Chapter Introduction 1.1 Background In nature, most of the amazing functions carried out by biomacromolecules, such as molecular recognition, catalysis and information storages, involve compact and stable solution structures approaching conformational uniqueness. In order to gain deeper insight into the operation of the nature’s biomacromolecules as well as to identify new molecules that display bio-functional performances, developing new molecules that adopt well-defined conformations have been the object of very active research during the last twenty years. This field of study has come to be known as foldamers. Foldamers were defined as oligomers that fold into a conformationally ordered state in solution, the structures of which are stabilized by a collection of noncovalent interactions among monomer units.1 To design foldamers rationally, several issues within the field of protein folding should be taken into consideration. Predictability is the primary consideration in the design of secondary motifs to determine the potential usefulness of foldamers. In addition, stability, tunability and ease of synthesis are also essential features for designing foldamers. Until now, two major categories of foldamers have been studied: single-stranded foldamers that fold (peptidomimetics and their abiotic analogues) as well as multiple-stranded foldamers that both fold and associate (nucleotidomimeitics and their abiotic analogues). Generally, single-stranded abiotics are unnatural backbones that mimic secondary structures, such as folding and helices, while multi-stranded foldamers simulate such as double-helical conformations existing in oligonucleotides. Since the pioneering work of Gellman,2 single-stranded oligomers that fold into well-defined secondary structures have been extensively investigated. In the earlier studies, a large number of artificial peptidomimetic systems such as aliphatic α-, β-, γ-, and δ-peptides3 were designed and synthesized. With the development of structurally unique folding patterns, the applications of such synthesized secondary structures in discrete areas have been broadened. For example, several folded α-peptides have been revealed to display strong antibacterial and antimicrobial activity.4,5 Recently, there has been increasing interest in identification of novel and unnatural backbones which fold into secondary structures akin to those found in proteins. The advantages of these foldamers include rigidity inherent in aromatic units, torsional flexibility of the linkers and various nonconvalent interactions that enforce discrete folded conformation. Considering these advantages, single-stranded foldamers with various abiotic backbones have been studied, including backbones utilizing bipyridine segments,6 solvophobic interaction,7 hydrogen-binding interactions8 and metal coordination.9 However, the challenges in designing synthetic folding oligomers exist in terms of folding stability, tunability, and the control of conformational changes under distinct conditions in which molecules adopt various secondary structures. Among the artificial foldamers reported, aromatic oligoamides utilizing hydrogen bonding to control the folding conformations have been proven to substantially alleviate these challenges. These foldamers aryl amide has been used very often to connect building blocks together. In general, most oligoamides make use of in H-bonding interactions between adjacent monomer units. Although interactions between remote units in the sequence may also contribute to the stability of the structure, it was not the predominant factor that determines how the molecule may fold. In this way, these foldamers often contain a few sets of distinct monomer building blocks that make up regularly ordered backbone. 1.2 Literature Review 1.2.1 Linear Aromatic Oligoamides The simplest structural motif of aromatic oligoamides is the linear strand. In a linear oligomer, there is almost no contact between aromatic units remote from each other. Several building blocks allowing the construction of linear conformation are shown in Figure 1.1. Oligoamides of anthranilic acid was first reported by Hamilton et al. as linear oligoamides.10 Another example is oligomers of 2,5-bis(2-aminophenylene) pyrazine (Figure 1.1b).11 Usually, those oligomers exhibit good linearity due to the formation of the hydrogen bonds on both sides of the molecular strand. In contrast, some linear strands are not expected to be strictly linear and a curvature in backbone could be observed due to the presence of hydrogen bond located at only one side of the strand. For example, oligoamides of 6-alkoxy-5-aminopicolinic acid form linear motif in which the amide protons hydrogen-bond to both the ether oxygen atom and the endocyclic pyridine nitrogen atom at the same side (Figure 1.1c).12 Due to the slight curvature, the facial polarity of those strands was reported to be