Structure-activity relationships in tripodal transmembrane anion transporters: the effect of fluorination.
Structure-activity relationships in tripodal transmembrane anion transporters: the effect of fluorination.
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DOI：
10.1021/ja205884y
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发表时间：
2011-09-07
影响因子：
15
通讯作者：
Gale, Philip A.
中科院分区：
文献类型：
--
作者：
Busschaert, Nathalie;Wenzel, Marco;Light, Mark E.;Iglesias-Hernandez, Paulina;Perez-Tomas, Ricardo;Gale, Philip A.
制备了一系列易于制备的含脲和硫脲基团的氟化三脚架型阴离子转运体，并研究了它们的阴离子转运性能。使用离子选择性电极的囊泡阴离子转运试验表明，这类化合物能够通过多种机制，包括氯化物/H+共转运和氯化物/硝酸盐，氯化物/碳酸氢盐，并在较小程度上不寻常的氯化物/硫酸盐反向转运过程中通过脂质双层转运氯化物。计算表明，增加三足跨膜转运蛋白的亲脂程度增加了转运蛋白的亲脂性，并且这被证明是氟化化合物的上级转运活性的主要贡献因素，其中对于堵塞物P = 8实现了最大转运速率。最活跃的转运蛋白5含有一个尿素功能附加一个3，5-双（三氟甲基）苯基基团，并能够介导跨膜氯离子转运在受体与脂质的比例低至1：250000。质子NMR滴定和单晶X-射线衍射揭示了三足受体在溶液和固态中以1：1或2：1的化学计量以不同的亲和力结合不同阴离子的能力。我们还提供了证据表明，最有效的阴离子转运蛋白能够诱导人类癌细胞凋亡，通过使用体外活力和荧光测定的选择。
A series of easy-to-make fluorinated tripodal anion transporters containing urea and thiourea groups have been prepared and their anion transport properties studied. Vesicle anion transport assays using ion-selective electrodes show that this class of compound is capable of transporting chloride through a lipid bilayer via a variety of mechanisms, including chloride/H+ cotransport and chloride/nitrate, chloride/bicarbonate, and to a lesser extent an unusual chloride/sulfate antiport process. Calculations indicate that increasing the degree of fluorination of the tripodal transmembrane transporters increases the lipophilicity of the transporter and this is shown to be the major contributing factor in the superior transport activity of the fluorinated compounds, with a maximum transport rate achieved for clog P = 8. The most active transporter 5 contained a urea functionality appended with a 3,5-bis(trifluoromethyl)phenyl group and was able to mediate transmembrane chloride transport at receptor to lipid ratios as low as 1:250000. Proton NMR titration and single crystal X-ray diffraction revealed the ability of the tripodal receptors to bind different anions with varying affinities in a 1:1 or 2:1 stoichiometry in solution and in the solid state. We also provide evidence that the most potent anion transporters are able to induce apoptosis in human cancer cells by using a selection of in vitro viability and fluorescence assays.
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影响因子：
15
作者：
Boon, JM;Smith, BD
通讯作者：
Smith, BD
影响因子：
8.4
作者：
Andrews, Natalie J.;Haynes, Cally J. E.;Gale, Philip A.
通讯作者：
Gale, Philip A.
影响因子：
15
作者：
Berezin, Sofya Kostina;Davis, Jeffery T.
通讯作者：
Davis, Jeffery T.
影响因子：
15
作者：
Bennett, W. F. Drew;MacCallum, Justin L.;Tieleman, D. Peter
通讯作者：
Tieleman, D. Peter
影响因子：
2.9
作者：
BIWERSI, J;TULK, B;VERKMAN, AS
通讯作者：
VERKMAN, AS