Structure-activity studies of ion channel mimics
Date
2018-06-28
Authors
James, Tony David
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Abstract
A sub-unit approach to synthetic ion channels is employed which allows
for easy construction of a set of candidate structures. The construction set
includes cores, walls and head groups. The cores are crown ethers derived
from tartaric acid: 2R,3R- or 2R,3S-(18C61)-2,3-dicarboxylic acid, 2R,3R,11R,-
12R- or 2R,3S,llR,12S-(18C61)-2,3,ll,12-tetracarboxylic acid and 2R,3R,8R,-
9R,14R,15R-(18C61)-2,3,8,9,14,15-hexacarboxylic acid. The crown ether is
attached via an ester and a three carbon spacer to a wall unit by a thioether
linkage. The walls are macrocyclic diene tetraesters derived from maleic
anhydride and diols: (compounds 2, 7, 11, 21 and 27). A Michael reaction with
3-thiopropanol produces the thioether linkage. The monoalcohol produced is
converted to an iodide; the esters to the crown ethers are then obtained by
nucleophilic displacement of this iodide by a crown ether carboxlate. The
resulting di-, tetra- and hexaene intermediates are converted to the final
compounds by addition of head groups by a second Michael reaction, with (β-D-
1-thioglucose, thioacetic acid or 3-thiopropanol. Using the construction set,
twenty-one compounds were prepared for transport evaluation.
The transport of alkali metal cations across lipid bilayers of large
unilamellar vesicles was monitored by the collapse of a proton gradient. Of the
twenty one compounds surveyed, twelve of the most active were studied in
118C6=1,4,7,10,13,16-hexaoxocyclooctadecane detail (compounds 44, 45, 46, 47, 48, 49, 50, 51, 55, 56, 62 and 63); the other
nine compounds (compounds 52, 53, 54, 57, 58, 59, 60, 61 and 64) were not
sufficiently active for full characterisation. Transport mechanisms for the
twelve active compounds were investigated in parallel with gramicidin D (a
channel) and valinomycin (a carrier). The transport properties examined were
concentration dependence of transporter, cation selectivity and concentration
dependence, and inhibition of the transport of K+ or Na+ by Li+. Catior
selectivities and inhibition studies proved the best tool for differentiating the
channel or carrier behaviours. Carriers exhibited Eisenman cation selectivity
sequences III or IV for metal ions and showed no inhibition of Na+ or K+
transport by added Li+. Conversely, channels exhibited non-Eisenman cation
selectivities and transport of Na+ or K+ is inhibited by Li+. From comparative
studies, five of the twelve compounds have strong similarities to valinomycin
and are presumed to act as ion carriers (compounds 44, 47, 48, 50 and 55).
The remaining seven are similar to gramicidin (compounds 45, 46, 49, 51, 56,
62 and 63). Within the group of ion channels, two classes of behaviour were
encountered. Most compounds produce a first order decay of the imposed
proton gradient (compounds 49, 51, 56 and 63) but some showed a zero order
decay in the proton gradient (compounds 45, 46 and 62). These results are
rationalised by a qualitative model which focuses on the relative rates of
transfer of ion channel between vesicles, the gating or activation of the ion
channel and the equilibration of a vesicle by the ion channel in an open form.
Description
Keywords
Ion channels, Biological transport, Active