The ion-coupled processes that occur in the plasma membrane regulate the cell machineries in all the living organisms. The details of the chemical events that allow ion transport in biological systems remain elusive. However, investigations of the structure and function of natural and artificial transporters has led to increasing insights about the conductance mechanisms. Since the publication of the first successful artificial system by Tabushi and co-workers in 1982, synthetic chemists have designed and constructed a variety of chemically diverse and effective low molecular weight ionophores. Despite their relative structural simplicity, ionophores must satisfy several requirements. They must partition in the membrane, interact specifically with ions, shield them from the hydrocarbon core of the phospholipid bilayer, and transport ions from one side of the membrane to the other. All these attributes require amphipathic molecules in which the polar donor set used for ion recognition (usually oxygens for cations and hydrogen bond donors for anions) is arranged on a lipophilic organic scaffold. Playing with these two structural motifs, donor atoms and scaffolds, researchers have constructed a variety of different ionophores, and we describe a subset of interesting examples in this Account. Despite the ample structural diversity, structure/activity relationships studies reveal common features. Even when they include different hydrophilic moieties (oxyethylene chains, free hydroxyl, etc.) and scaffolds (steroid derivatives, neutral or polar macrocycles, etc.), amphipathic molecules, that cannot span the entire phospholipid bilayer, generate defects in the contact zone between the ionophore and the lipids and increase the permeability in the bulk membrane. Therefore, topologically complex structures that span the entire membrane are needed to elicit channel-like and ion selective behaviors. In particular the alternatecalix[ 4]arene macrocycle proved to be a versatile platform to obtain 3D-structures that can form unimolecular channels in membranes. In these systems, the selection of proper donor groups allows us to control the ion selectivity of the process. We can switch from cation to anion transport by substituting protonated amines for the oxygen donors. Large and stable tubular structures with nanometric sized transmembrane nanopores that provide ample internal space represent a different approach for the preparation of synthetic ion channels. We used the metal-mediated self-assembly of porphyrin ligands with Re(I) corners as a new method for producing to robust channel-like structures. Such structures can survive in the complex membrane environment and show interesting ionophoric behavior. In addition to the development of new design principles, the selective modification of the biological membrane permeability could lead to important developments in medicine and technology.

Ion Transport through Lipid Bilayers by Synthetic Ionophores: Modulation of Activity and Selectivity

TECILLA, PAOLO
2013

Abstract

The ion-coupled processes that occur in the plasma membrane regulate the cell machineries in all the living organisms. The details of the chemical events that allow ion transport in biological systems remain elusive. However, investigations of the structure and function of natural and artificial transporters has led to increasing insights about the conductance mechanisms. Since the publication of the first successful artificial system by Tabushi and co-workers in 1982, synthetic chemists have designed and constructed a variety of chemically diverse and effective low molecular weight ionophores. Despite their relative structural simplicity, ionophores must satisfy several requirements. They must partition in the membrane, interact specifically with ions, shield them from the hydrocarbon core of the phospholipid bilayer, and transport ions from one side of the membrane to the other. All these attributes require amphipathic molecules in which the polar donor set used for ion recognition (usually oxygens for cations and hydrogen bond donors for anions) is arranged on a lipophilic organic scaffold. Playing with these two structural motifs, donor atoms and scaffolds, researchers have constructed a variety of different ionophores, and we describe a subset of interesting examples in this Account. Despite the ample structural diversity, structure/activity relationships studies reveal common features. Even when they include different hydrophilic moieties (oxyethylene chains, free hydroxyl, etc.) and scaffolds (steroid derivatives, neutral or polar macrocycles, etc.), amphipathic molecules, that cannot span the entire phospholipid bilayer, generate defects in the contact zone between the ionophore and the lipids and increase the permeability in the bulk membrane. Therefore, topologically complex structures that span the entire membrane are needed to elicit channel-like and ion selective behaviors. In particular the alternatecalix[ 4]arene macrocycle proved to be a versatile platform to obtain 3D-structures that can form unimolecular channels in membranes. In these systems, the selection of proper donor groups allows us to control the ion selectivity of the process. We can switch from cation to anion transport by substituting protonated amines for the oxygen donors. Large and stable tubular structures with nanometric sized transmembrane nanopores that provide ample internal space represent a different approach for the preparation of synthetic ion channels. We used the metal-mediated self-assembly of porphyrin ligands with Re(I) corners as a new method for producing to robust channel-like structures. Such structures can survive in the complex membrane environment and show interesting ionophoric behavior. In addition to the development of new design principles, the selective modification of the biological membrane permeability could lead to important developments in medicine and technology.
ACCOUNTS OF CHEMICAL RESEARCH
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11368/2737296
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