title: Structure/activity study of tris(2-aminoethyl)amine-derived translocases for phosphatidylcholine.
abstract: Sulfonamide and amide derivatives of tris(aminoethyl)amine (TREN) are known to facilitate phospholipid translocation across vesicle and erythrocyte membranes; that is, they act as synthetic translocases. In this report, a number of new TREN-based translocases are evaluated for their abilities to bind phosphatidylcholine and translocate a fluorescent phosphatidylcholine probe. Association constants were determined from (1)H NMR titration experiments, and translocation half-lives were determined via 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)/dithionite quenching assays. A rough correlation exists between translocase/phosphatidylcholine association constants and translocation half-lives. The tris-sulfonamide translocases are superior to the tris-amide versions because they associate more strongly with the phospholipid headgroup. The stronger association is due to the increased acidity of the sulfonamide NHs as well as a molecular geometry (as shown by X-ray crystallography) that is able to form tridentate complexes with one of the phosphate oxygens. Two fluorescent translocase analogues were synthesized and used to characterize membrane partitioning properties. The results indicate that the facilitated translocation of phospholipids by TREN-derived translocases is due to the formation of hydrogen-bonded complexes with the phospholipid headgroups. In the case of zwitterionic phosphatidylcholine, it is the neutral form of the translocases that rapidly associates with the phosphate portion of the phosphocholine headgroup. Complexation masks the headgroup polarity and promotes diffusion of the phospholipid-translocase complex across the lipophilic interior of the membrane.
authors.affiliation: Department of Chemistry and Biochemistry and the Walther Cancer Research Center, University of Notre Dame, Notre Dame, Indiana 46556, USA.
authors.forename: J Middleton
authors.initials: JM
authors.lastname: Boon
authors.forename: Timothy N
authors.initials: TN
authors.lastname: Lambert
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Smith
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Beatty
authors.forename: Vesela
authors.initials: V
authors.lastname: Ugrinova
authors.forename: Seth N
authors.initials: SN
authors.lastname: Brown
mesh_terms: D000588:Amines / Q000737:chemistry*; D001693:Biological Transport, Active; D002384:Catalysis; D018360:Crystallography, X-Ray; D005456:Fluorescent Dyes / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008566:Membranes / Q000737:chemistry / Q000201:enzymology*; D008958:Models, Molecular; D015394:Molecular Structure; D010713:Phosphatidylcholines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D014166:Transferases / Q000737:chemistry*
chemical_list: D000588:Amines; D005456:Fluorescent Dyes; D010713:Phosphatidylcholines; D013449:Sulfonamides; D014166:Transferases