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2.B.19 The Calix(4)pyrrole Macrocycle Derivative (C4PM) Family

Gale 2011 discussed three classes of synthetic compounds that were modified to bind and transport anions across lipid bilayer membranes, and these studies were updated in 2017 (Gale et al. 2017). All of these compounds were originally designed as anion receptors that form stable complexes with anions but were then further developed as transporters. By studying structurally simple systems and varying their properties to change the degree of preorganization, the affinity for anions, or their lipophilicity, they have rationalized why particular anion transport mechanisms (cotransport or antiport) occur in particular cases. For example, the chloride transport properties of receptors based on the closely related structures of isophthalamide and pyridine-2,6-dicarboxamide suggested that the central ring in each case was augmented with pendant methylimidazole groups designed to cotransport H+ and Cl- (Gale et al. 2017).

The more preorganized a pyridine-based receptor was the more efficient was the transporter, a finding replicated with a series of isophthalamides in which one contained hydroxyl groups designed to preorganize the receptor. This latter class of compound, together with the natural product prodigiosin, can transport bicarbonate (as part of a chloride/bicarbonate antiport process) across lipid bilayer membranes. These synthetic carriers include hydrogen-bonding anionophores as well as halogen-binding ionophores (Gale et al. 2017). A derivative of meso-octamethyloctafluoro-calix[4]pyrrole, compound 2, catalyzed HCO3-/Cl-/NO3- antiport. Still another derivative, strapped calix[4]pyrrole 6, bearing triazole groups, could catalyze both anion/anion antiport and cation/anion symport.  Mono- and bis-indolylurea derivatives as well as squaramide-based compounds also function as anion mobile carriers that can catalyze both Cl-/NO3- exchange and H+/Cl- antiport.

Gale 2011 also studied the membrane transport properties of calix[4]pyrroles. Although the parent meso-octamethylcalix[4]pyrrole functions solely as a Cs+/Cl- cotransporter, other compounds with increased anion affinities can function through an antiport process. One example is octafluoro-meso-octamethylcalix[4]pyrrole; with its electron-withdrawing substituents, it can operate by chloride/bicarbonate antiport. Moreover, calix[4]pyrroles with additional hydrogen bond donors can catalyze chloride/nitrate antiport. Thus, increasing the affinity of the receptor allows the compound to transport an anion in the absence of a cation.  The calix[4]arenes in linear alignment allow rapid anion transmembrane hopping along transmembrane rigid-rod scaffolds (Vargas Jentzsch and Matile 2013). However, Costa et al. 2014 estimated a barrier of ca. 58 kJ/mol for this mobile carrier to cross the membrane.

The transport properties of simple thioureas suggested that these compounds are highly potent chloride/bicarbonate antiport agents that function at low concentrations, although the urea analogues are inactive. The higher hydrophobicities and lower polar surface areas of the thiourea compounds compared to their urea analogues provide clues to the high potency of these compounds.

This family is related to the family with TC# 2.B.13.

References associated with 2.B.19 family:

Costa, P.J., I. Marques, and V. FĂ©lix. (2014). Interaction of a calix[4]arene derivative with a DOPC bilayer: biomolecular simulations towards chloride transport. Biochim. Biophys. Acta. 1838: 890-901. 24316169
Gale, P.A. (2011). From anion receptors to transporters. Acc Chem Res 44: 216-226. 21207951
Gale, P.A., J.T. Davis, and R. Quesada. (2017). Anion transport and supramolecular medicinal chemistry. Chem Soc Rev 46: 2497-2519. 28379234
Vargas Jentzsch, A. and S. Matile. (2013). Transmembrane halogen-bonding cascades. J. Am. Chem. Soc. 135: 5302-5303. 23517007