Construction of supramolecular polymers with alternating alpha-, beta-cyclodextrin units using conformational change induced by competitive guests

Supramolecular polymers having alternating alpha- and beta-cyclodextrin (CD) units have been prepared by using conformational change induced by competitive guests. Although each CD unit does not form intermolecular complexes, a mixture of an alpha-CD derivative and a beta-CD derivative formed intermolecular complexes to give supramolecular polymers having alternating CD units. This is the first example of construction of supramolecular polymers with alternating alpha-, beta-cyclodextrin units.     

Novel peptides bearing pyrene and coumarin units with or without beta-cyclodextrin in their side chains exhibit intramolecular fluorescence resonance energy transfer

Novel peptides bearing the pyrene/coumarin FRET pair in their side chains have been designed and synthesized. Peptide 1 having endogenous beta-cyclodextrin (beta-CD) in the side chain exhibits FRET in aqueous solution, indicating that coumarin, being accommodated into the CD cavity, is separated from pyrene. Guest-induced quenching of the fluorophores in 1 indicates that coumarin, being excluded from the CD cavity, comes into close contact with pyrene. Peptide 2 shows FRET only after addition of external beta-CD that again reflects the idea that beta-CD surely caps the coumarin unit in its hydrophobic cavity, and, therefore, quenching of the fluorophores can be prevented in FRET peptide probes. With this strategy, various peptide-based FRET probes can be developed that would be useful for studying biological phenomena in living cells.     

Fluorescent aromatic polyamides with urea binding sites and fluorene or dansyl signaling units

This work describes six novel fluorescent aromatic polyamides with bulky dansyl or fluorene pendant groups or with the fluorene moiety in the main chain. The fluorescent signaling dansyl or fluorene moieties are chemically connected to, or within, the main polymer chains through a urea group, a well-known binding site in supramolecular chemistry. These polyamides are amorphous and soluble in polar aprotic solvents and demonstrate a film-forming capability. They also show yellowish-green or blue fluorescence in solution and in the solid state depending on the signaling unit, with the former corresponding to the dansyl and the latter to the fluorene residue. The water uptake and the thermal behavior have also been evaluated and related to the chemical structure. The polar amide, urea, and sulfonamide groups give rise to a high water sorption of up to 3.8 water molecules per repeating unit. The thermal behavior has been investigated by means of DSC and TGA. The glass transition temperatures of the polymers are high (up to 331 °C) and the decomposition temperatures (around 300 °C) are due to the moderate thermal stability of the urea group.     

Theoretical comparison of molecular properties of linear and cyclic glycine derived peptides and their phosphor analogues

The cyclic compounds are common in nature and widely spread in medicinal chemistry. The cyclopeptides have a special position for their having numerous advantages over their linear, parent peptides. Here, cyclic glycine derived peptides and their linear equivalents were computationally modelled and the molecular properties of both these groups of the compounds were compared. The phosphor analogues of these peptides were also modelled and the same properties were considered. The studies were done by the ab initio methods. The stability and strength of peptide bonds were calculated and the susceptibility of studied compounds to spontaneous oxidation was estimated.     

Synthesis of polyamines with pendant cyanoimidazole units and their electrochemical properties

The 2-(1-methyl-4,5-dicyanoimidazolyl) group was attached to poly(diallylamine) and polyethylenimine, affording polymers containing an electron-withdrawing pendant group. The key to their preparation is high reactivity of 1-methyl-2-fluoro-4,5-dicyanoimidazole (1) toward nucleophilic aromatic substitution (NAS) reactions with aliphatic amines. Cyclic voltammograms of these polymers show reduction waves at −2.6 to −2.7 V vs. Ag/Ag⁺ but no reoxidation waves, unlike those of monomeric and oligomeric model compounds, which are quasi-reversible. The cyclic voltammetry studies of oligomeric model compounds with different alkyl spacers show that the degree of quasi-reversibility decreases as dicyanoimidazoles are crowded together in a molecule, suggesting that a certain degree of chemical reaction occurs between reduced dicyanoimidazole groups. © 1998 John Wiley & Sons, Inc. J. Polym. Sci. A Polym. Chem. 36: 2619–2629, 1998     

