Synthesis of uniform cyclodextrin thioethers to transport hydrophobic drugs

• Lisa F. Becker,
• Dennis H. Schwarz and
• Gerhard Wenz

Beilstein J. Org. Chem. 2014, 10, 2920–2927, doi:10.3762/bjoc.10.310

• anaesthesia. Keywords: active pharmaceutical ingredient; binding constant; cyclodextrin; derivatization; gas chromatography; sevoflurane; substitution pattern; Introduction Cyclodextrins (CDs) are cyclic oligomers of α-1,4-linked glucose units. Those CDs consisting of 6, 7, and 8 glucose units are called α

• Fourmentin et al. [30][52]. As shown in Figure 4, the vapour pressure of the guest sevoflurane significantly drops due to complexation by host 3b1. The corresponding binding constant K was calculated from the hyperbolic decay of the area A of the sevoflurane signal with the total concentration of the CD

• available native CDs and β-CD derivatives showed rather poor affinities to sevoflurane, as shown in Table 2. Among the native CDs β-CD had far the highest binding constant which was attributed to the best space filling of this host by sevoflurane. We recently demonstrated also for other guests that space

Synthesis of modified cyclic and acyclic dextrins and comparison of their complexation ability

• Kata Tuza,
• László Jicsinszky,
• Tamás Sohajda,
• István Puskás and
• Éva Fenyvesi

Beilstein J. Org. Chem. 2014, 10, 2836–2843, doi:10.3762/bjoc.10.301

• complex of lower binding constant than with β-CD [6]. The helical conformations may act as ‘semicavities’ as proposed by Schurig’s group [7] who found even enantioseparation with the acetylated/silylated G6 and G7 as chiral selectors in gas chromatography. In some cases these acyclodextrins showed similar

• of the tested drugs, ibuprofen and nateglinide showed significant interaction with both the cyclic and acyclic analogs. While the apparent binding constant of the ibuprofen/β-CD system is the highest, all the acyclic derivatives showed significant affinity towards this guest irrespective of the

Improving ITC studies of cyclodextrin inclusion compounds by global analysis of conventional and non-conventional experiments

• Eléonore Bertaut and
• David Landy

Beilstein J. Org. Chem. 2014, 10, 2630–2641, doi:10.3762/bjoc.10.275

• compare the efficiency of conventional and non-conventional experiments. All direct and competitive protocols were described and evaluated in terms of accuracy on both binding constant and inclusion enthalpy. Significant improvement in the calorimetric characterization may be obtained by means of the

• techniques ranging from spectroscopy to chromatography and including calorimetrical tools [1][2][3][4]. Within this scope, isothermal titration calorimetry (ITC) is gaining more and more importance, as it allows a complete thermodynamic description of the inclusion phenomena (binding constant K, inclusion

• investigations on the efficiency of all protocols. We used covariance matrixes to calculate the uncertainty in binding constant and inclusion enthalpy, not only for the individual analysis of each experiment, but also for the global analysis of coupled experiments. All these investigations were aimed at

Encapsulation of biocides by cyclodextrins: toward synergistic effects against pathogens

• Véronique Nardello-Rataj and
• Loïc Leclercq

Beilstein J. Org. Chem. 2014, 10, 2603–2622, doi:10.3762/bjoc.10.273

• carbendazim solubility [42]. From the method of continuous variations (Job’s method), it was found a 1:1 stoichiometry for the carbendazim–HP-β-CD inclusion complex. The complex was fully characterized by phase-solubility diagram, fluorescence, 1H and ROESY NMR and FTIR experiments. The binding constant of

• free p-hydroxybenzoic acid esters decreases with the binding constant increase. These results suggest that the degree of inactivation is completely dependent on the encapsulated fraction of the p-hydroxybenzoic acid ester. It is worth mentioning that the “deactivation” of parabens by CDs is less

