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

Abstract

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 β-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.

Keywords:

• 3-Fluoromethylenecyclopropanes
• cyclopropavir
• nucleoside analogues
• antivirals

Acknowledgments

We thank L. M. Hrihorczuk from the Central Instrumentation Facility, Department of Chemistry, Wayne State University (D.M. Coleman, Director) for mass spectra. We also thank research assistants and associates in Drs. Drach and Kern laboratories for expert performance of antiviral and cytotoxicity assays. The work described herein was supported by U.S. Public Health Service grants RO1-CA32779 (J.Z.) from the National Cancer Institute, contracts NO1-AI85347, NO1-AI30049 (E.R.K.) and program project PO1-AI46390 (J.C.D.) from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892.

Notes

^a CD₃SOCD₃ as solvent. For numbering of signals see Table 2.

^a Both halves of the doublet were observed separately.

^b Both halves of the doublet were irradiated separately.

^a DNA hybridization assay.

^b For cytotoxicity in HFF cells see HCMV/HFF (AD169).

^c Plaque reduction assay.

^d Visual cytotoxicity.

^e Cytopathic effect (CPE) inhibition assay in stationary HFF cells.

^f Cytotoxicity by neutral red uptake.

^g The EC₅₀ in plaque reduction assay was >20 μM.

^h The EC₅₀ in plaque reduction assay was >100 μM.

ⁱ Ganciclovir.

^j Acyclovir.