useful for molecular recognition. For example, Ishu Saraogi et al. reported a family of oligoamide with controlled curvature serving as α-helix mimetics.15 Another α-helix proteomimetics is N-alkylated aromatic oligoamides reported by Frederick Campbell.17 Further modification of those partially linear structures leads to bend structures. For example, Gong et al. prepared an oligoamides adopting bend structure by replacing the endocyclic nitrogen atom of 6-alkoxy-5-aminopicolinic acid with an exocyclic methoxy hydrogen-bond acceptors (Figure 1.1d).13 a) b) c) d) Figure 1.1. Aromatic Oligoamides adopting linear conformations (a,b,c). However, aromatic oligoamide foldmer may undergo conformational changes via a syn-to-anti or anti-to-syn 180º rotation. For example, A transition between linear to turn conformational switch of unsymmetrically linked phenolic oligoamides has been reported through deprotonation.22 The deprotonation of a hydroxyl group in each unit induces a rearrangement of the hydrogen-bonding mode within the unit from OH…O=C to NH…O (oxyanion), which leads to linear-to-turn conformational switching. Figure 1.2. Proposed conformational change of aromatic oligoamides in solution. 1.2.2 Crescent and Helical Aromatic Oligoamides Among all aromatic oligomers, crescent-shaped oligomers or helices have received particular interests. Usually, these oligomers consist of a single repeating unit. Some examples are shown in Figure 1.1. Curvature of aromatic oligoamide is resulted when amine and acid substituents define an angle smaller than 180o. For short oligomers having a rigid, curved backbone, the structures are planar and crescentshaped since there is no sufficient repulsive interactions between end units. As its chain length extends, oligomers are deviated from planarity so as to form helices. Based on this principle, the group of Hamilton,29 Lehn,28 Gong,13 Huc15 and Li16 made a great contribution in developing crescent and helical structures containing cavtities with tunable sizes since 1999. Gong’s group firstly designed a hydrogen-binding rigidified crescent aromatic oligoamides containing benzene residues meta-linked by amide linkages, as shown in Figure 1.1d.13a The reliability of the three-center H-bonds in rigidifying the oligoamide backbone was demonstrated by the well-defined crescent conformation of dimer, trimer and tetramer. According on this three-center H-bonding, a 9-mer and a 11-mer were synthesized and structures were investigated.13b-d The longer oligoamides adopt, both in the solid state and in the chloroform solution, a helical structure with approximately seven benzene rings per turn and an inner diameter of 10 Å. Huc’group has researched extensively into the helical structures enforced by aromatic pyridine oligoamides. They first reported an elegant system of double helical aromatic oligoamides consisting of pyridine residues, with backbones rigidified by intramolecular H-bonds in 2000.14a,14o The X-ray crystal structure demonstrated the presence of ellipsoid helices with an inner diameter of 5.5 Å (n=2) and Å (n=4). In addition, these oligoamide helices can also further dimerize at higher concentrations, forming a stable double helix in solution. Within the double helix, the two oligomer strands are held together by arene-arene interactions between pyridine rings lying opposite each other (Figure 1.3b). In addition, sequences comprised of quinoline,14f-h 8-fluoroquinoline14e and pyridoquinoline monomers,14g as well as combinations thereof,14i-l were reported to adopt double helices with a large diameter. Among these studied, the most prominent finding is the observation of a tetramer composed of fluoroqinolinecarboxamide-based oligomers that adopt a helical conformation with a large pitch, which allows the formation of a quadruple helix both in solution and the solid state (Figure 1.3c and 1.3d). Also, they found that naphthyridine oligoamides can spontaneously assemble in parallel and antiparallel triple helices.14m Figure 1.3.14e Crystal structures of Huc’s aromatic oligoamides: (a) a single helix made of 7-amino-8-fluoro-2-quinolinecarboxylic acid building blocks with the fluorine atoms shown as blue spheres that converge towards the helix hollow space, (b) a narrow double helix composed of pyridine rings only,14b (c) a quadruple helix composed of four identical single helices shown in (a), a string of sites partially occupied by water molecules is shown as spheres, (d) octameric amides of 7-amino-8-fluoro-2-quinolinecarboxylic acid, as a double helix. Other than above foldamers, aromatic oligoamides based on other monomeric units or linkages have also been reported recently. For example, alternating aromatic heterocycles and methyl-substituted aromatic carbocycles connected together through urea linkage have been synthesized.16 In addition, Li et al. reported a folding architecture utilizing F···H-N hydrogen