Self-assembled ionophores

Fig. 3 A self-assembling ionophore. Formation of a Ni(II)-salicylaldimine complex preorganizes a crown ether-like cation binding site...

Schepartz A, McDevitt JP (1989) Self-assembling ionophores. J Am Chem Soc 111 5976-5977... 

Other approaches to self-assembling receptors have been reported in recent years. A self-assembling, trimeric palladium complex based on the bis(benzimidazole) ligand (17) was designed by Williams and coworkers [4]. The complex contains a hydrophobic cavity that in the X-ray structure has included a molecule of acetonitrile. In a different context, Schepartz and McDevitt [70] have used the chelation of nickel(n) by A,7V -bis(salicylaldehy-de)ethylenediamine (salen) derivatives to control the position of K -binding glyme chains, and it has been shown that these self-assembled ionophores influence alkali metal transport across liquid membranes [71]. Also, Shinkai and coworkers [72] and Schneider and Ruf [73] have used metal chelation to induce an allosteric effect on binding at a second site. 

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]. 

Regen58 used amphotericin B as a design basis for the structural requirements of an ion channel. Composed of a rigid, hydrophobic sterol nucleus and flexible hydrophilic chains, 50 was expected to function via self-assembly in a membrane bilayer. Cation flux was assessed using Lehn s NMR method and comparisons were made with the bouquet molecules. Ionophoric activity was similar to the more sophisticated bouquet molecules (maximum entry achieved in ca. 60 h), but Na+ transport was significantly less than recorded with amphotericin B. 

Lee SC, Lamb JD, Cai M, Davis JT. Cs and Ba selective transport by a novel self-assembled isoguanosine ionophore through polymer inclusion and bulk hquid membranes. J Inclusion Phenom Macrocychc Chem 2001 40 51-57. 

The synthesis of cahx[4]arene dimelamines with different functionalities and their self-assembly with barbituric and cyanuric acid to hydrogen-bonded nanostructures have been published <05OBC3727> Unique ionophores of penta-crown ethers have been prepared by the reaction of l,3,5-triacryloylhexahydro-l,3,5-triazine (TAHTA) with diaza 18-crown-6 followed by Michael addition, and their binding capabilities towards alkali metal cations studied <05SL2257>. New silver complexes of polydentate ligands including a derivative of pyrazol-l-yl-l,3,5-triazine have been reported <05EJ14370>. 

Other self-assembly approaches have been applied in order to obtain polynuclear metallacycles for potential medical applications, for example, counterion encapsulation [84] or use as organometallic ionophores [85] employing halfsandwich Ru(II), Rh(III), or Ir(III) building blocks. Despite the fact that some of these species have a chiral environment around the metal, studies of comparative cytotoxicity between single homochiral or heterochiral systems have not been carried out as yet. 

During the past decade, numerous studies have been undertaken to develop synthetic ionophores that might permit cations or molecules to pass through a lipid bilayer [1]. Naturally-occurring gramicidin A is known to form transmembrane channels [2] and efforts to prepare a cation-conducting channel have been reported as well [3]. In our work, we have studied the selectivity of numerous crown ethers, lariat ethers [4, 5], and multi-armed versions of the latter [6]. Much has been learned about flexible ionophores and we have now attempted to utilize the concepts of flexibility and self-assembly to permit construction of a cation- or molecule-conducting channel. 

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