CHEMISTRY AND ANTI-HERPES SIMPLEX VIRUS TYPE-1 EVALUATION OF CYCLOSAL-NUCLEOTIDES OF ACYCLIC NUCLEOSIDE ANALOGS

The synthesis of different cycloSal-phosphotriesters of the acyclic nu cleoside analogues acyclovir (ACV), penciclovir (PCV) and T-penciclovi r (T-PCV) as potential new lipophilic, membrane-soluble pronucleotides is described. The introduction of the cycloSal moiety was achieved by using reactive cyclic chlorophosphane reagents. In addition to the cy cloSal-PCV monophosphate (MP) phosphotriesters, a second derivative be aring an acetyl group at the second primary alcohol function was prepa red. In hydrolysis studies the cycloSal-ACVMPs showed the expected ran ge of hydrolytic stability dependent on the substituent in the masking group (8-17 h). In contrast, the cycloSal-PCVMP derivatives exhibited a 11- to 15-fold increase in hydrolytic lability as compared to the c orresponding cycloSal-ACVMP derivatives. We demonstrated that the free primary alcohol group is responsible for this rate acceleration becau se cycloSal-OAc-PCVMP, in which the hydroxyl group was blocked by acet ylation, did not show the aforementioned acceleration. Unexpectedly, t he hydrolysis product was not PCVMP but according to NMR and mass spec trometry it was cycloPCVMP (cPCVMP). The title compounds were evaluate d in vitro for their ability to inhibit herpes simplex virus type 1 (H SV-1) and thymidine kinase-negative (TK-) HSV-1 replication in Vero ce lls. The cycloSal-ACVMP compounds exhibited high antiviral activity in HSV-1-infected cells. More importantly, one derivative retained all a ctivity from the wild-type virus strain in HSV-1/TK--infected Vero cel ls. The PCV derivatives were markedly less active. The reason for the failure of the cycloSal-PCVMPs seems to be due to the formation of cPC VMP instead of the desired PCVMP.