Crown ethers biological activity

Vbgtle and Elben have been particularly interested in attaching crown ethers to residues of known biological or pharmacological activity These efforts have been... 

Cleavage of mesyl or tosyl esters with K F in the presence of 18-crown-6 ether [46] or Kryptofix 222 [47] provides a reliable method for the preparation of F-labeled biologically active compounds... 

Supramolecnlar derivatives containing crown ether [228], calixarenes [264, 265] or dendrimers [267, 279] have been synthesized with the precursors shown in Table 4.10. Fullerene-flavonoid [268] or the fuUerene glycoconjugate [258] derived from 237 and 235, respectively, are expected to show biological activity. 

The ability of cyclic ethers to complex biologically important alkylammonium cations makes the choice of crown ethers as enzyme binding site models a natural one. In recent years a number of molecules containing both a crown ether-based substrate binding site and a potentially reactive group have been prepared as models for enzyme active sites (79PAC979, B-82MI52100). 

Competition between mono- and di-valent cations has an important role in biological processes. Furthermore, the lipophilicity of a ligand and its complex plays an important role in deciding whether a species is soluble in organic media of low polarity. This has important consequences in areas such as phase-transfer catalysis, the use of crown ethers as anion activators, and in cation transport through lipid membranes. Many crown ethers have now been synthesized with incorporation of long alkyl side chains and enhanced lipophilicity and used successfully in the above areas. 

Synthetic peptides containing side-chain modification have also been used as molecular scaffolds for the preparation of multiple receptors and molecular devices. 5 These include the use of crown ethers, cyclodextrins, porphyrins, and peptides with metal-binding sites (including ferrocenyl and EDTA side chains) (Section 9.4). Cyclization procedures have been developed to prepare biologically active cycloisodityrosine peptides which contain 14-or 17-membered rings (Section 9.5). The use of tryptathionine, a cross-linking dipeptide consisting of side-chain-to-side-chain linked L-Trp-L-Cys that is present in phallotoxins, 6 a family of cyclic heptapeptides, is also described (Section 9.6). 

Since the discovery in 1964 that the antibiotic valinomydn exhibited alkali cation specificity in rat liver mitochondria, a new area of research has developed, based not only on biological systems but also on model systems such as crown ethers.484 The ability of neutral compounds to form lipid-soluble alkali and alkaline earth complexes was observed in 1951. The structure of the corresponding ligand, the anion of the antibiotic nigericin (78), was characterized as its silver salt in 1968.488 486 Silver was used as a heavy atom crystaUographically, since the Ag+ cation had a radius between that of Na+ and K+, which were the two alkali cations with which nigericin was most active. 

Biological activity refers to a compound s ability either to alter or to mimic a living system or one of its components. A living system could be an entire animal, or even a cell in a Petri dish. Components of a living system would include organelles, proteins, or DNA. Crown ether compounds have been studied to determine their effects at these various levels of life. Crown ethers interact directly with such molecules as DNA and enzymes. Numerous crowns have also been tested for their toxic effects to various mammalian and bacterial cell lines, as well as animals including mice. 

A number of other synthetic ion channels have been developed that incorporate crown ethers as critical elements. They cannot all be described and illustrated in this short chapter but it is important to note them. Voyer and coworkers developed channels that use an a-helical backbone to align a series of crowns into a channel that was both functional and biologically active (Voyer and Robataille, 1995 Voyer et al., 1997). Pechulis and coworkers developed a channel in which a central crown used tartaric acid subunits to anchor steroids, which formed the channel s walls (Pechulis et al., 1997). Mendoza and coworkers prepared an active channel based on a calixaiene central unit but that had crown ether headgroups (de Mendoza et al., 1998). Hall and coworkers modified the tris(macrocycle) design originating in our lab to form a redox-switchable crown that was active in bilayers (Hall et al., 1999, 2003). 

Huang, S. Kuo, H. Hsiao, C. Lin, Y., (2002) Efficient synthesis of redox-switched naphthoquinone thio-crown ethers and their biological activity evaluation Bioorg. Med. Chem. 10, 1947-1952. 

Tsukube, H. Yamada, T. Shinoda, S., (2001) Crown ether strategy toward chemical activation of biological protein functions J. Heterocyclic Chem. 38, 1401-1408. 

Incidentally, C. J. Pedersen s first report on crown ethers and their complexes was published in the same year as the mechanism of the biological activity of valinomycin was clarified [2], Crown ethers are cyclic derivatives of polyethylene glycol of varying ring size, an example of which is also depicted in Figure 2.2.1. The structural relationship with the ionophores is clearly visible. It is thus not surprising that crown ethers also bind metal cations by coordination with the oxygen atoms [1, 3]. 

Owing to the different biological activity of D- and L-enantiomers of seleno-amino acids, the chiral separation of optical isomers has been undertaken in sele-nized yeast and in yeast-based commercial supplements. Both, chiral stationary phase (crown ether) and chiral derivatization prior to reversed-phase HPLC were used [16, 77, 78],... 

There are thousands of discoveries in molecular science reported every year but very few of these are destined to promote a new generation of research activity. The serendipitous preparation of di-benzo-18-crown-6 1 by Pedersen in 1967 [1] and the subsequent discovery [1,2] that 1 and other crown ethers selectively complex biologically relevant alkali and alkaline earth cations was, however, the catalyst for a huge explosion of activity in the field of host-guest or supramolecular chemistry. The resulting inspired and innovative work by Lehn [3,4] on, in particular, the 3-dimensional bicyclic cryptands (e.g., 2) and by Cram [5] on chiral crown ethers and rigid spherands (e.g., 3) was recognised by the award to Pedersen... 

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