Ionophores artificial

Schemes of electron transfer interactions of FNR in thylakoid membranes are deduced mainly from experimental results obtained in model systems (reviewed in 1). Pioneering works by Bouges-Bocquet (4), who studied flash-induced transient of FNR in algal cells, has not tDeen followed by systematic investigations in isolated chloroplasts and thylakoid membranes. In algal cells, ambiguity arises from intense light scattering (5). Low permeability of the cell wall also restricts the use of inhibitors, ionophores, artificial acceptors and substrates. It is consequently necessary to confirm and extend these earlier studies using isolated thylakoid membranes and/or subchloroplast particles.

In mimicking this type of function, noncyclic artificial carboxylic ionophores having two terminal groups of hydroxyl and carboxylic acid moieties were synthesized and the selective transport of alkali metal cations were examined by Yamazaki et al. 9 10). Noncyclic polyethers take on a pseudo-cyclic structure when coordinating cations and so it is possible to achieve the desired selectivity for specific cations by adjusting the length of the polyether chain 2). However, they were not able to observe any relationship between the selectivity and the structure of the host molecules in an active transport system using ionophores 1-3 10). (Table 1)... 

Anyway, it is clear that the fmdings obtained in these artificial transport systems do contribute to the understanding of biological phenomena and point the way to possible practical applications, such as the separation of ions. Accordingly, the development of synthetic ionophores which possess high selectivity for specific cations is expected to gain importance in the future. 

In the biological field, much attention has been directed toward the transport phenomena through membrane. Although the function of some natural ionophores has been known, the investigation of active and selective transport of ions using the artificial ionophores in the simple model systems may be important to simulate the biological systems and clarify the transport behaviour of natural membranes. 

The effects can be mimicked in vitro by a Ca ionophore, an agent that increases Ca ion entry into a cell, plus artificial activation of the phospholipase. 

I would like to extend Prof. Simon s characterizations of these beautiful new molecules to include a description of the effects on lipid bilayers of his Na+ selective compound number 11, which my post-doctoral student, Kun-Hung Kuo, and I have found to induce an Na+ selective permeation across lipid bilayer membranes [K.-H. Kuo and G. Eisenman, Naf Selective Permeation of Lipid Bilayers, mediated by a Neutral Ionophore, Abstracts 21st Nat. Biophysical Society meeting (Biophys. J., 17, 212a (1977))]. This is the first example, to my knowledge, of the successful reconstitution of an Na+ selective permeation in an artificial bilayer system. (Presumably the previous failure of such well known lipophilic, Na+ complexing molecules as antamanide, perhydroan-tamanide, or Lehn s cryptates to render bilayers selectively permeable to Na+ is due to kinetic limitations on their rate of complexation and decomplexation). 

Examples such as this show the importance of alkali metal cation binding and transport in biochemistry, and a great deal of effort has been expended in supramolecular chemistry in attempts to understand natural cation binding and transport of the ionophore and channel type and to develop artificial systems capable of similar selectivities and reactivities. We will take a close look at many of these compounds in Chapter 3. 

Alkali metal transport in biochemistry is a vital process in maintenance of cell membrane potentials of use, for example, in nerve signal transduction and is at the core of some of the early work on artificial ionophores that mimic natural ion carriers such as valinomycin. Ionophore mediated ion transport is much slower than transport through cation and anion ion channel proteins, however. 

From your answers to question 3.6 or otherwise, suggest artificial systems that mimic (a) some of the properties of the natural ionophores and (b) features of transmembrane ion channels. 

We have already seen in Section 2.2 how the transport of both anions and cations is a vital part of biochemistry. We will examine supramolecular models of biological ion channels in detail in Chapter 12 but here we focus on some simple ion transport systems (ionophores) relevant to simultaneous anion and cation binding. Because of the need to maintain overall and local charge neutrality during any transport process the transport of individual ions across a biological or artificial membrane never occurs in isolation. There are two kinds of primary transport processes. Ion exchange or antiport, occurs when chemically different ions of like charge such as Na+ and K+ are simultaneously transported in... 

