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A series of large, 44-membered macrocycles 7a – e were synthesized and characterized, which display two different diagonal binding modes. The unsubstituted macrocycle 7a strongly binds naphthalene-2,6-dicarboxylate through hydrogen bonds with the association constant ( K a ± 15%) of 4500 M −1 in 40% (v/v) CD 3 CN/CDCl 3 at 23 ± 1 °C. Introduction of an electron-withdrawing substituent (Cl) at all four corners increases the binding affinity (22,000 M −1 for 7b ), while that of an electron-donating substituent (pyrrolidinyl) greatly decreases it (150 M −1 for 7c ). The same propensity has been observed with macrocycles 7d and 7e bearing different substituents at two diagonal corners, suggesting that the relative population of the binding modes would be modulated by controlling the electron density of the aromatic ring.

Molecular clefts were synthesized from 2,2′-biindolyl scaffold that contains good hydrogen bond donors of two indole NHs. The molecular clefts were systematically modified in two different manners to increase binding affinities toward chloride. The association constant dramatically increased when additional hydrogen-bonding sites of two benzamide units were incorporated to the biindolyl scaffold. For example, the association constants of 1a and 1b are 5.1 × 103 and 1.4 × 104 M−1 in CH3CN at 22 ± 1 °C, while reference molecule 10 having only two indole NHs showed the association constant of 340 M−1 under the same conditions. When the biindolyl backbone was structurally preorganized, the binding affinities toward anions were further increased with additional stabilization energy (−ΔΔG) of 2.0 ± 0.2 kcal/mol).

A large, covalent macrocycle that can be served as an artificial allosteric model was prepared in a reasonable yield (36%) through the template-directed synthesis. The macrocycle contains two topologically discrete subcavities, each of which consists of four amide NHs of pyridine-2,6-dicarboxamide units. The macrocycle strongly binds two molecules of N , N , N ′, N ′-tetramethylterephthalamide in positive cooperative manner by hydrogen-bonding interactions. The association constants were calculated to be K 1 = 1480 ± 90 and K 2 = 5580 ± 150 M −1 with the Hill coefficient ( h ) of 1.6 at 25 °C in CDCl 3 .

A giant, 100-membered metallocycle 3 was prepared via coordination bond-based self-assembly from W-shaped ligand 9 and a palladium complex. Metallocycle 3 may create three topologically discrete subcavities, thus capable of binding up to three molecules of a diamide guest by hydrogen-bonding interactions. Elemental analysis, 1 H NMR, and the ESI-mass spectra, and vapor pressure osmometry (VPO) data were all consistent with the structure of 3 . N , N , N ′, N ′-tetramethylterephthalamide G was used as a guest for the binding study, and ESI-mass spectrum clearly displayed a characteristic, intense peak at m / z 1542 (41%), attributed to the fragment [ 3 · G 3 -3CF 3 SO 3 ] 3+ of 1:3 (host/guest) complex. The 1 H NMR titration experiments gave association constants of 2300 ± 300 and 1200 ± 200 M −1 in CDCl 3 at 25 °C for two identical outer cavities, with weak positive cooperativity (Hill coefficient h = 1.3).

Interlocked supramolecular dendrimers were spontaneously self-assembled from molecular components, metallocycles, and dumbbells bearing benzyl ether repeating units. Here, the metallocycles were in situ self-assembled from L-shaped ligands with dendritic branches, 2,3-dimethyl-2-butene and osmium tetraoxide. The supramolecular dendrimers were stabilized by hydrogen-bonding interactions between the pyridine-2,6-dicarboxamide unit in the metallocycle and the adipamide unit in the dumbbell.