• problem of unstability of chloramine phosphate (chloramidophos, see Figure 3) as a pesticide by the formation of 1:1 inclusion complexes with β-CD [49]. The formation of inclusion complex was proved by DSC, Fourier transform infrared and X-ray diffraction [50]. The binding constant was estimated at 203 M

Towards the sequence-specific multivalent molecular recognition of cyclodextrin oligomers

• Michael Kurlemann and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2014, 10, 2428–2440, doi:10.3762/bjoc.10.253

• interaction between 17 and β-CD has a ca. 400-fold higher binding constant than the interaction of 17 and α-CD the preferred complexation behavior towards β-CD can be expected (Figure 5A). The n-butyl derivate 18 also interacts with both α- and β-CD. In the case of α-CD the formation of a 1:1 adduct with a

• binding constant of ca. 102 M−1 is observed. The complexation is driven by a negative complexation enthalpy (Table 1) and leads to the inclusion of the n-butyl moiety of 18. This is confirmed by NMR spectra, where the protons of the n-butyl unit show strong shifting to higher ppm values after addition of

• spectra of pure 18, giving a strong hint that complexation takes place (Figure 6A and B). Taking the results of both experiments into account, a binding constant lower than 102 M−1 can be assumed for the interaction between 18 and β-CD. Additional measurements with 10-fold increased concentrations of both

Reversibly locked thionucleobase pairs in DNA to study base flipping enzymes

• Christine Beuck and
• Elmar Weinhold

Beilstein J. Org. Chem. 2014, 10, 2293–2306, doi:10.3762/bjoc.10.239

• subsequent flipping of the target base. Kflip can therefore be calculated from two binding experiments, one with an unlocked I6S/U4S pair, giving the overall binding constant that comprises both binding and base flipping, and one with the locked cross-linked target base pair (Figure 6), which reports the

• -fluorescent DNA. (a) Binding of M.TaqI to duplex 1I6S∙2U4S with unlocked target base pair (top reaction scheme and open circles) allows base flipping of the target base into the active site. The observed dissociation constant comprises both the initial binding constant KD,init and the base flipping

The effect of permodified cyclodextrins encapsulation on the photophysical properties of a polyfluorene with randomly distributed electron-donor and rotaxane electron-acceptor units

• Aurica Farcas,
• Ana-Maria Resmerita,
• Pierre-Henri Aubert,
• Flavian Farcas,
• Iuliana Stoica and
• Anton Airinei

Beilstein J. Org. Chem. 2014, 10, 2145–2156, doi:10.3762/bjoc.10.222

• -CD, respectively. Changes in the absorption spectra of the monomer 1 upon the addition of increasing amounts of TMS-γ-CD in CHCl3. The inset shows the fitted binding constant curve based on a 1:1 host–guest complexation stoichiometry. 1H NMR spectrum of the polyrotaxane 4a copolymer in toluene-d8

Macrocyclic bis(ureas) as ligands for anion complexation

• Claudia Kretschmer,
• Gertrud Dittmann and
• Johannes Beck

Beilstein J. Org. Chem. 2014, 10, 1834–1839, doi:10.3762/bjoc.10.193

• ethynylene or butadiynylene group gives a stiff arrangement but leaves one degree of freedom in the system, since rotation around the linking group is possible. This approach was realized by Steed and coworkers, who showed that on adding chloride ions planarization occurs and a rather high binding constant

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• presence sodium acetate in dioxane at 100 °C. The compound was prepared on the 10 mg scale in 67% yield. In contrast to its (3R,4R)-enantiomer (not shown), compound (3S,4S)-23 showed inhibitory activity toward human purine nucleoside phosphorylase (PNP) with a slow-onset binding constant Ki* = 0.032 nM. In

Biantennary oligoglycines and glyco-oligoglycines self-associating in aqueous medium

