Chloride, carboxylate and carbonate transport by ortho-phenylenediamine-based bisureas

abstract

Highly potent but structurally simple transmembrane anion transporters are reported that function at receptor to lipid ratios as low as 1 : 1 000 000. The compounds, based on the simple ortho-phenylenediamine-based bisurea scaffold, have been studied for their ability to facilitate chloride/nitrate and chloride/bicarbonate antiport, and HCl symport processes using a combination of ion selective electrode and fluorescence techniques. In addition, the transmembrane transport of dicarboxylate anions (maleate and fumarate) by the compounds was examined. Molecular dynamics simulations showed that these compounds permeate the membrane more easily than other promising receptors corroborating the experimental efflux data. Moreover, cell based assays revealed that the majority of the compounds showed cytotoxicity in cancer cells, which may be linked to their ability to function as ion transporters.

keywords

TRANSMEMBRANE ANION TRANSPORTERS; ISOMERIC DICARBOXYLATE ANIONS; STEROID-BASED RECEPTORS; CONFORMATIONAL CONTROL; MOLECULAR RECOGNITION; INTRACELLULAR PH; IN-VITRO; SELECTIVE DISCRIMINATION; GLUTAMATE TRANSPORTERS; MEMBRANE TRANSPORTERS

subject category

Chemistry

authors

Moore, SJ; Haynes, CJE; Gonzalez, J; Sutton, JL; Brooks, SJ; Light, ME; Herniman, J; Langley, GJ; Soto-Cerrato, V; Perez-Tomas, R; Marques, I; Costa, PJ; Felix, V; Gale, PA

our authors

acknowledgements

PAG thanks the EPSRC for a PhD studentship (SJM) and for access to the crystallographic facilities at the University of Southampton.72 CJEH thanks the EPSRC for a Doctoral Prize. This work was supported by a research grant from the Spanish government and the European Union (FIS-PI10/00338). The modelling studies were supported by the FEDER, through the Operational Program Competitiveness Factors - COMPETE and National Funds through FCT (Fundacao para a Ciencia e a Tecnologia) under project PTDC/QUI-QUI/101022/2008. PJC thanks FCT for the postdoctoral grant SFRH/BPD/27082/2006.

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