Large and Stable Transmembrane Pores from Guanosine−Bile Acid Conjugates

Abstract

A variety of natural and synthetic compounds are known to selfassemble to give transmembrane ion channels. 1 Hydrogen-bonded macrocycles that can π-stack are a new type of channel motif. 2 Thus, folate quartets stack to give ion channels in lipid bilayers. 3 This folate assembly had a single-channel conductance of 10-20 picosiemens (pS), values consistent with the quartet's 3 Å diameter. We found that a noncovalent assembly of 16 guanosine monomers could be cross-linked to give a "unimolecular" G-quadruplex that can transport Na + across lipid membranes. 4 We now report that the ditopic guanosine-lithocholate 1 forms discrete channels in phospholipid membranes (Figure 1). These pores are large (nS conductance) and stable, with "open" times of seconds, distinguishing them from most synthetic channels, which typically conduct in the pS range with millisecond lifetimes. 1,5 Lehn and Barboiu have independently shown that ditopic monomers with guanine end groups form supramolecular polymers in cation-templated processes. 6 Possible supramolecular structures built from these ion-templated G 4 -quartets are depicted in Figure 2. In addition to the G 4 -quartet channel, such structures might well stack to form pores for transmembrane transport. Of relevance was Barboiu's demonstration that Na + and K + could be transported across films made from G 4 -quartet polymers. 6b The nucleoside-sterol conjugate 1 has two guanosine groups connected by a bis-lithocholate linker. This spacer was inspired by Kobuke's studies that showed that bis-cholic acid derivatives formed cation-selective channels with pS conductance. 7,8 We envisioned that membrane insertion of 1, followed by formation of G 4 -quartets, might well provide functional pores (Figure 2).Compound 1 was made by coupling 2′,3′-tBDMSi-5′-amino G, 9 with a bis-lithocholic acid. Compound 2, with -NMe amide end groups, was a control. The 1 H NMR spectrum of 1 gave sharp peaks in DMSO-d 6 , a polar solvent that inhibits self-assembly mediated by hydrogen bonding. In contrast, the NMR spectrum of 1 in CDCl 3 gave much broader signals, consistent with self-association in this "poor" solvent.We used CD spectroscopy to gain evidence that 1 forms stacked G 4 -quartets in a nonpolar solvent. 10 Figure 3 shows CD spectra for samples of 1 in CHCl 3 . The CD spectrum of 1 (blue) was taken after isolation from a silica gel. This sample showed a weak Cotton band in the 200-280 nm region, suggesting some stacked G 4 -quartets. 10 We added [2.2.2]-cryptand to ensure that any adventitious cations bound by 1 were sequestered. Indeed, the resulting spectrum (green trace) was inactive. We next stirred the mixture of 1 and [2.2.2]-cryptand in the presence of excess K + 2,6-dinitrophenolate (DNP). The CD spectrum of ditopic 1 was much different after extraction of K + DNP -(red trace). This sample showed a CD signature diagnostic for stacked G-quartets, with a positive band at λ ) 266 nm and a negative peak at λ ) 240 nm. 10 The complex formed by 1 and K + also showed a strong Cotton ba...

Biologically derived metal organic frameworks

“…[134][135][136][137] While the above examples highlight the rich coordination modes of Ade leading in the formation of highly porous bio-MOFs, nucleobases such as Gua and their derivatives, are known to form Gquartet, and G-quadruplexes structures which have emerged as powerful tools for developing nanoscale porous materials and devices. [138][139][140][141][142][143][144][145] Verma et al reacted N9-allylguanine and N9-propargylguanine with cupric halides to form three structures ranging from discreet trinuclear motif to a mixed valence coordination polymer (Table 3, entry 16). [146] The first existing example of a crystallographically characterized nucleobase-incorporated metal-organic polyhedron (TMOP-1, Thyincorporated MOP) has also been reported by Zhou et al (Table 3, entry 17).…”

Effects of Amphiphile Topology on the Aggregation of Oligocholates in Lipid Membranes: Macrocyclic versus Linear Amphiphiles

“…27,28 Synthetic pore-forming agents in recent years have attracted many researchers' attention. Although a number of designs are available, the noncovalent forces utilized in the self-assembling are mostly limited to hydrogen bonds, 29−32 aromatic interactions, 33,34 and metal−ligand coordination. 35,36 The main evidence for the hydrophobically driven pore formation came from leakage assays and various control experiments.…”

Highly Selective Artificial Cholesteryl Crown Ether K+‐Channels

“…Within this context, steroids are important cyclic compounds, [16] intensively used in the construction and stabilization of many ion channel superstructures. [16][17][18] Based on these observations,wedesigned and prepared in this study,aseries of cholesteryl-thioureido-ethylamide crown ethers that selfassemble into robust ion-channels and show ar emarkably high selectivity for the K + against Na + cations,close to that of natural channels.T he thioureido-ethylamide linker connecting crown ether and cholesterol moieties form H-bonded arrays of channel-type stacks of crown ethers disposed in very close proximity pointing towards the center of the channel and expected to serve as ion selectivity filters. [19] Cholesterol moieties aiming to stabilize the channels,a ct as anchoring arms inducing low diffusivity,clustering,and higher preorganization of the macrocycles in lipid bilayers.…”