Synthesis of dioxane-based antiviral agents and evaluation of their biological activities as inhibitors of Sindbis virus replication.
The crystal structure of the Sindbis virus capsid protein contains one or two solvent-derived dioxane molecules in the hydrophobic binding pocket. A bis-dioxane antiviral agent was designed by linking the two dioxane molecules with a three-carbon chain having R,R connecting stereochemistry, and a stereospecific synthesis was performed. This resulted in an effective antiviral agent that inhibited Sindbis virus replication with an EC(50) of 14 microM. The synthesis proceeded through an intermediate (R)-2-hydroxymethyl-[1,4]dioxane, which unexpectedly proved to be a more effecting antiviral agent than the target compound, as evidenced by its EC(50) of 3.4 microM as an inhibitor of Sindbis virus replication. Both compounds were not cytotoxic in uninfected BHK cells at concentrations of 1mM.
Kim
Ha Young
HY
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, The Purdue Cancer Center, West Lafayette, IN 47907, USA.
Kuhn
Richard J
RJ
Patkar
Chinmay
C
Warrier
Ranjit
R
Cushman
Mark
M
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D036022:Capsid Proteins / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D018360:Crystallography, X-Ray; D004146:Dioxanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D006023:Glycoproteins / Q000737:chemistry; D007202:Indicators and Reagents; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D012845:Sindbis Virus / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D036022:Capsid Proteins; D004146:Dioxanes; D006023:Glycoproteins; D007202:Indicators and Reagents; D008024:Ligands