Imine metathesis between m-phenylene ethynylene oligomers of various lengths was performed in acetonitrile, a solvent in which oligomers containing eight or more repeat units adopt a compact helical conformation. The equilibrium constants and corresponding free energy change for the imine metathesis reactions were estimated. The results showed that the magnitude of equilibrium shifting measured by the free energy change for the formation of imine-containing oligomers increases linearly below a critical product chain length and grows asymptotically above it. The linear region is ascribed to the constant increase in contact area between monomer units of adjacent helical turns as the product chain grows to the 12-mer. Once the ligation product is 12 units in length, full contact is made between adjacent helical turns. On the other hand, for imine metathesis between oligomers leading to products having more than 12 units, the driving force is the difference between the folding energy of products and that of reactants. The additional stabilizing energy is roughly constant, regardless of the chain length, since the contact area between adjacent helical turns is unchanged. Consistent with the notion that the imine bond only minimally destabilizes the helical conformation, the position of the imine bond in the ligation product has been observed to have no significant effect on the folding stability. The magnitudes of equilibrium shifting are similar for ligation products of the same length but having the imine at various positions along the sequence. This suggests that the imine bond is compatible with the m-phenylene ethynylene backbone, regardless of the position in the sequence. Imine metathesis of m-phenylene ethynylene oligomers could allow a quick access to an unbiased, dynamic library of oligomer sequences joined by imine linkages.

Synthetic chloride transporters containing two urea groups linked through a diazobenzene spacer have been prepared and the trans-to-cis isomerization by light stimulation results in dramatic changes in the chloride transport activities across lipid and cell membranes.

Glutamate is the major excitatory neurotransmitter and known to activate the metabotropic and ionotropic glutamate receptors in the brain. Among these glutamate receptors, metabotropic glutamate receptor 1 (mGluR1) has been implicated in various brain disorders including anxiety, schizophrenia and chronic pain. Several studies demonstrated that the blockade of mGluR1 signaling reduced pain responses in animal models, suggesting that mGluR1 is a promising target for the treatment of neuropathic pain. In this study, we have developed mGluR1 antagonists with an aryl isoxazole scaffold, and identify several compounds that are orally active in vivo. We believe that these compounds can serve as a useful tool for the investigation of the role of mGluR1 and a promising lead for the potential treatment of neuropathic pain.

Synthetic molecules which selectively transport sodium or potassium chloride across a lipid membrane have been prepared. The salt carriers consist of two heteroditopic binding sites, an anion-binding cavity with three hydrogen bond donors and an azacrown ether for binding an alkali metal cation. The association constants between the carriers and chloride ion have been enhanced by 1 order of the magnitude in the presence of sodium or potassium ion in 10% (v/v) CD3OH/CD3CN, due to the formation of a contact ion-pair between the bound cation and chloride as demonstrated by the single-crystal X-ray structure of a sodium chloride complex. A series of transport experiments have demonstrated that the synthetic molecule functions as a mobile carrier of transporting salts via M(+)/Cl(-) symport. Among alkali metal chlorides, the carrier with an 18-azacrown-6 exhibits a strong selectivity toward potassium chloride, while the carrier with a 15-azacrown-5 displays a moderate selectivity for sodium chloride.

With a dinuclear macrocycle 2 that contains weak reversible OsVI-N coordinate bonds, self-assembly and equilibrium dynamics of [2]- and [3]rotaxanes have been investigated. When the macrocycle 2 was mixed together with threads 4a-e, which all contain an adipamide station but different sizes of end groups, [2]pseudorotaxane- and rotaxane-like complexes were immediately formed with large association constants of >7 x 103M(-1) in CDCl3 at 298 K. Exchange dynamics, explored by 2D-EXSY experiments, suggest that assembly and disassembly of complexes occur through two distinct pathways, slipping or clipping, and this depends on the size of the end groups. The slipping pathway is predominant with smaller end groups that give pseudorotaxane-like complexes, while the clipping pathway is observed with larger end groups that yield rotaxane-like complexes. Under the same conditions, exchange barriers (deltaG++) were 14.3 kcalmol(-1) for 4a and 16.7 kcalmol(-1) for 4d, and indicate that the slipping process is at least one order of magnitude faster than the clipping process. Using threads 13a and 13b that contain two adipamide groups, more complicated systems have been investigated in which [2]rotaxane, [3]rotaxane, and free components are in equilibrium. Concentration- and temperature-dependent 1H NMR spectroscopic studies allowed the identification of all possible elements and the determination of their relative distributions in solution. For example, the relative distribution of the free components, [2]rotaxane, and [3]rotaxane are 30, 45, and 25 %, respectively, in a mixture of 2 (2mM) and 13a (2mM) in CDCl3 at 10 degrees C. However, [3]rotaxane exists nearly quantitatively in a mixture of 2 (4 mM) and 13 a (2 mM) in CDCl3 at a low temperature - 10 degrees C.