Redox-controlled interaction of biferrocenyl-terminated dendrimers with beta-cyclodextrin molecular printboards

This paper describes the synthesis and electrochemistry of biferrocenyl-terminated dendrimers and their beta-cyclodextrin (beta-CD) inclusion complexes in aqueous solution and at surfaces. Three generations of poly(propylene imine) (PPI) dendrimers, decorated with 4, 8, and 16 biferrocenyl (BFc) units, respectively, were synthesized. A water-soluble BFc derivative forms stable inclusion complexes with beta-CD. The intrinsic binding constant is K(i)=2.5 x 10(4) M(-1). The BFc dendrimers were solubilized in water by complexation of the end groups with beta-CD, resulting in large water-soluble supramolecular assemblies. Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) showed that all the end groups are complexed to beta-CD. Adsorption of the dendrimers at self-assembled monolayers (SAMs) of heptathioether-functionalized beta-CD on gold ("molecular printboards") resulted in stable monolayers of the dendrimers due to the formation of multivalent host-guest interactions between the BFc end groups of the dendrimers and the immobilized beta-CD molecules. The number of interacting end groups is 3, 4, and 4 for dendrimer generations 1, 2, and 3, respectively. The complexation of BFc to beta-CD is sensitive to the oxidation state of the BFc unit. Oxidation of neutral BFc-Fe(2) ((II,II)) to the cationic, mixed-valence biferrocenium BFc-Fe(2) ((II,III)+) resulted in dissociation of the host-guest complexes. Scan-rate-dependent CV and DPV analyses of the dendrimer-beta-CD assemblies immobilized at the beta-CD host surface and in solution revealed that the dendrimers are oxidized in three steps. First, the surface-beta-CD-bound BFc moieties are oxidized to the mixed-valence state, Fe(2) ((II,III)+), followed by the oxidation of the non-surface-interacting BFc groups to the Fe(2) ((II,III)+) state. The third step involves the oxidation of all the BFc moieties to the Fe(2) ((III,III)2+) state.     

Synthesis of novel bis(beta-cyclodextrin)s and metallobridged bis(beta-cyclodextrin)s with 2,2'-diselenobis(benzoyl) tethers and their molecular multiple recognition with model substrates

To investigate quantitatively the cooperative binding ability of beta-cyclodextrin dimers, a series of bridged bis(beta-cyclodextrin)s with 2,2'-diselenobis(benzoyl) spacer connected by different lengths of oligo(ethylenediamine)s (2-5) and their platinum(IV) complexes (6-9) have been synthesized and their inclusion complexation behavior with selected substrates, such as Acridine Red, Neutral Red, Brilliant Green, Rhodamine B, ammonium 8-anilino-1-naphthalenesulfonate, and 6-p-toluidino-2-naphthalenesulfonic acid, were investigated by means of ultraviolet, fluorescence, fluorescence lifetime, circular dichroism, and 2D-NMR spectroscopy. The spectral titrations have been performed in aqueous phosphate buffer solution (pH 7.20) at 25 degrees C to give the complex stability constants (K(S)) and Gibbs free energy changes (-DeltaG degrees ) for the inclusion complexation of hosts 2-9 with organic dyes and other thermodynamic parameters (DeltaH degrees and TDeltaS degrees ) for the inclusion complexation of 2-5with fluorescent dyes ANS and TNS. The results obtained indicate that beta-cyclodextrin dimers 2-5 can coordinate with one or two platinum(IV) ions to form 1:1 or 1:2 stoichiometry metallobridged bis(beta-cyclodextrin)s. As compared with parent beta-cyclodextrin (1) and bis(beta-cyclodextrin)s 2-5, metallobridged bis(beta-cyclodextrin)s 6-9 can further switch the original molecular binding ability through the coordinating metal to orientate two beta-cyclodextrin cavities and an additional binding site upon the inclusion complexation with model substrates, giving the enhanced binding constants K(S) for both ANS and TNS. The tether length between two cyclodextrin units plays a crucial role in the molecular recognition with guest dyes. The binding constants for TNS decrease linearly with an increase in the tether length of dimeric beta-cyclodextrins. The Gibbs free energy change (-DeltaG degrees ) for the unit increment per ethylene is 0.32 kJ.mol(-)(1) for TNS. Thermodynamically, the higher complex stabilities of both ANS and TNS upon the inclusion complexation with 2-5 are mainly contributed to the favorable enthalpic gain (-DeltaH degrees ) by the cooperative binding of one guest molecule in the closely located two beta-cyclodextrin cavities as compared with parent beta-cyclodextrin. The molecular binding ability and selectivity of organic dyes by hosts 1-9 are discussed from the viewpoints of the multiple recognition mechanism and the size/shape-fitting relationship between host and guest.     

