Synthesis and antiherpes simplex virus activity of 9-[(1,3-dihydroxy-2-propylthio)methyl]guanine.
The synthesis of the thio analogue (thio-DHPG, 2) of 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG, 1) is described. The synthesis of 2 proceeded via the condensation of acetoxymethyl sulfide 9 with diacetylguanine 10 to give the protected nucleoside analogue 11. Although catalytic hydrogenolysis failed, the benzyl ether functionalities of 11 were successfully cleaved by an acetolysis reaction to furnish 14. Ammonolysis of 14 gave 2, which was also transformed to sulfoxide 15 and sulfone 16. Preliminary in vitro screening indicated that 2 exhibited comparable activity to DHPG against herpes simplex virus type 1 (HSV-1) but was less active against the type 2 virus (HSV-2) and human cytomegalovirus (HCMV). In a mouse encephalitis model (HSV-2), subcutaneous treatment with 2 led to a 53% reduction in mortality at a dose of 100 mg/kg per day.
McGee
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DP
Martin
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JC
Smee
D F
DF
Matthews
T R
TR
Verheyden
J P
JP
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D003587:Cytomegalovirus / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004660:Encephalitis / Q000209:etiology; D005260:Female; D015774:Ganciclovir; D006561:Herpes Simplex / Q000188:drug therapy*; D051379:Mice; D018139:Simplexvirus / Q000187:drug effects
C046481:9-((1,3-dihydroxy-2-propylthio)methyl)guanine; D015774:Ganciclovir; D000212:Acyclovir