• Svetlana V. Tsygankova,
• Alexander A. Chinarev,
• Alexander B. Tuzikov,
• Nikolai Severin,
• Alexey A. Kalachev,
• Juergen P. Rabe,
• Alexandra S. Gambaryan and
• Nicolai V. Bovin

Beilstein J. Org. Chem. 2014, 10, 1372–1382, doi:10.3762/bjoc.10.140

• inhibition or the blocking of the binding of the influenza virus with target cells [15]. Monovalent oligosaccharides are incapable of an efficient competition for analogous glycans on the cell surface due to the low binding constant with viral hemagglutinin. An attractive way of increasing the affinity of a

Homochiral BINOL-based macrocycles with π-electron-rich, electron-withdrawing or extended spacing units as receptors for C₆₀

• Marco Caricato,
• Silvia Díez González,
• Idoia Arandia Ariño and
• Dario Pasini

Beilstein J. Org. Chem. 2014, 10, 1308–1316, doi:10.3762/bjoc.10.132

• the Hill equation [42] gave an average binding constant of 1600 M−1, thus confirming a higher affinity for the π-electron rich thiophene-derived spacer units. The Hill coefficient [43][44] suggests the presence of concomitant 1:1 and 1:2 C60:macrocycle complexes in solution. Even more interestingly

Staudinger ligation towards cyclodextrin dimers in aqueous/organic media. Synthesis, conformations and guest-encapsulation ability

• Malamatenia D. Manouilidou,
• Yannis G. Lazarou,
• Irene M. Mavridis and
• Konstantina Yannakopoulou

Beilstein J. Org. Chem. 2014, 10, 774–783, doi:10.3762/bjoc.10.73

• titration experiments: the binding constant with 1-adamantylamine was similar to that of natural β-CD. Theoretical calculations for isolated molecules (PM3 level of theory) and in the presence of solvent [water, PM3(COSMO)] as well as DFT calculations suggested that the compounds prefer to adopt

• binding constant is moderately strong, therefore an average diffusion coefficient is observed. Cavity availability for inclusion complexation. – The above results suggest that the phenyl groups might be serious competitors to any incoming guest molecule. To test the accessibility of the cavities and the

Structure elucidation of β-cyclodextrin–xylazine complex by a combination of quantitative ¹H–¹H ROESY and molecular dynamics studies

• Syed Mashhood Ali,
• Kehkeshan Fatma and
• Snehal Dhokale

Beilstein J. Org. Chem. 2013, 9, 1917–1924, doi:10.3762/bjoc.9.226

• stoichiometry and binding constant of host–guest complexes, 1H NMR titration experiments are most common. These titration experiments give Δδ data for many independent signals which can independently be used to determine the stoichiometry and binding constant. Several NMR versions of Benesi–Hildebrand equations

• [17] are used for this purpose and we have used Scott’s method [18]. The Scott’s equation gives the relationship between the apparent binding constant (Ka), the complexation-induced shift at saturation (Δδs), the guest or host concentrations (the species whose concentration is varied), and the

• taking 9 mg of β-CD and adding a calculated amount of xylazine in 0.5 ml D2O. The ΔδH-3’ and ΔδH-5’ data was plotted in the form of [XZ]/Δδobs versus [XZ] (Figure 3) which gave linear fits confirming the 1:1 stoichiometry of the complex. The binding constant of the complex was calculated to be 86.45 M−1

Topochemical control of the photodimerization of aromatic compounds by γ-cyclodextrin thioethers in aqueous solution

• Hai Ming Wang and
• Gerhard Wenz

Beilstein J. Org. Chem. 2013, 9, 1858–1866, doi:10.3762/bjoc.9.217

• previously by fluorescence measurements [25]. The quantum yield Φ did not correlate with the binding constant K, possibly because dissolved ANT is mainly converted in the complexed state in presence of hosts 1–7. Only a small portion of ANT remains in the free state due to its low solubility (0.4 μM, [25

