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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 lipophilicities, 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.

Ballester and co-workers have studied the influence of the method of insertion of aryl-extended calix[4]pyrroles (Grauwels et al. 2019) (see figure below) on their anion transport properties (Martínez-Crespo et al. 2019). An HPTS assay was used to assess the chloride transport properties of these compounds. EYPC LUVs of 100 nm were loaded with HPTS (1 mM) and the internal and external solutions were buffered with NaCl (100 mM) and HEPES (10 mM) at pH 7.0. A pH gradient was generated by adding a NaOH pulse to the external solution, and the transporter was added as a DMSO solution, and dissipation of the pH gradient was monitored by following the ratiometric change in the fluorescence of HPTS (Davis et al. 2020). At the end of the experiment, the proton channel, gramicidin D, was added to equilibrate the pH on both sides of the membrane. Dose–response studies were conducted, and the data fitted to the Hill equation to give EC50 values for the compounds – showing that compound 19 is the most effective chloride transporter from this group of compounds under the conditions of this assay.

The structures of calix[4]pyrroles 19–21.

The compounds in this family are related to those in the family with TC# 2.B.13.

This family belongs to the: Calix[4]Pyrrole Superfamily.

References associated with 2.B.19 family:

Costa, P.J., I. Marques, and V. Félix. (2014). Interaction of a calix[4]arene derivative with a DOPC bilayer: biomolecular simulations towards chloride transport. Biochim. Biophys. Acta. 1838: 890-901. 24316169
Davis, J.T., P.A. Gale, and R. Quesada. (2020). Advances in anion transport and supramolecular medicinal chemistry. Chem Soc Rev. [Epub: Ahead of Print] 32692794
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
Grauwels, G., H. Valkenier, A.P. Davis, I. Jabin, and K. Bartik. (2019). Repositioning Chloride Transmembrane Transporters: Transport of Organic Ion Pairs. Angew Chem Int Ed Engl 58: 6921-6925. 30925004
Martínez-Crespo, L., J.L. Sun-Wang, P. Ferreira, C.F.M. Mirabella, G. Aragay, and P. Ballester. (2019). Influence of the Insertion Method of Aryl-Extended Calix[4]pyrroles into Liposomal Membranes on Their Properties as Anion Carriers. Chemistry 25: 4775-4781. 30830693
Vargas Jentzsch, A. and S. Matile. (2013). Transmembrane halogen-bonding cascades. J. Am. Chem. Soc. 135: 5302-5303. 23517007