Improved Syntheses of Benzyl Hydraphile Synthetic Cation-Conducting Channels

Abstract

The tris(macrocycle)s that function in bilayer membranes as ion channels have recently shown versatile new applications such as antibiotic synergists and as agents for direct injection chemotherapy. This report records the development of new and versatile approaches to these molecules that produce significantly better overall yields for a group of previously reported hydraphiles having spacer chains ranging from octylene to hexadecylene.The advent of synthetic ion channels can be traced to studies by Tabushi and his coworkers, who attached hydrophobic chains to β-cyclodextrin. 1 Subsequent to that, the results of three separate efforts to develop synthetic ion channels appeared almost simultaneously. In the first of these, Jullien and Lehn attached multiple, polar-groupterminated chains to an 18-crown-6 unit. 2 A similar structural element was used by Fyles and coworkers. 3 The hydraphile synthetic ion channels developed in the author's lab also incorporated a macrocycle as a central unit, but it was 4,13-diaza-18-crown-6 rather than a tetracarboxyl-18-crown-6 derivative. 4 The logic of using a diazacrown followed the experience gained from study of the lariat ethers. 5 When residues are attached to all-oxygen crowns, there is a stereochemical issue and the residues must remain on only one side of the macrocycle. When chains are linked through nitrogen atoms within the macrocycle, the system retains a high degree of flexibility and, owing to nitrogen's invertibility, does not experience stereochemical limitations. Of course, these initial examples led to a field of study: numerous synthetic ion channels are now known. 6 Synthetic ion channels have often been described as channel models. To be sure, they are channel models, but they are more than that. In many cases they selectively conduct alkali metal cations or anions such as chloride across liposomal and natural bilayer membranes. These amphiphiles insert into bilayer membranes from the bulk aqueous phase and they show the open-close behavior that is characteristic of natural protein channels. The cation channels exhibit selectivities for one alkali metal over another and larger metals block their function just as is observed in protein channels. Extensive studies defined the biophysics of the hydraphile channels and these results have been reported both in a series of papers and in summary form. 7 Recently, a number of new applications have been discovered for hydraphiles. These include antibiotic activity, 8 antibiotic synergy, 9 and direct injection chemotherapy. 10 Owing to the applications under study, we revisited our initial approach to these compounds in an attempt to develop simpler, more reliable, and versatile syntheses of hydraphiles. Our need was both for different spacer chain lengths and varied side chains. The essential hydraphile core structure is illustrated in Figure 1. In much of our previous work, we have sought to obtain compounds primarily for biological testing and the efficacy of the synthetic approach was a secondary consideration. Th...

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