Synthesis and conformational studies of gamma-aminoxy peptides

We have synthesized a series of gamma-aminoxy acids, including unsubstituted and gamma4-Ph-, gamma4-alkyl-, and gamma(3,4)-cyclohexyl-substituted systems. Coupling of these monomers to oligomers can be realized using EDCI/HOBt (or HOAt) as the coupling agent. gamma-Aminoxy peptides can form 10-membered-ring intramolecular hydrogen bonds-so-called "gamma N-O turns"-between adjacent residues, the extent of which is controlled by the nature of the side chain of each gamma-aminoxy acid residue, increasing from the unsubstituted gamma-aminoxy peptide to the gamma4-alkyl aminoxy peptides to the gamma4-phenyl- and gamma(3,4)-cyclohexyl-substituted aminoxy peptides. The presence of two consecutive homochiral 10-membered-ring intramolecular hydrogen bonds leads to the formation of a novel helical structure. Theoretical studies on a series of model peptides rationalize very well the experimentally observed conformational features of these gamma-aminoxy peptides.     

Velcrands with snaps and their conformational control

A novel class of self-folding velcrands was prepared that dimerize through intermolecular forces. Solvophobic interactions on extended pi surfaces stabilize the dimer similar to velcrands, while eight hydrogen bonds act like snaps to hold the molecules together. The self-complementary array of hydrogen bonding sites were incorporated on the upper rim of a resorcinarene-based cavitand. A dramatic reorganization of shape and size of the internal cavity was manifested through changes in solvent polarity. Specifically, the equilibrium between the extended surface (D2d symmetry) and a deep cavity (C4v symmetry) could be manipulated in mixtures of aromatic solvents (or CDCl3) and [D6]DMSO. The switching of conformations and the dimerization motif are well-suited for the assembly of noncovalent polymeric materials.     

Attachment of ferrocene nanotubes on beta-cyclodextrin self-assembled monolayers with molecular recognitions

Ferrocene nanotubes were fabricated by binding carboxylic acid-derivatized ferrocenes onto template peptide nanotubes via hydrogen bonding. When these ferrocene-functionalized nanotubes were incubated with beta-cyclodextrin (beta-CD) self-assembled monolayers (SAMs) coated on patterned Au substrates in solution, the ferrocene nanotubes recognized and attached onto the beta-CD SAMs via host-guest molecular recognition. The ferrocene nanotubes were also observed to recognize the certain cavity size of CD. The attachment/detachment of nanotubes on the beta-CD SAMs was controlled electrochemically by tuning the redox states of ferrocene nanotubes. This electric field-responsive building block may be applied to build nanometer-sized switching components in electronics and sensors.     

Determination of serotonin and bufotenin as their dansyl derivatives.

