Channel-mediated transport of ions through lipid bilayers is a particularly important molecular function. [1] Synthetic ion channels can contribute to the understanding of the active conformations of biological ion channels. [2,3] As a result of the ability of tetrahydrofurans (THFs) to complex cations, a channel approach based on oligo-THFs [4] and oligo-THFamino acids [5] was developed. Herein we report on the synthesis of a functional cation channel with a biomimetic channel entrance and exit where THF-amino acids are incorporated as building blocks.
Our biomimetic concept originates at gramicidin A, an ion channel active pentadecapeptide with the sequence HCO-l-Val 1 -Gly 2 -l-Ala 3 -d-Leu 4 -l-Ala 5 -d-Val 6 -l-Val 7 -d-Val 8 -l-Trp 9d-Leu 10 -l-Trp 11 -d-Leu 12 -l-Trp 13 -d-Leu 14 -l-Trp 15 -CONHCH 2 -CH 2 OH. [6] The active conformation of the gramicidin channel in lipid bilayers is a H-bonded head-to-head dimer consisting of two right-handed, single-stranded b 6.3 -helices. [7] The helix turns forming the channel entrance and exit each contain four l-tryptophan residues. It is proposed that the indole side chains of the tryptophan groups contribute to the stabilization of the channel structure by H-bonding to the polar lipid head groups and through electrostatic dipole interactions with the surface potential of the membrane. [8] Our goal is to construct a unimolecular ion channel that would have the advantage of better structural characterization and functional control relative to a self-assembled channel consisting of numerous subunits. THF-gramicidin hybrids 1 and 2 were chosen as target compounds.
Compound 1 contains the heptapetide part (l-Trp-d-Leu) 3l-Trp, a tetra-THF-peptide part, a linker derived from tartaric [**] This work was supported by the Deutschen Forschungsgemeinschaft, the Fonds der Chemischen Industrie, the Volkswagenstiftung, Schering AG, and the Pinguin Foundation.