A catenated anion receptor 7 comprising two indolocarbazole units was prepared by olefin ring-closing metathesis using Grubbs’ catalyst. Receptor 7 possesses a cage-like cavity where anions are encapsulated by forming four hydrogen bonds in the order of Cl − > AcO − > N 3 - > H 2 PO 4 - > Br − > HSO 4 - > I − ≈ NO 3 - in 1% H 2 O/acetone.

Osmium (VI)-bridged macrocycles 1a−c, 2, and 3 assemble spontaneously when osmium tetraoxide, olefins, and L-shaped bispyridyl ligands are mixed in CHCl3. The macrocycles possess well-defined square or rectangular cavities enclosed by aryl walls and act as host molecules. Hydrogen-bond donors on the inner surface of the hosts offer binding sites to acceptors of guests with complementary dimensions. The host 1a binds adipamide G2 (Ka = 3.6 × 104 M-1) and terephthalamide G6 (Ka = 2.0 × 104 M-1), while it binds negligibly (Ka < 10 M-1) benzamide G5, isophthalamide G9, or 1,4-naphthalenedicarboxamide G10. The larger hosts 2 and 3 bind the longer guests biphenyldicarboxamide G12 and terphenyldicarboxamide G17, respectively, but shorter guests such as adipamide G2 and terephthalamide G6 are not well-bound (Ka < 10 M-1). Hosts 1a−c with different remote substituents (H, OMe, NO2) but identical cavity size were prepared and their binding affinities were measured. The relative binding affinities of the hosts 1a−c ...

An acyclic receptor 1 with a binding cavity surrounded by electron-rich aryl surfaces has been synthesized for binding quaternary ammonium salts through cation-π interactions. The association constants of the receptor 1 with salts in CDCl3 depend on the anions due to the hydrogen bonds between the exchangeable protons in the receptor 1 and anions.

A dihydrogen phosphate-binding receptor (4) containing both hydrogen bond donors and acceptors has been prepared by incorporating two pyridyl units to a preorganized biindole scaffold. Receptor 4 strongly and selectively binds dihydrogen phosphate via multiple hydrogen bonds with an association constant (Ka) of 1.1 × 105 M−1 in CH3CN at 22 ± 1 °C. The high selectivity toward the target anion over other anions is proven to be due to two additional hydrogen bonds between the phosphate hydroxyl groups and the pyridyl nitrogens, each of which increases the complex stability by the free energy of 1.6 kcal/mol. This result clearly demonstrates that a selective receptor for a polyprotic anion can be developed by combining both hydrogen bond donors and acceptors.

A molecular model has been synthesized to determine the hydrogen-bonding strength between AT and T in the base triplet, T:AT. A strong preference (>95%) of Watson-Crick mode along with 91% hydrogen-bonded conformation is observed in the model compound. The association constants of the AT model with 1-propyluracil and glutarimide are 15 M −1 and 5.2 M −1 , respectively, in CDCl 3 at 296 ± 0.5 K. Negative cooperativity by pre-existing hydrogen bonds might be involved in the intermolecular binding events.

Mono- and bispyridinium salts are shown to bind strongly with carboxylates in polar media through multiple hydrogen bonds and additional electrostatic interactions. The association constants of monopyridinium salt with various benzoates are in the range of 110–430 M −1 in DMSO-d 6 , depending on substituents, while those between bispyridinium salts and adipate are >10 3 M −1 in 10% D 2 O/DMSO-d 6 .

