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2.B.32 The Acyclic Tetrabutylamide (ACTB) Family 

H+/Cl- co-transport activities of six acyclic tetrabutylamides were compared in synthetic EYPC liposomes (Sidorov et al. 2003). The ion transport activity of the most active compound, trimer 3, was an order of magnitude greater than that of calix[4]arene tetrabutylamide C1, a macrocycle known to function as a synthetic ion channel. Trimer 3 induces a stable potential in liposomes experiencing a transmembrane Cl-/SO42- gradient. It co-transports H+ and Cl-. The overall process is not electrically silent as trimer 3 induces a stable potential  due to the transmembrane anionic gradient. Thus, the low molecular weight trimer 3 transports Cl-, maintains a transmembrane potential, and has high activity at μM concentrations (Sidorov et al. 2003).

Amide functionalized calix[4]-arenes and acyclic oligophenoxyacetamides transport Cl- across membranes. zmost effective of these Cl- transporters were the partial cone calix[4]arene (paco3), snd an acyclic trimer of phenoxyacetamide (Seganish et al. 2006). The C3-symmetric triamide selectively transports NO3- anions across lipid vesicles. This H+:NO3- co-transporter alters the pH inside of liposomes experiencing a NO3-/Cl- gradient (Santacroce et al. 2006). For example, tris(5-nitro-2-butylamidomethoxyphenyl) methane selectively transports NO3- over Cl-

Prodigiosin is the parent compound of the tripyrrolic natural products known as the prodigiosenes. Some of these natural products and their synthetic analogs show anti-cancer, immunosuppressive and antimicrobial actions, amongst otherbiological activities. One mechanism put forth to explain their biological activity is that since prodigiosenes are typically protonated at physiological pH, they can alter intracellular pH via HCl co-transport (or Cl-/OH- exchange) across cell membranes. Prodigiosene analogs with different -O-aryl substituents attached to the B-ring of the tripyrrolic skeleton have been synthesized, and these analogs can exist as a mixture of two stable α and β conformers in acidic solution, both of which can bind anions in solution. The electronic nature of the O-aryl substituent on the B-ring influences the rate at which these prodigiosenes catalyze transmembrane anion transport, i.e. the prodigiosenes with the higher pKa had greater Cl-/NO3- exchange rates (Marchal et al. 2014). Synthetic ion transporters can induce apoptosis by allowing Cl- transport into cells (Davis 2014). The design of small molecule anion carriers has been reviewed in addition to advances in the design of synthetic anion channels (Gale et al. 2017).

Calixarene-based artificial ionophores catalyze chloride transport across natural liposomal bilayers. For example, an amphiphilic calix[6]arene, alone or complexed with an axle to form a pseudo-rotaxane, has been embedded into liposomes prepared from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and the permeability of the membrane-doped liposomes towards Cl- ions has been evaluated by using lucigenin as the fluorescent probe. The pseudo-rotaxane promotes transmembrane transport of Cl- ions more than calix[6]arene does. The quenching of lucigenin was very fast for liposomes doped with the positively charged axle alone. Molecular dynamics (MD) simulations and quantum-chemical calculations provided semi-quantitative support for these results (Pilato et al. 2021). The rotaxanes described here may be structurally related to those in TC family 2.B.60.

Photoswitchable calixarenes are available for the light-controlled transport activation of cationic peptide cargos across model lipid bilayers and inside living cells. This approach was based on rationally designed p-sulfonatocalix[4]arene receptors equipped with a hydrophobic azobenzene arm, which recognize cationic peptide sequences in  the nM range (Martins et al. 2023). Activation of membrane peptide transport occurs in synthetic vesicles and living cells, especially for calixarene activators featuring the azobenzene arm in the E configuration.



References associated with 2.B.32 family:

Davis, J.T. (2014). Ion transport: Tipping a cell''s ionic balance. Nat Chem 6: 852-853. 25242476
Gale, P.A., J.T. Davis, and R. Quesada. (2017). Anion transport and supramolecular medicinal chemistry. Chem Soc Rev 46: 2497-2519. 28379234
Marchal, E., S. Rastogi, A. Thompson, and J.T. Davis. (2014). Influence of B-ring modifications on proton affinity, transmembrane anion transport and anti-cancer properties of synthetic prodigiosenes. Org Biomol Chem 12: 7515-7522. 25204645
Martins, J.N., B. Raimundo, A. Rioboo, Y. Folgar-Cameán, J. Montenegro, and N. Basílio. (2023). Photoswitchable Calixarene Activators for Controlled Peptide Transport across Lipid Membranes. J. Am. Chem. Soc. [Epub: Ahead of Print] 37289668
Pilato, S., M. Aschi, M. Bazzoni, F. Cester Bonati, G. Cera, S. Moffa, V. Canale, M. Ciulla, A. Secchi, A. Arduini, A. Fontana, and G. Siani. (2021). Calixarene-based artificial ionophores for chloride transport across natural liposomal bilayer: Synthesis, structure-function relationships, and computational study. Biochim. Biophys. Acta. Biomembr 1863: 183667. 34111414
Santacroce, P.V., O.A. Okunola, P.Y. Zavalij, and J.T. Davis. (2006). A transmembrane anion transporter selective for nitrate over chloride. Chem Commun (Camb) 3246-3248. 17028758
Seganish, J.L., P.V. Santacroce, K.J. Salimian, J.C. Fettinger, P. Zavalij, and J.T. Davis. (2006). Regulating supramolecular function in membranes: calixarenes that enable or inhibit transmembrane Cl- transport. Angew Chem Int Ed Engl 45: 3334-3338. 16607664
Sidorov, V., F.W. Kotch, J.L. Kuebler, Y.F. Lam, and J.T. Davis. (2003). Chloride transport across lipid bilayers and transmembrane potential induction by an oligophenoxyacetamide. J. Am. Chem. Soc. 125: 2840-2841. 12617627