A method is described which permits the determination of serotonin and bufotenin in the same tissue sample. It comprises the following steps: (a) tissue extraction with acetone-0.1 M hydrochloric acid (19:1); (b) reaction of the tissue extract with dansyl (Dns) chloride; (c) pre-separation of O-Dns-bufotenin from O,N-bis-Dns-serotonin and other Dns-amides on a small silica gel column (this step is dispensable if only serotonin or bufotonin is being determined); (d) TLC separation of O-Dns-bufotenin and O,N-bis-Dns-serotonin from other Dns derivatives; (e) quantitative evaluation of the separated compounds by fluorimetry for O-Dns-bufotenin and by fluorimetry or mass spectrometry for the serotonin derivative. The photometer response is linear within the range 0.1-300 nmole. With the mass spectrometric method, 2 pmole of O,N-bis-Dns-serotonin could be determined with a standard deivation of +/-9%. The recovery of the amines from tissue was better than 85%. Reserpine treatment of toads caused a concomitant decrease in serotonin and bufotenin in the brain, but not in the skin of the animals. Repletion of bufotenin in the brain occurs at a higher rate than the repletion of the serotonin pool.     

Influence of conformational parameters on physical properties of copolyimides containing pendant diphenylphosphine oxide units

Modification or designing new molecular architectures are the key strategies to obtain materials with improved/tunable properties able to address environmental restrictions and public needs. Herein, a series of copolyimides containing bulky diphenylphosphine oxide pendant units was synthesized and the physical properties were studied and correlated with the conformational parameters, such as Kuhn segments, Van der Waals and free volumes. It is shown that conformational rigidity determines the packing of macromolecules in glass state, and therefore the free volume, glass transition and dielectric permittivity. The Kuhn segment of the synthesized random copolyimides calculated by Monte Carlo method exhibited a nonlinear dependence on chemical composition. The use of correlations between the chemical structure and conformational parameters is the key to achieve polymers with tailored physicochemical characteristics by varying the comonomers’ ratio.     

Biquinolino-modified beta-cyclodextrin dimers and their metal complexes as efficient fluorescent sensors for the molecular recognition of steroids

A series of bridged beta-cyclodextrin (beta-CyD) dimers possessing functional tethers of various lengths was synthesized in moderate yield by the treatment of 2,2'-biquinoline- 4,4'-dicarboxylic dichloride with beta-CyD or mono[6-oligo(ethylenediamino)-6-deoxy]-beta-CyDs. The products were 2,2'-biquinoline-4,4'-dicarboxy-bridged bis(6-O-beta-CyD) (8), N,N'-bis(2-aminoethyl)-2,2'-biquinoline-4,4'-dicarboxamide-bridged bis(6-amino-6-deoxy-beta-CyD) (9), and N,N'-bis(5-amino-3-azapentyl)-2,2'-biquinoline-4,4'-dicarboxamide-bridged bis(6-amino-6-deoxy-beta-CyD) (10). The reaction of 8-10 with copper perchlorate give their copper(II) complexes 11-13 in satisfactory yields of over 77 %. All the bis(beta-CyD)s 8-13 act as efficient fluorescent sensors and display remarkable fluorescence enhancement upon addition of optically inert steroids. The inclusion complexation behaviors of 8-13 when treated with the representative steroids cholate (14), deoxycholate (15), and glycocholate (16) in aqueous solution at 25 degrees C were investigated by means of UV/Vis spectroscopy, conductivity and fluorescence measurements, circular dichroism spectroscopy, and 2D NMR spectroscopy. The tether length of bis(beta-CyD) 9 allows it to adopt a cooperative host-tether-guest binding mode in which the spacer and guest are co-included in the two CyD cavities. As a result of this cooperation, 9 has a stability constant (K(s)) about 2x10(2) times higher than that of monomodified beta-CyD 4 for inclusion complexation with cholate. Metallooligo(beta-CyD)s with four beta-CyD units have enhanced binding abilities compared with monomodified beta-CyDs. These metallo compounds have binding affinities for guest steroids that are up to 50-4.1x10(3) times higher than those of CyDs 2-4. The guest-induced fluorescence enhancement of bis(CyD)s opens a new channel for the design of sensor materials. The complex stability constants of these compounds are discussed from the viewpoint of induced-fit interaction and cooperative multiple binding between host and guest.     

