New neplanocin analogues. VIII. 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-ethynyl, -ethenyl, and -ethyl derivatives of neplanocin A (7a, 8a, and 9a, respectively) and the corresponding 6'S-diastereomers (7b, 8b, and 9b, respectively), as examples of 6'-C-substituted analogues of neplanocin 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 5a and 5b. After removal of the protecting groups, (6'R)- and (6'S)-6'-C-ethynylneplanocin A's (7a, 7b) were separated. The corresponding ethenyl derivatives 8a and 8b and ethyl derivatives 9a and 9b were prepared by catalytic hydrogenation of 7a and 7b, respectively. As compared to neplanocin A, the new neplanocin A derivatives were much weaker inhibitors of S-adenosyl-L-homocysteine hydrolase, the R-diastereomers being more inhibitory than the S-diastereomers. The decreasing order of activity was 7a > 8a > 7b > 9a > 8b > 9b. The cytotoxicity (for CEM cells) followed exactly the same order. Of these compounds, (6'R)-6'-C-ethynylneplanocin A (7a, RENPA) showed an antiviral activity spectrum that was comparable to, and an antiviral specificity that was higher than, that of neplanocin A. RENPA was particularly active against those viruses (i.e. vaccinia virus, vesicular stomatitis virus) that are known to be highly sensitive to AdoHcy hydrolase inhibitors.
Shuto
S
S
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Obara
T
T
Saito
Y
Y
Yamashita
K
K
Tanaka
M
M
Sasaki
T
T
Andrei
G
G
Snoeck
R
R
Neyts
J
J
Padalko
E
E
Balzarini
J
J
De Clercq
E
E
Matsuda
A
A
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D058892:Adenosine Deaminase Inhibitors; D043383:Adenosylhomocysteinase; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006867:Hydrolases / Q000037:antagonists & inhibitors; D051379:Mice; D015394:Molecular Structure; D013237:Stereoisomerism; D014709:Vero Cells
D058892:Adenosine Deaminase Inhibitors; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; C031096:neplanocin A; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine