Synthesis and antiherpes virus activity of phosphate and phosphonate derivatives of 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine.
A series of phosphate esters of 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG, 1) were synthesized and evaluated for antiherpes virus activity. The cyclic phosphate esters were made by a new, efficient method utilizing stannic chloride as a solubilizing agent. Monophosphate 2 and bisphosphate 4 showed comparable activity to DHPG and probably acted as prodrugs of DHPG. On the other hand, the cyclic phosphate of DHPG 3 was taken up by cells and bypassed the virus-specified thymidine kinase. As a result, 3 was active against DHPG-resistant HSV mutants that lacked the viral-specified thymidine kinase and was more toxic than DHPG to uninfected cells. The phosphonate 5, the least toxic of the derivatives tested, was only marginally active against HSV but showed substantial activity against human cytomegalovirus in vitro.
D000212:Acyclovir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects; D005260:Female; D015774:Ganciclovir / Q000031:analogs & derivatives*; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D007279:Injections, Subcutaneous; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008826:Microbial Sensitivity Tests; D063065:Organophosphonates; D010710:Phosphates; D018139:Simplexvirus / Q000187:drug effects* / Q000201:enzymology; D013937:Thymidine Kinase / Q000378:metabolism
D063065:Organophosphonates; D010710:Phosphates; C045895:9-((2,3-dihydroxy-1-propoxy)methyl)guanine; D013937:Thymidine Kinase; D015774:Ganciclovir; D000212:Acyclovir