Synthesis and Antiviral Activity of Novel Fluorinated 2′,3′‐Dideoxynucleosides

Abstract

A series of 5‐(trifluoroethoxymethyl)‐2′,3′‐dideoxyuridines and 5‐[bis(trifluoroethoxy)‐methyl]‐2′,3′‐dideoxyuridines have been prepared and screened for antiviral activity. The conformations of these compounds are discussed on the bases of NOE studies and the MO calculations. Modelling and NOE studies suggest both syn‐ and anti conformations for these 5‐(2,2,2‐trifluoroethoxymethyl)‐ and 5‐[bis(2,2,2‐trifluoroethoxy)‐methyl]‐ derivatives. The NOE parameters are also suggested to be more attributable to the nature of the fluorine atom than to structural or conformational changes. Compounds 17, 26 and 30 showed some activity in anti‐HIV‐1 and anti‐HIV‐2 assays, but the compounds were devoid of activity against HSV and human rhinovirus. The compounds tested exhibited low cytotoxicity and were inactive against a bank of cancer cells in vitro.

^†In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.

Keywords:

• Fluorinated 2′,3′‐dideoxynucleosides
• Syntheses
• NOE
• Antiviral nucleosides

Acknowledgments

The authors gratefully acknowledge the financial support from the Medical Research Council of Canada (now Canadian Institutes for Health Research). We thank Dr. V.V. Somayaji for his assistance in recording and interpreting the NMR spectra, Dr. M. Daneshtalab, Mark Tempest and Cathy Koski (Synphar, Inc, Edmonton) for anti‐rhinovirus testing, Dr. Chris Tseng (NIH/NCI, Bethesda) for HSV‐1 and HSV‐2 tests, and Dr. Michael Grever (NIH/NCI, Bethesda) for antitumor screening.

Notes

^†In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.

^aIn the absence of cuprous iodide, most of the bromomethylthymidine was hydrolyzed to the corresponding 5‐hydroxymethyl‐3′azido‐5′‐O‐TBDPS‐thymidine.