SYNTHESIS AND ANTIVIRAL ACTIVITY OF NOVEL ISONUCLEOSIDE ANALOGS

A series of branched-chain sugar isonucleosides was synthesized and ev aluated for antiviral activity against herpesviruses. The preparation of homochiral o-4,5-bis(hydroxymethyl)-3-furanyl]-6H-purin-6-one (7, B MS-181,164) and related compounds was stereospecifically achieved star ting from 1,2-isopropylidene-D-xylofuranose (10). An efficient two-ste p reduction of the anomeric center of bis-acetate 18 involved formatio n of the chloride intermediate 19, followed by diisobutylaluminum hydr ide reduction. Tosylation of the resulting alcohol 20 provided the key intermediate 21, which was coupled with a variety of nucleobase anion s. Several members of this new class of compounds possess activity aga inst herpes simplex virus types 1 and 2 (HSV-1 and -2), varicella-zost er virus (VZV), and human cytomegalovirus (HCMV). Compound 7 exhibits potent and selective activity against thymidine kinase encoding herpes viruses, in particular, HSV-1 and HSV-2. Evaluation of compound 7 for inhibition of WI-38 cell growth indicated an ID50 of > 700 muM. Althou gh the antiherpetic activity in vitro of 7 is less than that of acyclo vir (1), compound 7 displays superior efficacy in mouse model infectio ns. The (bromovinyl)uridine analog 8 (BMS-181,165) also exhibits selec tive activity against HSV-1 and VZV, with no cytostatic effect on WI-3 8 cell growth at > 800 muM. Compound 8 is active against simian varice lla virus and is efficacious in the corresponding monkey model.