Catechols as Membrane Anion Transporters

Abstract

ABSTRACT

Title of Document: CATECHOLS AS MEMBRANE ANION

TRANSPORTERS

Sofya Berezin, Doctor of Philosophy, 2009

Directed By:

Professor, Jeffery T. Davis,

Department of Chemistry and Biochemistry

Synthetic anion transporters have potential as antimicrobials, extractants, sensors, etc. Anionophores may also help us understand how natural systems move ions across hydrophobic barriers. While bacterial siderophores and synthetic analogues use catecholates for Fe3+ uptake, this work reports of catechols facilitating biomembrane transport of anions. We demonstrate that simple bis-catechol III-25 is an anion transporter whose activity depends on catechol's substitution and amphiphilicity. We also describe liposomal assays and devised quantitative description that allows one to study facilitated anion transport. These assays indicate that selectivity of III-25 follows the Hofmeister bias: anions which are easier to dehydrate are made more permeable to the membrane by this bis-catechol. We believe that our description of the ion selectivity and mechanism for III-25 opens an outstanding opportunity for those interested in determining the selectivity and mechanism for other synthetic and natural biomembrane ion transporters.

In the beginning of this project we investigated number of simple amides and phenols to evaluate their relative affinity and stoichiometry of interaction with Cl- anion. ESI-MS and 1H NMR analysis showed that a dimer, catechol2*Cl-, was the major complex formed when TBA+Cl- was mixed with excess catechol. Based on this finding we attached two catechols to a TREN scaffold. A hydrophobic alkyl amide groups were linked to TREN's third position. Surprisingly, this simple design led to the active analogs III-23 - III-26. A medium-length, III-25, was the most active compound, indicating that ion transport ability depends on the ability to partition into the biomembrane.

Finally, we noticed that the experimentally observed weak dependence of the transport rates on the anion's hydration energy, namely, kAnion decreasing in the order ClO4- > I- > NO3- > Br- > Cl-, is also seen for some of Nature's anion transporters. Thus, anion permeation into the CFTR chloride channel shows a similar trend. We also observed a nonlinear dependence of kAnion on the concentration of bis-catechol. These findings led us to believe that self-association of III-25 provides transient pores that allow permeation without requiring complete dehydration of the inorganic anions. Future efforts will include incorporating selectivity filters into these bis-catechols to help overcome the Hofmeister bias.