bonds.25d Figure 1.4. Helix formation by intramolecular hydrogen bond.13c The deviation of helices from planarity is achieved by slight changes of the torsional angles involving every aryl-amide bond. When one helical turn comprises many repeating units,13 the torsion is minimal. The torsions are larger for highly curved helices with only a few units per turn (Figure 1.4). By tuning parameters of helical cavity, the applications of these helical oligoamides have been extended. Usually, helices with a large hole or those with few units per turn permit easy access to objects with a high aspect ratio at minimal synthetic efforts.18 On the other hand, helices with a large diameter can be exploited as a cylindrical channel that may be applied for molecule recognition, catalysis and transport.19 a) b) Figure 1.5. A typical structure of aromatic oligoamide -Cl- complex.20a Those helical aromatic foldamers have been demonstrated to display a number of interesting supramolecular properties, especially host-guest chemistry.20a One noticeable example is the helices formed by oligoamides of 2,6 pyridinediarboxylic acid and 2,6-diaminopyridine that contain a polar hollow which may bind water molecules (Figure 1.3c).14b What’s more, helically folded oligomers possessing a hollow cavity is able to provide confined environments suitable for recognizing chiral guests due to their inherent chirality. Based on this concept, the encapsulation of tartaric acid in a helically folded aromatic oligoamide was presented.20b Very high affinities, guest selectivities and diasteroselectivies have been observed that bode well for extensions of this approach to larger and more complex guests. Finally, crescent oligoamides have also been found to act as hosts for substituted guanidinium ions21 or dialkylammonium25d with high specificity and affinity. Figure 1.6. Solid state structure of L-tartaric Acid-binding M-1 helix. (a) CPK and (b) stick representations of the M-1 helix. (c) Top view of the central part of the M-1 helix, showing tartaric acid H-bonded to N2-pyr-pyz-pyr-N2. Therefore, oligoamides with helical conformation are fascinating considering their nonplanar structures. Such molecules should be inherently chiral, resulting in amazing optical and electronic properties. In addition, supramolecular helices could be formed by the columnar stacks caused by π-π interaction. However, until now, the consistent columnar packing of these shape-persistent crescent and helical oligoamides has rarely been studied. 1.2.3 Circular Aromatic Oligoamides As mentioned in 1.2.2, one of the most important applications of hollow cavities contained within the aromatic oligoamides is their potential to bind corresponding guest molecules. Based on this intention, circular oligoamides, as a kind of macrocycles, were designed. Shape-persistent circular oligoamides are structures with rigid, noncollapsible backbones and lumens of various sizes. These structures are very interesting because of their unique properties that differ from their linear analogues. However, examples of these molecules are rare, mainly attributed to the difficulty in their preparation and lack of the suitable building blocks. Some of reported examples are elaborated below. Gong’s group pioneered the work of H-bonding enforced macrocycles by synthesizing a new class of shape-persistent, cyclic hexa(armides) from the one-step macrocyclization involving monomeric diamine and diacid chloride.23 Macrocycles contain a large (8Å across), noncollapsible hydrophilic cavity defined by six introverted amide oxygen atoms. The face-to-face stacking of may align the macrocycles into nanotubes containing a large channel (or nanopore) (Figure 1.7). As expected, this class of macrocycle was demonstrated to form transmembrane channel with very large conductance and a model of the transport pore was prompted as 10 Figure 1.7b.24 Figure 1.7. Circular aromatic oligoamides from Gong’s group. (a) Chemical structures of shape persistent macrocyles 1, (b) with their large aromatic surfaces, assemble anisotropically into a tubular structure that acts as a transmembrane channel or pore in the hydrophobic environment of a lipid bilayer. Li’s group also demonsrated that hydrogen bonding-induced aryl amide foldamer could function as new synthetic receptors for binding neutral and ionic species or as preorganized scaffolds for assembling well-defined architectures.25 Furthermore, they prepared a new rigidified macrocycle that complex fullerene or coronene in chloroform viah intromolecular π-stacking interactions, as in Figure 1.8.25i Figure 1.8. Stacking interaction between C60 and macrocycle from Li’s group. In addition to the application in molecular recognition and ion transportation, macrocycle based on aromatic oligoamides was also found to bind to DNA G-quadruplex through intermolecular hydrogen bonding and/or л-л stacking 11 