SYNTHESIS AND ANTIHERPES VIRUS ACTIVITY OF 1,5-ANHYDROHEXITOL NUCLEOSIDES

The synthesis of 1,5-anhydrohexitol nucleosides is described. These nu cleoside analogues were obtained by alkylation of the heterocyclic bas es with the tosylate 10 or by alkylation of the bases with the alcohol 12 under Mitsunobu conditions. The compounds were evaluated for antiv iral and cytostatic activity. Highly selective activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) was noted for ,3-dide oxy-2-(5-iodouracil-1-yl)-D-arabino-hexitol 4b at a concentration of 0 .07 mug/mL. This activity must be dependent on a specific phosphorylat ion by the virus-encoded thymidine kinase (TK), since compound 4b was inactive against TK-deficient mutants of HSV-1. The corresponding cyto sine 4c and guanine 4e analogues showed activity against HSV-1, HSV-2, and other herpes viruses (i.e. cytomegalovirus, varicella-zoster viru s) at concentrations well below the cytotoxicity threshold (2 and 20 m ug/mL, respectively). At these concentrations, compounds 4c and 4e pro ved also inhibitory to the growth of human T-cells (i.e. MT-4, CEM, MO LT-4).