Synthesis and biological activity of tricyclic analogues of 9-[[cis-1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine.
The base moiety of the potent antiherpetic agent 9-[[cis-1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine 3 was transformed into that of the tricyclic 3,9-dihydro-9-oxo-6-R-5H-imidazo[1,2-a]purine system. The tricyclic analogues 5a-d were evaluated for their activity against herpes viruses as well as for cytostatic activity against HSV-1 thymidine kinase (TK) gene-transduced human osteosarcoma tumor cells. Marked activity was found against VZV. The 6-phenyl-substituted fluorescent analogues 5c and d were comparable to that of parent 3 in activity against the VZV strain YS and were 3-fold less active against the VZV strain OKA. The compounds 5a-d also showed marked activity against HSV-1 (KOS) and HSV-2 (G)-against the former generally approximately comparable to that of acyclovir 1a and one order of magnitude lower than 3; against the latter comparable to that of 1a and approximately 6- to 30-fold lower than that of 3. The most pronounced cytostatic activity (5-fold lower than that of 3) was exhibited by compounds 5c and d. Tricyclic analogues with pseudosugar moieties are intrinsically bio-active.
Ostrowski
Tomasz
T
Institute of Bioorganic Chemistry, Polish Academy of Sciences, ul. Noskowskiego 12/14, 61-704 Poznan, Poland.
Golankiewicz
Bozenna
B
De Clercq
Erik
E
Balzarini
Jan
J
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D014779:Virus Replication / Q000187:drug effects
C111645:9-((cis-1,2-bis(hydroxymethyl)cycloprop-1-yl)methyl)guanine; D000998:Antiviral Agents; D006575:Heterocyclic Compounds, 3-Ring; D006147:Guanine