A number of indolocarbazole-based anion receptors were prepared and their anion-binding behaviors were characterized in solution and in the solid state. First, chain- length-dependent binding affinities of chloride ion were revealed using a series of indolo - carbazoles that consisted of one to four indolocarbazole units. The binding affinities were steadily enhanced from monomer to dimer, then to trimer by Gibb's free energy (-ΔΔG) = 2.4 ± 0.1 kcal/mol, and then nearly saturated. Second, a water-soluble trimer folded to gen- erate an internal helical cavity with six convergent NHs, wherein small halides bound in water in the order of Cl - (65 M -1 ) > F - (46 M -1 ), and Br - (19 M -1 ). Third, X-ray crystal structures clearly proved helical folding of a trimer in the presence of sulfate ion, in which left- and right-handed helices stacked alternatively. It was also shown that the selectivity of anion binding could be varied by the modification of the spacer groups connecting indolo- carbazole units. Finally, we prepared chiral indolocabazole dimers that adopted helical structures by intramolecular hydrogen bonds and displayed complete inversion of the helical sense upon anion binding. The dimers gave characteristic optical readouts in a reversible manner according to chemical stimuli, thus functioning as chirooptical molecular switches.

A new dicarboxylic acid 4 was synthesized from 1,5-dichloroanthraquinone ( 1 ) and modified to ditopic receptors for binding of diammonium and dicarboxylate salts by multiple hydrogen bonds. The cis and trans isomers of 4 were assigned by the relative binding affinities of the bis(crown ether) derivatives, 5a and 5b to alkyl diammonium dipicrates. The association constants (K a ) between p -substituted bis-phenylureas and adipate vary from 5 × 10 2 to 2 × 10 4 M −1 in DMSO-d 6 , depending on substituents in the phenyl ring.

A series of podand hosts having suitable cavities for metal cations in virtue of intramolecular interactions between the terminal groups were designed and synthesized. The conformational informations of hosts were obtained by NMR studies including homonuclear NOE difference experiments. Intramolecular interactions between the terminal groups of podand hosts markedly increase binding affinities and selectivities to metal cations.

Several bis(crown ether)s consisting of benzo-12-crown-4, benzo-15-crown-5, and benzo-18-crown-6, were prepared and their complexation properties with Na + and K + were determined by the liquid-liquid extraction method. The remarkable “biscrown effect” was observed in the extractions of both Na + and K + using bis(benzo-12-crown-4) and bis(benzo-15-crown-5). Unsymmetrical bis(crown ether)s also exhibit much higher extractabilities of both Na + and K + than the corresponding mono(benzocrown ether)s.

Chiral indolocarbazole dimers fold into a helical conformation by virtue of intramolecular hydrogen bonds, as demonstrated by (1)H NMR and CD spectra and optical rotations. In particular, the optical properties of the dimers were found to be extremely sensitive to the nature of the solvent, depending on whether they are folded or not. The helical sense of the dimers can be reversibly switched by binding sulfate ion, which gives rise to complete inversion of the CD spectra. The binding mode and absolute stereochemistry of the sulfate complexes was unequivocally determined by single-crystal X-ray structures, which are all consistent with the CD and (1)H NMR spectra in solution.

This tutorial review provides a summary of anion-mediated folding of linear and cyclic oligomers as well as anion-responsive behaviours of related polymeric architectures. Anions have emerged as a significant focus of the supramolecular community and here we review their impact on directing the secondary structures of synthetic oligomers and polymers while modulating physical properties e.g. molecular recognition. Oligomers and polymers responsive to anionic guests are typically constructed with hydrogen bond donors complementary to the target anions. Anion binding within the cavities leads to folding and helical wrapping of linear and cyclic oligomers as well as control over macromolecular properties of polymers. This review covers the impact of anion binding on guiding the secondary structures of single-stranded folded oligomers (foldamers) and cyclic oligomers (macrocycles), and on modulating the physical properties of select polymer architectures.

The monomeric (VIII) and dimeric (XI) benzofuran scaffolds can be used as molecular building blocks for the construction of new aryl stand foldamers capable of folding into helical conformation by cation binding.

This tutorial review provides a summary of the binding of neutral molecules, cations and anions within helical cavities formed specifically by the folding of unnatural oligomers, called foldamers. Foldamers are emerging as a new class of synthetic receptors whose binding sites are not formed by preorganization of covalent bonds, but rather through the combination of various noncovalent interactions that induce folding and subsequent arrangement of functional groups within a helical cavity. The function of foldamers as synthetic receptors can be tuned by careful selection of modular building blocks displaying the appropriate functionality required for guest complexation. As the molecular toolbox expands to create well-defined helical structures, new and interesting functions emerge. It is the purpose of this review to provide the reader with an introduction to helical cavities formed specifically by foldamers and their subsequent function as molecular and ionic receptors. It will interest the supramolecular, organic and bioorganic communities.