interaction. G-quadruplexs, unlike double-stranded oligonucleotides, are made up of symmetric planar guanine-mediated quartets (G-quartets) in which each guanine forms two hydrogen bonds with its neighbors (Figure 1.9). Since these G-quartets have large π-surfaces, they tend to stack on each other by π-π stacking. In particular, oligonucleotides with contiguous runs of guanine bases can form stacked G-quadruplex structures.26 Accordingly, G-quadruplex ligands generally comprise a planar π-rich pharmacophore, presumed to bind to guanine tetrads, with appended side chains to enhance the binding interaction. Some additional lines of evidences suggest that stable G-quadruplex structures are poor substrates for interaction with telomerase, thereby disfavoring the telomere extension by telomerase.30-32 The above findings provide compelling evidence33-39 that small molecules that target and stabilize telomeric G-quadruplexes may display anticancer activity by interfering with either the 1:1 complex formed between telomerase and telomere or other molecular pathways underlying the telomere elongation by telomerase, a process that enables cancer cells to proliferate indefinitely; consequently, immortal cancer cells may become mortal while the corresponding side effects on human cells could be very minimal as, contrasting with cancel cells, most human somatic tissues have very limiting telomerase activity.40,41 Since circular oligoamides rich in π-electrons usually adopt very stable, planar conformations, they should be able to stabilize G-quadruplex structures. For example, 8-amino-2-quinoline carboxylic acid showed significant potential as potent G-quadruplex stabilization without any evidence of duplex stabilization.27 The 12 modular nature of these molecules makes them amenable to chemical modification to improve G-quadruplex-binding affinity and selectivity. However, so far, progress along these lines is still very limited. a) b) Figure 1.9. Structure of G-tetrads and its ligands: (a) G-tetrad, (b) oligoamides binding to G-quadruplexes. 1.3 Aim of the Study Although there have been many recent advances in devised folding systems geared toward designing unnatural folding helices and macrocycles, substantial challenges are yet to be met on building simpler, yet flexible abiotic systems with biopolymer-like functions. Particularly, the exact helical dimensions and properties for a large portion of molecular helices have still remained to be illuminated in the absence of crystal structures. In addition, few synthetic macrocyclic oligoamides have been reported to allow systematic fine-tuning of interior properties while maintaining overall topographic persistence. Lastly, until now, few studies have detailed the interactions of the crescent-shpaed tunable folding aromatic oligoamides with biomacromolecules, such as oligonucleotides and proteins. The aim of this thesis was to investigate the structural and physical properties of a 13 new class of backbone-rigidified molecular strand with repeating aromatic units, as well as their potential applications as stabilizers of oligonucleotides. The specific objectives of the thesis were to: 1) Study the H-bonding strength of multiply centered intramolecular H-bonding systems. 2) Investigate the structure feature of crescent-shaped and helically folded backbones of oligoamides. 3) Design and synthesize planar circular pentamers of varying types, by changing interior functional groups and adding hydrophobic side chains on their exterior surfaces. 4) Systematically evaluate the binding affinity of synthesized circular pentamers toward DNA G-quadruplexs. 5) Develop a new nanosensor method to detect the G-quadruplex ligands as well as specific protein. The results of the present study may have significant impacts on both providing the quantitative descriptions of molecular properties in solid state and solution studies for various helical or circular oligoamides and developing a new category of aromatic oligoamides serving as G-quadruplex stabilizers with tunable affinities and selectivities. In order to achieve these objectives, 1H NMR technique and X-ray diffraction method were used for studying the structures of aromatic oligoamides, while CD, PAGE, PCR stop assay were adopted for detecting their binding affinity toward G-quadruplexs. Furthermore, a highly sensitive aptamer-based gold 14 nanoparticle biosensor was developed to identify G-quadruplex-binding ligands, as well as to detect proteins. 15 Reference: 1. Huc, I. Chem. Rev. 2001, 3893. 2. Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. 3. (a) Seebach, D.; Matthews, J. L. Chem. Commun. 1997, 2015. (b) Hanessian, S.; Luo, X. H.; Schaum, R.; Michnick, S. J. Am. Chem. Soc. 1998, 120, 8569. (c) Seebach, D.; Brenner, M.; Rueping, M.; Jaun, B. Chem. Eur. J. 2002, 8, 573. (d) Szabo, L.; Smith, B. L.; McReynolds, K. D.; Parrill, A. L.; Morris, E. R.; Gervay, J. J. Org. Chem. 1998, 63, 1074. (e) Rowan, A. E.; Nolte, R. J. M. Angew. Chem. Int. Ed. 1998, 37, 63. 