ABSTRACT
The synthesis of a series of neoglycolipid conjugates of foscarnet as potential drug targeting forms or lipophilic prodrugs of foscarnet is described. The compounds were obtained from suitably protected neoglycolipids, in which the lipid chain consisted of 12 to 20 carbon atoms, by ethoxycarbonylphosphonylation at the 6-hydroxyl or 4-hydroxyl group followed by deprotection. The in vitro antiviral activity of the compounds was determined in human foetal lung cells infected with human cytomegalovirus (HCMV) or herpes simplex virus type 1 (HSV-1). Compounds in which the lipid chain consisted of 14 to 20 carbon atoms showed pronounced antiviral activity against HCMV and HSV-1, the highest activity being shown by trans-9-octadecen-1-yl 6-O-carboxyphosphonyl-alpha-D-glucopyranoside against HCMV (approximately 50 times that of foscarnet) and by eicosyl 6-O-carboxyphosphonyl-beta-D-galactopyranoside against HSV-1 (approximately 15 times that of foscarnet). Cytotoxicity was determined by assessing the capability of mitochondrial enzymes to metabolise MTT and gave TC50 values for the compounds that were 30 to 350 times higher than their IC50 values against HCMV and 5 to 15 times higher than their IC50 values against HSV-1. Foscarnet was not liberated on incubation of n-tetradecyl 6-O-carboxyphosphonyl-alpha-D-glucopyranoside with rat liver or intestine homogenate, neither could the neoglycolipid conjugate nor foscarnet be detected in rat plasma following oral administration. Further metabolic and pharmacokinetic studies are required in order to determine whether neoglycolipid conjugates of foscarnet can find a use as drug targeting forms of foscarnet.
Subject(s)
Antiviral Agents/pharmacology , Cytomegalovirus/drug effects , Foscarnet/analogs & derivatives , Glycolipids/chemistry , Herpesvirus 1, Human/drug effects , Animals , Antiviral Agents/blood , Cells, Cultured , Foscarnet/chemistry , Foscarnet/pharmacology , Humans , Magnetic Resonance Spectroscopy , Molecular Structure , RatsSubject(s)
Antigens, Bacterial/chemistry , Bacterial Capsules/chemistry , Disaccharides/chemical synthesis , Haemophilus influenzae/chemistry , Iduronic Acid/analogs & derivatives , Polysaccharides, Bacterial/chemistry , Carbohydrate Sequence , Iduronic Acid/chemical synthesis , Molecular Sequence DataABSTRACT
The synthesis is described of p-nitrophenyl 2-acetamido-3-O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-2-deoxy-beta -D- mannopyranosiduronic acid, corresponding to the disaccharide repeating unit of the capsular polysaccharide of Haemophilus influenzae type d, which, after conversion of the p-nitro- into a p-amino-phenyl residue, may be attached to a protein to make an artificial antigen for immunological studies. The synthesis incorporates a facile route to the 2-acetamido-2-deoxy-beta-D-mannopyranosyl unit.