• quantum yields and molar fractions of the syn-HH isomer, listed in Table 5, are in good agreement with the measured values, listed in Table 4. It also shoes, that the binding constant K, calculated according to the law of mass action for the 1:2 (host/guest) complex, tremendously increases with the salt

• . Influence of CDs on the quantum yield Φ of the photodimerization of ANT and 1:2 binding constant K [25]. Quantum yields Φ, distributions of the photodimers, and binding constants K [25] of ACE for various reaction media. Distribution of the photodimers of COU for various media. Influence of the sodium

Space filling of β-cyclodextrin and β-cyclodextrin derivatives by volatile hydrophobic guests

• Sophie Fourmentin,
• Anca Ciobanu,
• David Landy and
• Gerhard Wenz

Beilstein J. Org. Chem. 2013, 9, 1185–1191, doi:10.3762/bjoc.9.133

• ]. Generally, the binding constant K increases with the degree of space filling of the β-CD cavity. The volume of the guest is often expressed by the number of carbon atoms n of its hydrophobic part. The Gibbs free enthalpy ΔG° of binding decreases nearly linearly with n by δΔG0/δn = −3.1 kJ mol−1 for linear

• alkanols [1]. Similar values were found for cyclic and polycyclic alkanoic acids δΔG0/δn = −3.3 kJ mol−1 [7]. We found an even higher slope for a series of p-substituted benzoic acids δΔG0/δn = −4.2 kJ mol−1, where the binding constant remarkably increased from K = 20 L mol−1 for benzoate to K = 18,400 L

• constants could be determined for all of the five guests in parallel. The different decays of the signal intensities of the guests due to the complexation in β-CD are obvious in Figure 3. The binding constant K was calculated from the ratio y = A0/A of the peak area of the guest without and with CD, A0 and

Inclusion of the insecticide fenitrothion in dimethylated-β-cyclodextrin: unusual guest disorder in the solid state and efficient retardation of the hydrolysis rate of the complexed guest in alkaline solution

• Dyanne L. Cruickshank,
• Natalia M. Rougier,
• Raquel V. Vico,
• Susan A. Bourne,
• Elba I. Buján,
• Mino R. Caira and
• Rita H. de Rossi

Beilstein J. Org. Chem. 2013, 9, 106–117, doi:10.3762/bjoc.9.14

• Spectroscopic methods are frequently used to determine association constants between cyclodextrins and different guests [16]. We attempted to determine the binding constant of 1 with DIMEB by UV–vis spectroscopy; however, when we recorded the spectra of 1 in the presence of DIMEB, only a small hypsochromic

• shift was noted and the change in absorbance was not large enough for an accurate determination of the binding constant. The induced circular dichroism (ICD) spectrum of DIMEB and 1 is shown in Figure 9a, where the spectrum recorded for β-CD and TRIMEB with 1 is also shown for comparison. It can be seen

Amino-substituted diazocines as pincer-type photochromic switches

• Hanno Sell,
• Christian Näther and
• Rainer Herges

Beilstein J. Org. Chem. 2013, 9, 1–7, doi:10.3762/bjoc.9.1

• methods (for details see Supporting Information File 1) [18][19] yielded a binding constant for the 1:1 ethylenediamine complex of the cis isomer of Ka,cis = 0.88 ± 0.03 M−1. For the corresponding complex of the trans isomer a slightly lower binding constant of Ka,trans = 0.61 ± 0.05 M−1 was determined in

Influence of intramolecular hydrogen bonds on the binding potential of methylated β-cyclodextrin derivatives

• Gerhard Wenz

Beilstein J. Org. Chem. 2012, 8, 1890–1895, doi:10.3762/bjoc.8.218

• : binding constant; cyclodextrin; hydrogen bond; methylation; regioselective; Introduction Cyclodextrins (CDs) are a well-known class of organic hosts able to include various guests, preferably in aqueous solution [1][2][3]. Inclusion is mainly driven by hydrophobic and van der Waals interactions [4][5][6

