Synthesis of cyclopentenyl carbocyclic nucleosides as potential antiviral agents against orthopoxviruses and SARS.
A practical and convenient methodology for the synthesis of chiral cyclopentenol derivative (+)-12a has been developed as the key intermediate that was utilized for the synthesis of biologically active carbocyclic nucleosides. The selective protection of allylic hydroxyl group followed by the ring-closing metathesis (RCM) reaction with Grubbs catalysts provided (+)-12a on a 10 g scale with 52% overall yield from D-ribose (4). The key intermediate (+)-12a was utilized for the synthesis of unnatural five-membered ring heterocyclic carbocyclic nucleosides. The newly synthesized 1,2,3-triazole analogue (17c) exhibited potent antiviral activity (EC(50) 0.4 microM) against vaccinia virus and moderate activities (EC(50) 39 microM) against cowpox virus and severe acute respiratory syndrome coronavirus (SARSCoV) (EC(50) 47 microM). The 1,2,4-triazole analogue (17a) also exhibited moderate antiviral activity (EC(50) 21 microM) against SARSCoV.
Cho
Jong Hyun
JH
The University of Georgia College of Pharmacy, Athens, GA 30602, USA.
Bernard
Dale L
DL
Sidwell
Robert W
RW
Kern
Earl R
ER
Chu
Chung K
CK
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D018155:Orthopoxvirus / Q000187:drug effects*; D012266:Ribose / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
C508999:1-(4,5-dihydroxy-3-hydroxymethylcyclopenten-2-enyl)-1H-1,2,3-triazole-4-carboxylic acid amide; D000998:Antiviral Agents; D009705:Nucleosides; D014230:Triazoles; D012266:Ribose