title: Molecular umbrella-assisted transport of thiolated AMP and ATP across phospholipid bilayers.
abstract: Two molecular umbrella-nucleoside conjugates (1a and 1b) have been synthesized via thiolate-disulfide displacement by adenosine 5'-O-(3-thiomonophosphate) and adenosine 5'-O-(3-thiotriphosphate) on an activated dimer derived from cholic acid, spermidine, and 5,5'-dithiobis-(2-nitrobenzoic acid). Both conjugates readily enter the aqueous compartment of liposomes made from 1-palmitoyl-2-oleyol-sn-glycero-3-phosphocholine (POPC) and release the free nucleoside upon reaction with entrapped glutathione. Approximately 50% of the thiolated form of AMP is released within 20 min at 23 degrees C; 120 min is required for a similar release of the thiolated form of ATP. The facile cleavage of these conjugates by glutathione, together with the fact that mammalian cells contain millimolar concentrations of this tripeptide in their cytoplasm, suggest that such chemistry may be extended to the practical development of prodrugs, e.g., antisense oligonucleotides that can be delivered into cells.
authors.affiliation: Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania 18015, USA.
authors.forename: Vaclav
authors.initials: V
authors.lastname: Janout
authors.forename: Bingwen
authors.initials: B
authors.lastname: Jing
authors.forename: Steven L
authors.initials: SL
authors.lastname: Regen
mesh_terms: D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism*; D001692:Biological Transport; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism*; D013058:Mass Spectrometry; D015394:Molecular Structure; D010743:Phospholipids / Q000378:metabolism*; D013997:Time Factors
chemical_list: D004337:Drug Carriers; D008051:Lipid Bilayers; D010743:Phospholipids; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate