Chloride transport across lipid bilayers and transmembrane potential induction by an oligophenoxyacetamide.
This contribution describes the discovery and properties of a synthetic, low-molecular weight compound that transports Cl- across bilayer membranes. Such compounds have potential as therapeutics for cystic fibrosis and cancer. The H+/Cl- co-transport activities of acyclic tetrabutylamides 1-6 were compared by using a pH-stat assay with synthetic EYPC liposomes. The ion transport activity of the most active compound, trimer 3, was an order of magnitude greater than that of calix[4]arene tetrabutylamide C1 a macrocycle known to function as a synthetic ion channel. Trimer 3 has an unprecedented function for a synthetic compound, as it induces a stable potential in liposomes experiencing a transmembrane Cl-/SO42- gradient. Data from both pH-stat and 35Cl NMR experiments indicate that 3 co-transports H+/Cl-. Although 3 transports both Cl- and H+ the overall process is not electrically silent. Thus, trimer 3 induces a stable potential in LUVs due to a transmembrane anionic gradient. The ability of trimer 3 to transport Cl-, to maintain a transmembrane potential, along with its high activity at uM concentrations, its low molecular weight, and its simple preparation, make this compound a valuable lead in drug development for diseases caused by Cl- transport malfunction.
Sidorov
Vladimir
V
Department of Chemistry and Biochemistry, University of Maryland at College Park, College Park, MD, 20742, USA.
Kotch
Frank W
FW
Kuebler
Jennifer L
JL
Lam
Yiu-Fai
YF
Davis
Jeffery T
JT
D000081:Acetamides / Q000737:chemistry* / Q000378:metabolism; D000085:Acetates / Q000737:chemistry; D002712:Chlorides / Q000737:chemistry* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D008564:Membrane Potentials; D011522:Protons
D000081:Acetamides; D000085:Acetates; D002712:Chlorides; D008051:Lipid Bilayers; D011522:Protons; C415326:phenoxyacetic acid