NUCLEOSIDES AND NUCLEOTIDES .154. NEW NEPLANOCIN ANALOGS .8. SYNTHESIS AND BIOLOGICAL-ACTIVITY OF 6'-C-ETHYL, -ETHENYL, AND -ETHYNYL DERIVATIVES OF NEPLANOCIN A

This report describes the synthesis and antiviral effects of (6'R)-6'- C-ethnyl, -ethenyl, and -ethyl derivatives of neplanocin A (7a, 8a, an d 9a, respectively) and the corresponding 6'S-diastereomers (7b, 8b, a nd 9b, respectively), as examples of 6'-C-substituted analogues of nep lanocin A. Grignard reaction of the 6'-formyl derivative 4, which was readily prepared from neplanocin A, with ethynylmagnesium bromide gave a diastereomeric mixture of the corresponding 1,2-addition products 5 a and 5b. After removal of the protecting groups, (6'R)- and (6'S)-6'- C-ethynylneplanocin A's (7a, 7b) were separated. The corresponding eth enyl derivatives 8a and 8b and ethyl derivatives 9a and 9b were prepar ed by catalytic hydrogenation of 7a and 7b, respectively. As compared to neplanocin A, the new neplanocin A derivatives were much weaker inh ibitors of S-adenosyl-L-homocysteine hydrolase, the R-diastereomers be ing more inhibitory than the S-diastereomers. The decreasing order of activity was 7a>8a>7b>9a>8b>9b. The cytotoxicity (for CEM cells) follo wed exactly the same order. Of these compounds, (6'R)-6'-C-ethynylnepl anocin A (7a, RENPA) showed an antiviral activity spectrum that was co mparable to, and an antiviral specificity that was higher than, that o f neplanocin A. RENPA was particularly active against those viruses (i .e. vaccinia virus, vesicular stomatitis virus) that are known to be h ighly sensitive to AdoHcy hydrolase inhibitors.