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Receptors of Other Organic Molecules

The foldamers presented so far rely on the folding process to create a cavity that can host smaller molecules (endo-recognition). A different alternative is to use the foldamer molecule as a structural scaffold from which to project appropriate functionality that will interact with potential guests in a spatially controlled manner (exo-recognition).

An example of the second approach is the work of Li et al. in which a previously reported polyarylamide foldamer was ingeniously used as the framework from which to project multiple zinc porphyrins in a radial manner [39, 40]. A short oligomer containing two porphyrin units was synthesized and NMR studies demonstrated that the new receptor was able to bind C60 and C70 derivatives in apolar solvents [39]. As an extension of this work, a longer foldamer was synthesized (Fig. 7.11a) [40]. JH NMR experiments confirmed the presence of intramolecular hydrogen bonds expected in the folded conformation of the circular core. Fullerenes have been shown to interact with porphyrins through p-p interactions, whereas pyridine and imidazole functionalities are well-known zinc binders. A series ofbidentate guest molecules containing both types of functionalities were therefore synthesized (Fig. 7.11b) and their binding to the foldamer was studied. Both the change in the UV-vis spectra and the quenching of the fluorescence of the porphyrins were used to monitor the titrations and estimate the binding constants and stoichiometry of the complexes. Binding constants of up to 106 M_1 were obtained in chloroform. Interestingly, the Job plots for these systems revealed that up to six guests bind to one receptor.

Recently, polymers containing an average of 60 m-phenylene ethynylene units have been functionalized with alkyl sulfonate and l-alanine derivatives to increase their water solubility (Fig. 7.12a) [41, 42]. Like the previously discussed oligo-meric analogs, the polymers have a high propensity to undergo folding in polar solvents. The presence of the sulfonic acid in 16 and the carboxylic acids in 17 ensured that the polymers were completely soluble in water and in other polar solvents such as methanol and DMSO. UV-vis, CD and fluorescence spectra were all consistent with a fully folded structure of 17 at water contents of 60% or more in methanol.

Fig. 7.11 (a) Porphyrin-containing foldamer; (b) Bidentate ligands for the porphyrin-containing foldamer b)

Fig. 7.11 (a) Porphyrin-containing foldamer; (b) Bidentate ligands for the porphyrin-containing foldamer

The foldamers have a central helical hydrophobic core formed by stacked aromatic units and project the negatively charged groups outwards. This general structure presents interesting analogies with a DNA double helix and the possibility of using well known DNA binders to interact with the foldamers. The complex [Ru(bpy)2(dppz)]2+ is a well-known DNA intercalator that becomes photoluminescent after intercalation into the DNA. When the ruthenium complex was

Fig. 7.12 (a) Alkyl sulfonate and L-alanine derivatives of the poly(m-phenylene ethynylene) foldamer; (b) Cationic cyanine dyes used in the binding studies.

added to a solution of the foldamers in water the characteristic orange-red photoluminescence of the complex could be observed. The stoichiometry was estimated as being approximately two metal complexes bound per turn of the helix.

Foldamer 17 was used as a receptor for a series of cationic cyanine dyes (Fig. 7.12b). Binding of these species was studied by the changes in the absorption spectra of the dyes. Additionally, the dyes presented a CD signature when bound to the chiral foldamer 17 which led the authors to suggest that the flat dye molecules form an aggregate in which they intercalate between the turns of the helix. This arrangement maintains the positive charges of the guest molecules and the negative charges of the foldamer in close proximity.

In addition to the foldamers discussed so far, there are a growing number of examples of oligomers that acquire a rigid folded conformation upon binding to a guest molecule or ion. For instance, an oligoindole scaffold has been shown to fold into a helical conformation when chloride is added to a chloroform solution

[43]. Hydrogen bonding to the chloride ion stabilized the folded conformation even in highly competitive solvents such as 10% water in acetonitrile. In a previous study nitrile groups were added to Moore's phenylene ethynylene oligomer

[44]. The modified foldamer underwent folding upon complexation of silver ions in THF. Additionally, many oligomers with coordinating groups such as pyridine and pyrrole have also been studied and their complexes with different metals ions characterized. These complexes receive the general name of helicates and have been extensively reviewed elsewhere [45].

210 | 7 Foldamer-based Molecular Recognition 7.3

Protein Recognition

Biomacromolecules such as DNA and proteins use a variety of structural elements to recognize their respective binding partners including a-helices, b-sheets, bulges, and turns. Subtle differences on the interacting surfaces of biomacromolecules are advantageously used to achieve high levels of specificity and affinity. Disruption of these sensitive interactions can affect cellular pathways and ultimately lead to a variety of diseases. The use of molecular recognition principles to design synthetic molecules that modulate the interaction between biomacromolecules, is therefore an attractive strategy for therapeutic intervention.

Within the past decade, peptides and oligonucleotides have been successfully used to recognize macromolecules such as proteins and DNA; unfortunately, their intrinsic susceptibility to enzyme degradation by proteases and peptidases limit their applicability in vivo. Foldamers, or well-folded non-natural oligomers, offer an attractive alternative due to their structural similarity to natural biopolymers and stability towards degradation [46]. A commonly used approach to target biomacromolecules of interest is to use their native substrates as templates for the design of new foldamers. The use of this strategy led to the development of a plethora of structural mimetics, such as b-peptides, peptoids, and peptide nucleic acids (PNAs), that mimic naturally occurring biopolymers (see Chapters 1, 2 and 8) [47-49]. A common feature of this family of peptidomimetics is a polyamide backbone similar to the one found in natural systems. Alternatively, totally synthetic foldamers that mimic only the functional epitope of extended regions of proteins but not the polyamide backbone have also been developed [50, 51]. In the following section, we will focus on the design strategies used by various groups to develop foldamers to target biomolecules. As in the previous section, we will discuss only those examples where the presence of a folded structure prior to binding was well characterized.

The development of modulators of protein-protein interactions has remained a challenging task primarily because such large interfacial areas are involved [52]. However, despite these obstacles there is an increasing number of examples where non-natural ligands (small molecules and foldamers) have succeeded in disrupting protein-protein interactions [52-56].

When developing modulators of protein-protein interactions, one of the two interacting partners is often used as a template for the design. Structural analysis of the complex, with methods such as X-ray crystallography, NMR, and alanine scanning, can reveal those structural features that are important for complex formation. With this information in hand, it may be possible to reproduce or graft the functional epitope onto a non-natural scaffold. Furthermore, the affinity of a molecule can be improved by developing stabilizing interactions not present in the natural system through the modification of functional groups.

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