Another way to assess ion channel conductance is to use artificial phospholipid vesicles (liposomes) as cell models. These structures (described in more detail in the next chapter) are commonly used to transport vaccines, drugs, enzymes, or other substances to target cells or organs. The vesicles, which are several hundred nanometres in diameter, do not suffer from interference from residual natural ion channel peptides or ionophores, unlike purified natural cells. A liposome model was used to test the ion transport behaviour of the redox-active hydraphile 12.36. The compound transports Na+ and the process can also be monitored using 23Na NMR spectroscopy.26 The presence of the ferrocene-derived group in the central relay allows the ion transport to be redox-controlled - oxidation to ferrocinium completely prevents Na+ transport for electrostatic reasons. Some representative data from a planar bilayer measurement is shown for hydraphile 12.36 in Figure 12.16. 

Model systems have been developed for many of these ion-transport mechanisms in the context of bioorganic chemistry. Examples are the cyclic peptides, described by M. R. Ghadiri et al., that have antibiotic activity similar to that of ionophores, a property that is most probably caused by the ability of these peptides to self-assemble inside biological membranes into channels [1], Other compounds able to induce the formation of membrane pores are the bouquet-molecules introduced by J.-M. Lehn [2]. Artificial / -barrels have been developed by S. Matile s group [3]. Many host molecules used in bioorganic chemistry can serve as carriers for ions across membranes and have even made possible the development of systems with which active ion transport can be achieved [4]. 

Many artificial complexants, in particular the crown ethers, are proposed to work by ionophore-facilitated ion transport. Crown ethers, such as those in Fig. 5.12, have... 

Fig. 5.12 Artificial ionophores and siderophores (left to right) Na+-selective [15]crown-5, K+-selective [18]crown-6, Fe3+-selective cryptand and podand...

Channels may be created artificially by substances called ionophores. Many ionophores are antibiotics and are specific for small ions. Thus, gramicidin (see Chapter 4) creates channels that permit the flow of K+, Na+, and H+ across membranes. Gramicidin is a small a-helical peptide, but when two molecules are lined up end to end, the complex becomes about 3 nm in length and can span the lipid bilayer. The ions pass through its central pore. 

Artificial systems permitting the transport of cations have been inserted into natural membranes and into artificial vesicles. These are known as ionophores, and there are two types, exemplified by gramicidin A and valinomycin. 

A diverse number of approaches to the design of artificial ion channels and the study of their transport has been described. The ability of these systems to be effective as ion channels varies considerably, but taken together they show that the activity of structurally simple ionophores can mimic those of their more illustrious natural counterparts. The challenge of controlling selectivity and the phenomenon of gating or rectification remains to be overcome in artificial systems but the expansion of knowledge in the field of supramolecular chemistry promises to resolve many of the outstanding questions in the near future. 

Crown ethers were the first artificial host molecules discovered. They were accidentally found as a byproduct of an organic reaction. When Pedersen synthesized bisphenol, contaminations from impurities led to the production of a small amount of a cyclic hexaether (Fig. 2.1). This cychc compound increased the solubihty of potassium permanganate in benzene or chloroform. The solubility of this cyclic compound in methanol was enhanced in the presence of sodiiun ion. Based on the observed phenomena, Pedersen proposed that a complex structure was formed where the metal ion was trapped in a cavity created by the cychc ether. At that time, it was already known that naturally occurring ionophores such as valinomycin incorporated specific metal ions to form stable complexes because of this, compounds able to selectively include metal ions were the source of much attention from researchers. Pedersen called the cychc compound a crown ether, because the cychc host wears the ion guest like a crown. 

Figure 8.29. Ion transport mechanisms through lipid membranes in living cells. There are principally two kinds of transport protein (a) channel proteins, that is, a channelforming ionophore, and (b) carrier proteins, that is, a mobile ion carrier ionophore. The phenomena observed in living cells have much in common with those in artificial polymer membrane ion-selective electrodes. (From Widmer, 1993.)...

Fig. 2.1 Chelate effects in high affinity artificial complexes (1) an artificial siderophore with K =l0 M (2) a ionophore binding Cs" ions in chloroform with AC = 90 kj/mol (3) an azacrown ether and triphosphate residue (as in ATP) as guest, with /f=10" M" (only 7 out of the possible 10 to 12 charge-charge...

To achieve high selectivity, a substrate-specific receptor must be present in the membrane phase, in which it can act as a carrier between source and receiving phase. Whereas in biological membranes this task is fulfilled by ionophores such as vahnomycin (1), in artificial membranes we rely on the realm of synthetic macrocyclic receptors developed during the past two decade [83]. 

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