Supramolecular control of split-GFP reassembly by conjugation of beta-cyclodextrin and coumarin units

The design of proteins whose structure and function can be manipulated by binding with specific ligands has been of great interest in the field of protein engineering. Some successful examples of small-molecule-dependent proteins have been reported, but their ligand-binding domains have mainly been limited to those derived from natural proteins. The introduction of synthetic components for ligand responsiveness may expand the versatility of small-molecule-dependent proteins. In this study, we designed and constructed a fragmented green fluorescent protein (split GFP) whose reassembly could be modulated by the non-natural supramolecular interaction. In the design of split GFP, beta-cyclodextrin (betaCDx) and coumarin units were introduced into a C-terminal fragment (residues 214-230) of split GFP. The C-terminal peptide with betaCDx and coumarin, DC-M2-betaCDx, which contains both host and guest moieties in the same peptide chain, formed an intramolecular inclusion complex in the absence of exogenous guest molecules. This interaction strongly inhibited reconstitution with the GFP N-terminal fragment (residues 2-214) (GFP 1-10 OPT). However, the addition of suitable guest molecules for betaCDx terminated the intramolecular host-guest interaction in the C-terminal peptide, leading to reassembly of the protein fragments and concomitant fluorescence recovery due to the formation of mature GFP. These results successfully demonstrated direct control of protein structure and function by application of synthetic supramolecular interaction to a fragmented protein. The combined system of fragmented protein and synthetic supramolecular elements is expected to be a useful and flexible strategy for regulation of protein structure and function via binding to synthetic ligands.     

The molecular and crystal structure of 1,2-diazepines and their conformational mobility in solution

X-ray diagrams of 1,2-diazepines showed them to be boat-shaped molecules with a localized imine double-bond. Variable temperature NMR and variable temperature CD of the optically active 1,2-diazepine (15) indicated the existence of a fast equilibrium between the two boat shaped diastereoisomeric conformations. In the iron-tricarbonyl complex (6) of the 1-isopropoxycarbonyl 1,2-diazepine (4) the seven-membered ring is bent by 40° along the C(4)–C(7) line.     

H-bonding cooperativity and energetics of alpha-helix formation of five 17-amino acid peptides

Five peptides, each containing 17 amino acids, have been completely geometrically optimized in their alpha-helical and beta-strand forms using a mixed DFT/AM1 procedure. B3LYP/D95** was used for the entire helical structures, while AM1 was initially used to optimize the side chains, followed by reoptimization at the DFT level. The energetic and structural results show (1) that the helices are favored over the strands by 29.5 to 37.4 kcal/mol; (2) that alkyl groups on the amino acid side chains favor helix formation even in the absence of solvent; (3) that C-H...O hydrogen bonds contribute to the relative stability of the helices that contain amino acids (val, leu and ile) with beta-hydrogens in their alkyl side chains; (4) that formation of these helices entails approximately 6.6 kcal/mol of strain within the backbone per hydrogen bond; and (5) that H-bond cooperativity is essential for the alpha-helix to become more stable than a corresponding beta-strand. This last observation strongly suggests that pairwise potentials are inadequate for modeling of peptides and proteins.     

Redox responsive molecular tweezers with tetrathiafulvalene units: synthesis, electrochemistry, and binding properties

Several new molecular tweezers with tetrathiafulvalene (TTF) arms as well as mono-TTF derivatives bearing 3,5-di-tert-butylbenzylthio groups to provide enhanced solubility were prepared starting from a bis-cyanoethyl-protected tetrathiafulvalene derivative. The X-ray crystallographic analysis of 3 and 7a showed highly distorted TTF groups and absence of close TTF-TTF contacts in the crystalline state. Comparative cyclic voltammetry (CV) measurements demonstrated that through space distance-dependent TTF-TTF interactions take place in the TTF-containing molecular tweezers, leading to electronic pairing with formation of mixed valence [TTF]₂⁺ species and splitting of the first oxidation wave. TTF-containing molecular tweezers were successfully tested as receptors for several electron-deficient substances.     

