Synthesis of enantiomerically pure d- and l-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation

Abstract

Based upon the fact that l-nucleosides have been generally known to be less cytotoxic than d-counterparts, l-bicyclo[3.1.0]hexenyl carbanucleoside derivatives with a fixed north conformation were designed and synthesized by employing a novel synthetic strategy starting from ( R)-epichlorohydrin in order to search for new anti-HIV agents with high potency and less cytotoxicity. A tandem alkylation, γ-lactonization, a chemoselective reduction of ester in the presence of γ-lactone functional group, a RCM reaction, and a Mitsunobu coupling reaction were used as key reactions. d-Counterpart nucleosides were also prepared according to the same synthetic method. Among the synthesized carbanucleosides, d-thymine nucleoside, d- 2 and l-thymine nucleoside, l- 2 exhibited excellent anti-HIV-1 and -2 activities, in MT-4 cells, which were higher than those of ddI, an anti-AIDS drug. Whereas d- 2 exhibited high cytotoxicity in MT-4 cell lines, l- 2 did not show any discernible cytotoxicity in all cell lines tested, reflecting that l- 2 may be a good candidate for an anti-AIDS drug. l- 2 also showed weak anti-HSV-2 activity without cytotoxicity. However, none of the synthesized nucleosides exhibited antiviral activities against RNA viruses including coxsakie, influenza, corona and polio viruses, maybe due to their 2′,3′-dideoxy structure. Potent antiviral effects of d- 2 and l- 2 indicate that nucleosides belonging to a class of D4Ns can be an excellent candidate for anti-DNA virus agents. This research strongly supports l-nucleosides of a class of D4Ns to be a very promising candidate for antiviral agents due to its low cytotoxicity and a good antiviral activity.