Synthesis and antiherpetic activity of (S)-, (R)-, and (.+-.)-9-[(2,3-dihydroxy-1-propoxy)methyl]guanine, linear isomers of 2'-nor-2'-deoxyguanosine

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Abstract
Racemic 9-[(2,3-dihydroxy-1-propoxy)methyl]guanine [(.+-.)-iNDG], a new analog of acyclovir (ACV) and a structural analog of 2''-nor-2''-deoxyguanosine (2''NDG), was synthesized and inhibited the replication of herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). Subsequently, its optical isomers, (R)-and (S)-iNDG, were prepared from chiral intermediates. The chloromethyl ethers of 1,2-di-O-benzyl-D- and -L-glycerol were made and reacted with tris(trimethylsilyl)guanine to give the 9-alkylated guanines, which were deprotected by catalytic hydrogenolysis. Against HSV-1 and HSV-2 in cell culture, (S)-iNDG was approximately 10-25-fold more active than the R enantiomer and had an ED50 comparable to those for ACV and 2''NDG. The inferior activity of (R)-iNDG paralleled the poor inhibition of viral DNA polymerase by its phosphorylation products. In mice infected i.p. or orofacially with HSV-1 or intravaginally with HSV-2, (S)-iNDG was less efficacious than 2''NDG but comparable to or more active than ACV.