Chloride transport across lipid bilayers and transmembrane potential induction by an oligophenoxyacetamide

被引:68
作者
Sidorov, V [1 ]
Kotch, FW [1 ]
Kuebler, JL [1 ]
Lam, YF [1 ]
Davis, JT [1 ]
机构
[1] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA
关键词
D O I
10.1021/ja029372t
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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. Copyright © 2003 American Chemical Society.
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收藏
页码:2840 / 2841
页数:2
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