4. Cheng, R. P.; Gellman, S. H.; Degrado, W. F. Chem. 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Urol. 2001, 166, 666. 18 [...]... recognition and ion transportation, macrocycle based on aromatic oligoamides was also found to bind to DNA G- quadruplex through intermolecular hydrogen bonding and/ or л-л stacking 11 interaction G- quadruplexs, unlike double-stranded oligonucleotides, are made up of symmetric planar guanine-mediated quartets (G- quartets) in which each guanine forms two hydrogen bonds with its neighbors (Figure 1. 9) Since... still very limited a) b) Figure 1. 9 Structure of G- tetrads and its ligands: (a) G- tetrad, (b) oligoamides binding to G- quadruplexes 1. 3 Aim of the Study Although there have been many recent advances in devised folding systems geared toward designing unnatural folding helices and macrocycles, substantial challenges are yet to be met on building simpler, yet flexible abiotic systems with biopolymer-like functions...Figure 1. 7b.24 Figure 1. 7 Circular aromatic oligoamides from Gong’s group (a) Chemical structures of shape persistent macrocyles 1, (b) with their large aromatic surfaces, 1 assemble anisotropically into a tubular structure that acts as a transmembrane channel or pore in the hydrophobic environment of a lipid bilayer Li’s group also demonsrated that hydrogen bonding-induced aryl amide... folding aromatic oligoamides with biomacromolecules, such as oligonucleotides and proteins The aim of this thesis was to investigate the structural and physical properties of a 13 new class of backbone-rigidified molecular strand with repeating aromatic units, as well as their potential applications as stabilizers of oligonucleotides The specific objectives of the thesis were to: 1) Study the H-bonding... DNA G- quadruplexs 5) Develop a new nanosensor method to detect the G- quadruplex ligands as well as specific protein The results of the present study may have significant impacts on both providing the quantitative descriptions of molecular properties in solid state and solution studies for various helical or circular oligoamides and developing a new category of aromatic oligoamides serving as G- quadruplex. .. H-bonding strength of multiply centered intramolecular H-bonding systems 2) Investigate the structure feature of crescent-shaped and helically folded backbones of oligoamides 3) Design and synthesize planar circular pentamers of varying types, by changing interior functional groups and adding hydrophobic side chains on their exterior surfaces 4) Systematically evaluate the binding affinity of synthesized... 1. 9) Since these G- quartets have large π-surfaces, they tend to stack on each other by π-π stacking In particular, oligonucleotides with contiguous runs of guanine bases can form stacked G- quadruplex structures. 26 Accordingly, G- quadruplex ligands generally comprise a planar π-rich pharmacophore, presumed to bind to guanine tetrads, with appended side chains to enhance the binding interaction Some... stabilizers with tunable affinities and selectivities In order to achieve these objectives, 1H NMR technique and X-ray diffraction method were used for studying the structures of aromatic oligoamides, while CD, PAGE, PCR stop assay were adopted for detecting their binding affinity toward G- quadruplexs Furthermore, a highly sensitive aptamer-based gold 14 nanoparticle biosensor was developed to identify G- quadruplex- binding... lines of evidences suggest that stable G- quadruplex structures are poor substrates for interaction with telomerase, thereby disfavoring the telomere extension by telomerase.30-32 The above findings provide compelling evidence33-39 that small molecules that target and stabilize telomeric G- quadruplexes may display anticancer activity by interfering with either the 1: 1 complex formed between telomerase and. .. Soc 2 010 , 13 2, 7858 21 Yamato, K.; Yuan, L H.; Feng, W.; Helsel, A J.; Sanford, A R.; Zhu, J.; Deng, J G. ; Zeng, X C.; Gong, B Org Biomol Chem., 2009, 7, 3643 22 Kanamori, D.; Okamura, T A.; Yamamoto, H.; Ueyama, N Angew.Chem Int Ed 2005, 44, 969 23 (a) Yuan, L H.; Feng, W.; Yamato, K.; Sanford, A R.; Xu, D G. ; Guo, H.; Gong, B J Am Chem Soc 2004, 12 6, 11 120 (b) Sanford, A R.; Yuan, L H.; Feng, W.; . circular oligoamides are structures with rigid, noncollapsible backbones and lumens of various sizes. These structures are very interesting because of their unique properties that differ from their. Figure 1. 7. Circular aromatic oligoamides from Gong’s group. (a) Chemical structures of shape persistent macrocyles 1, (b) with their large aromatic surfaces, 1 assemble anisotropically. the group of Hamilton, 29 Lehn, 28 Gong, 13 Huc 15 and Li 16 made a great contribution in developing crescent and helical structures containing cavtities with tunable sizes since 19 99. 6