2-Amino-7-[(1,3-dihydroxy-2-propoxy)methyl]
purine (compound
S2242) represents the first antivirally active
nucleoside analog with the side chain attached to the N-7 position of the
purine ring. Compound
S2242 strongly inhibits the in vitro replication of both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) (50% effective concentration [EC50], 0.1 to 0.2 microgram/ml), varicella-zoster virus (EC50, 0.01 to 0.02 microgram/ml) and
thymidine kinase (TK)-deficient strains of HSV (EC50, 0.4 microgram/ml) and varicella-zoster virus (EC50, 0.2 to 0.5 microgram/ml). Potent activity was also observed against murine cytomegalovirus (EC50, 1 microgram/ml), human cytomegalovirus (HCMV) (EC50, 0.04 to 0.1 microgram/ml), and human herpesvirus 6 (EC50, 0.0005 microgram/ml). Compound
S2242 (i) was not cytotoxic to confluent Vero, HeLa, or human fibroblast cells at concentrations of > 100 micrograms/
ml, (ii) proved somewhat more
cytostatic to Vero, HEL, HeLa, and C127I cells than
ganciclovir, and (iii) was markedly more
cytostatic than
ganciclovir to the growth of the human lymphocytic cell lines HSB-2 and CEM degrees. In contrast to
ganciclovir, (i) compound
S2242 proved not to be cytocidal to murine mammary
carcinoma (FM3A) cells transfected with the HSV-1 or HSV-2 TK gene, (ii) exogenously added
thymidine had only a limited effect on its anti-HSV-1 activity, and (iii) the compound was not phosphorylated by HSV-1-encoded TK derived from HSV-1 TK-transfected FM3A cells, indicating that the compound is not activated by a virally encoded TK. Compound
S2242 inhibited (i) the expression of late HCHV
antigens at an EC50 of 0.07 microgram/ml (0.6 microgram/ml for
ganciclovir) and (ii) HCMV
DNA synthesis at an EC50 of 0.1 microgram/ml (0.32 microgram/ml for
ganciclovir), i.e., values that are close to the EC50S for inhibition of HCMV-induced cytopathogenicity. Neither
ganciclovir nor
S2242 had any effect on the expression of immediate-early HCMV
antigens, which occurs before
viral DNA synthesis. In time-of-addition experiments,
S2242 behaved like
ganciclovir and
acyclovir; i.e., the addition of the drugs could be delayed until the onset of
viral DNA synthesis.