agents; D003521:Cyclopropanes; D009696:Nucleic Acids; D009705:Nucleosides; D006147:Guanine; C495219:cyclopropavir; D000225:Adenine; D001966:Bromine