Hydrogen bonding to anions drives the helical folding of an indolocarbazole oligomer, thus resulting in an internal cavity with six NHs and two OHs for binding sulfate with high selectivity.

Indole and the related heterocycles have emerged as efficient building blocks for the creation of novel anion receptors. This chapter focuses on the employment of indoles, carbazoles, and indolocarbazoles in the creation of molecular clefts, macrocycles, oligomers, and sensors. The majority of these structures utilize the heterocyclic NH as a hydrogen bond donor in binding to anions of various sizes and geometries. These heterocycles are often connected by amides and ureas which also function as hydrogen bond donors in anion binding. Finally, molecular sensors based on indoles and carbazoles have been described, showing color or fluorescence changes upon anion binding or deprotonation of the heterocyclic NH by basic anions.

Catalytic asymmetric dihydroxylations of 1,3-enynes were studied using 9-O-(9′-phenanthryl) dihydroquinidine (PHN-DHQD) 1 and 1,4-bis-(9-O-dihydroquinidine) phthalazine (DHQD2-PHAL) 2. Terminal olefins showed moderate (38-79% ee) and trans-disubstituted olefins high enantioselectivities (73 – 97% ee).

Two key improvements in the osmiuun-catalyzed asymmetric dihydroxylation have led to a simple procedure which is applicable to a wide range of olefins.

Liposomes are nano-scale vesicles that can be used as one of drug carriers. The liposomes are, however, plagued by rapid opsonization of them and hence making their circulation time in bloodstream to be shortened. In this study, cationically charged liposomes of which surface was modified with bovine serum albumin (BSA) were prepared by using electrostatic interaction between cationic liposomes and anionically charged BSA molecules at higher pH than isoelectric point (pI) of BSA. The BSA-coated liposomes (BLs) were denatured by thermal treatment of BL at 100 degrees C. The thermally denatured BSA-coated liposomes (DBLs) have mean particle diameter of 109+/-1 nm. Encapsulation of model drug, doxorubicin (DOX), in the liposomes was carried out by using, so called, remote loading method and loading efficiency of DOX in liposomes was about 90%. DBL800 showed higher stability in plasma compared to Doxil. Results of intracellular uptake evaluated by flow cytometry and confocal microscopy studies showed higher intracellular uptake of DBL800 than that of Doxil. Consequently, the DBL, of which surface was complexed with denatured protein may be applicable as drug delivery carriers for increasing stability in plasma and enhanced cellular uptake efficacy of anticancer drugs.

Sterically stabilized liposomes (SSL) were known to be accumulated passively in cancer due to the effect of enhanced permeability and retention (EPR). However, drug delivery via SSL to cancer seemed to show an insufficient improvement of chemotherapeutic efficacy. Herein, carbohydrate-binding proteins (lectins) of cell surface, which express on the plasmic membrane of many malignant cells, can be a good model of surface-modified liposomes. In this study, we investigated the in vitro characteristics of liposomes of which the surface was modified with a disaccharide molecule, sucrose or maltose. The disaccharide-modified lipids such as sucrose-modified lipid and maltose-modified lipid, in which the disaccharide was conjugated to the one end of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol)-2000 (DSPE-PEG2000), was synthesized. The disaccharide-modified liposomes were prepared by thin film-hydration method and then doxorubicin (DOX), an anticancer drug, was loaded to the prepared liposomes by the remote loading method with ammonium ion gradient. Flow cytometry and confocal microscopy analyses showed that the disaccharide-modified liposomes enhanced the intracellular uptake of liposomes into various cancer cell lines via lectin-mediated endocytosis. The disaccharide-modified liposomes in which DOX was loaded inside of liposomes exhibited higher cytotoxicity against various cancer cells than DOX-loaded SSL did. These results suggest that disaccharide-modified liposomes may be promising cancer targeting carriers which can enhance intracellular uptake and cytotoxicity of the drug-loaded liposomes via lectin-mediated endocytosis.

Complexation de molecules pinces avec des derives de l'adenine et des nucleosides puriques et pyrimidiques