Designed peptides with homochiral and heterochiral diproline templates as conformational constraints

Diproline segments have been advanced as templates for nucleation of folded structure in designed peptides. The conformational space available to homochiral and heterochiral diproline segments has been probed by crystallographic and NMR studies on model peptides containing L-Pro-L-Pro and D-Pro-L-Pro units. Four distinct classes of model peptides have been investigated: a) isolated D-Pro-L-Pro segments which form type II' beta-turn; b) D-Pro-L-Pro-L-Xxx sequences which form type II'-I (betaII'-I, consecutive beta-turns) turns; c) D-Pro-L-Pro-D-Xxx sequences; d) L-Pro-L-Pro-L-Xxx sequences. A total of 17 peptide crystal structures containing diproline segments are reported. Peptides of the type Piv-D-Pro-L-Pro-L-Xxx-NHMe are conformationally homogeneous, adopting consecutive beta-turn conformations. Peptides in the series Piv-D-Pro-L-Pro-D-Xxx-NHMe and Piv-L-Pro-L-Pro-L-Xxx-NHMe, display a heterogeneity of structures in crystals. A type VIa beta-turn conformation is characterized in Piv-L-Pro-L-Pro-L-Phe-OMe (18), while an example of a 5-->1 hydrogen bonded alpha-turn is observed in crystals of Piv-D-Pro-L-Pro-D-Ala-NHMe (11). An analysis of pyrrolidine conformations suggests a preferred proline puckering geometry is favored only in the case of heterochiral diproline segments. Solution NMR studies, reveal a strong conformational influence of the C-terminal Xxx residues on the structures of diproline segments. In L-Pro-L-Pro-L-Xxx sequences, the Xxx residues strongly determine the population of Pro-Pro cis conformers, with an overwhelming population of the trans form in L-Xxx=L-Ala (19).     

Effect of poly(ethylene glycol) (PEG) spacers on the conformational properties of small peptides: a molecular dynamics study

Poly(ethylene glycol) (PEG) is used as an inert spacer in a wide range of biotechnological applications such as to display peptides and proteins on surfaces for diagnostic purposes. In such applications it is critical that the peptide is accessible to solvent and that the PEG does not affect the conformational properties of the peptide to which it is attached. Using molecular dynamics (MD) simulation techniques, we have investigated the influence of a commonly used PEG spacer on the conformation properties of a series of five peptides with differing physical-chemical properties (YGSLPQ, VFVVFV, GSGGSG, EEGEEG, and KKGKKG). The conformational properties of the peptides were compared (a) free in solution, (b) attached to a PEG-11 spacer in solution, and (c) constrained to a two-dimensional lattice via a (PEG-11)(3) spacer, mimicking a peptide displayed on a surface as used in microarray techniques. The simulations suggest that the PEG spacer has little effect on the conformational properties of small neutral peptides but has a significant effect on the conformational properties of small highly charged peptides. When constrained to a two-dimensional surface at peptide densities similar to those used experimentally, it was found that the peptides, in particular the polar and nonpolar peptides, aggregated strongly. The peptides also partitioned into the PEG layer. Potentially, this means that at high packing densities only a small fraction of the peptide attached to the surface would in fact be accessible to a potential interaction partner.     

Preparation of macroreticular redox resins with hydroquinone and catechol units as pendant groups and their properties

Macroreticular redox resins with hydroquinone and catechol units as pendant groups were prepared by the Friedel-Crafts reaction of macroreticular styrene/divinylbenzene copolymer with 2,5- and 3,4-dimethoxybenzyl chlorides, followed by removal of the methyl groups with hydrobromic acid. The redox capacity of the macroreticular resins was determined by oxidation of hydrazobenzene with resins in oxidized form. Resins with 1,4-benzoquinone units were capable of oxidizing hydrazobenzene, whereas those with 1,2-benzoquinone (catechol quinone) units exhibited no apparent oxidative ability; this seems to be due to a complex formation between azobenzene and the catechol units in the reduced resins. Adsorption of metallic ions onto catechol-containing resins showed a high selectivity for Hg²⁺ ion. The effects of pH, reaction time, and ion concentration on the adsorption were also studied.