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2.B.29 The Tambjamine Derivative Anion Channel (TD-AC) or

Anionophoric Marine Alkaloid Tambjamine (AMAT) Family 

The tambjamine alkaloids and related synthetic analogs are potent transmembrane anion tranporters promoting bicarbonate/chloride exchange in model phospholipid liposomes and discharging pH gradients in living cells (Iglesias Hernández et al. 2012). Ten synthetic analogs of tambjamines, bearing aromatic enamine moieties, have been synthesized (Hernando et al. 2014). These compounds proved to be highly efficient transmembrane anion transporters in liposomes. Changes in the electronic nature of the substituents of the aromatic enamine or the alkoxy group of the central pyrrole group did not affect this anionophore activity. These compounds trigger apoptosis in several cancer cell lines with IC50 values in the low micromolar range.  They also modify the intracellular pH, inducing the basification of acidic organelles (Hernando et al. 2014).

Soto-Cerrato et al. 2015 used two potent anionophore analogues of  tambjamines to study the effects induced by these compounds at the cellular level. They showed that active anionophores, capable of facilitating the transmembrane transport of chloride and bicarbonate in model phospholipid liposomes, induce acidification of the cytosol and hyperpolarization of plasma cell membranes, the combined effects of which can be used against cancer stem cells (Soto-Cerrato et al. 2015).

The transmembrane anion transport activity of a series of synthetic molecules, based on the structure of tambjamine alkaloids, can be tuned by varying the lipophilicity of the receptor, with carriers within a certain log P value (n-octanol/water partition coefficient) range performing best (Saggiomo et al. 2012). These compounds transport Cl-, OH- and HCO3-, probably using an antiport mechanism; see Figure 10 in Gale et al. 2017 for the structures of effective derivatives.

References associated with 2.B.29 family:

Gale, P.A., J.T. Davis, and R. Quesada. (2017). Anion transport and supramolecular medicinal chemistry. Chem Soc Rev 46: 2497-2519. 28379234
Hernando, E., V. Soto-Cerrato, S. Cortés-Arroyo, R. Pérez-Tomás, and R. Quesada. (2014). Transmembrane anion transport and cytotoxicity of synthetic tambjamine analogs. Org Biomol Chem 12: 1771-1778. 24500335
Iglesias Hernández, P., D. Moreno, A.A. Javier, T. Torroba, R. Pérez-Tomás, and R. Quesada. (2012). Tambjamine alkaloids and related synthetic analogs: efficient transmembrane anion transporters. Chem Commun (Camb) 48: 1556-1558. 21528145
Saggiomo, V., S. Otto, I. Marques, V. Félix, T. Torroba, and R. Quesada. (2012). The role of lipophilicity in transmembrane anion transport. Chem Commun (Camb) 48: 5274-5276. 22531689
Soto-Cerrato, V., P. Manuel-Manresa, E. Hernando, S. Calabuig-Fariñas, A. Martínez-Romero, V. Fernández-Dueñas, K. Sahlholm, T. Knöpfel, M. García-Valverde, A.M. Rodilla, E. Jantus-Lewintre, R. Farràs, F. Ciruela, R. Pérez-Tomás, and R. Quesada. (2015). Facilitated Anion Transport Induces Hyperpolarization of the Cell Membrane That Triggers Differentiation and Cell Death in Cancer Stem Cells. J. Am. Chem. Soc. 137: 15892-15898. 26632983