• constants of the 2,6-di-O-methyl derivative 2 as well as the 6-O-methyl derivative were higher than the one of β-CD. Apparently, methylations of secondary hydroxy groups lead to a decrease of the binding constant, while methylation at primary hydroxy groups leads to an increase. For the 2,6-di-O-methyl

• derivative both effects seem to compensate each other giving rise to a binding constant K similar to the one of native β-CD. The randomly methylated β-CD 7 also showed an inclusion potential very similar to β-CD for the same reason. The thermodynamic data (Table 2) measured for the inclusion of adamantane-1

Molecular solubilization of fullerene C₆₀ in water by γ-cyclodextrin thioethers

• Hai Ming Wang and
• Gerhard Wenz

Beilstein J. Org. Chem. 2012, 8, 1644–1651, doi:10.3762/bjoc.8.188

• initial rate of complexation is predicted to be proportional to CD concentration, which was already experimentally found for native γ-CD [37]. On the other hand, the one step model (b) leads to the classical binding constant K. The initial complexation rate should be proportional to the square of the host

Mannose-decorated cyclodextrin vesicles: The interplay of multivalency and surface density in lectin–carbohydrate recognition

• Ulrike Kauscher and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2012, 8, 1543–1551, doi:10.3762/bjoc.8.175

• , the stoichiometry appears to be less than 1:1, the binding constant is somewhat lower, and the thermodynamic parameters are different (notably, ΔS is negative). This observation can be explained by steric hindrance in the trivalent host–guest complex: apparently, three β-cyclodextrins are too large to

• , the guest molecules are expected to form inclusion complexes at the surface of vesicles of amphiphilic cyclodextrin 5. More importantly, guest molecules 2–4 are expected to form multivalent host–guest complexes with a much higher effective binding constant than the monovalent binding constant reported

• in Table 1. According to a quantitative treatment of multivalent host–guest interactions at surfaces, it may be expected that for a 1:1 monovalent interaction with a binding constant of ≈104 M−1, a divalent interaction can have an apparent binding constant of ≈107 M−1 and a trivalent interaction can

Cyclodextrin nanosponge-sensitized enantiodifferentiating photoisomerization of cyclooctene and 1,3-cyclooctadiene

• Wenting Liang,
• Cheng Yang,
• Masaki Nishijima,
• Gaku Fukuhara,
• Tadashi Mori,
• Andrea Mele,
• Franca Castiglione,
• Fabrizio Caldera,
• Francesco Trotta and
• Yoshihisa Inoue

Beilstein J. Org. Chem. 2012, 8, 1305–1311, doi:10.3762/bjoc.8.149

• , inducing stronger ICD at the 1La band (Figure 1c). Assuming the 1:1 stoichiometry, we calculated the apparent binding constant, averaged over the CD units of CDNS, as 4000 M−1 in water at 25 °C. This value is smaller than those obtained with the sensitizer-modified CDs reported previously [36], for which

• 5 (50 μg/mL) (blue) in pure water at 25 ºC, and (b) of 3 (560 μg/mL) in the presence of 0–2.3 mM 1Z; Inset shows the nonlinear least-squares curve fit of the ellipticity changes at 257 nm, assuming the 1:1 stoichiometry, from which the apparent binding constant was determined to be 4000 ± 1000 M−1

Binding of group 15 and group 16 oxides by a concave host containing an isophthalamide unit

• Jens Eckelmann,
• Vittorio Saggiomo,
• Svenja Fischmann and
• Ulrich Lüning

Beilstein J. Org. Chem. 2012, 8, 11–17, doi:10.3762/bjoc.8.2

• . The syn/syn conformation can be stabilized by using isophthalamide derivatives capable of intramolecular hydrogen bonding to the CO part of the amide groups [10][11], or by other means of bridging [12]. Due to the preorganization of such molecules, the binding constant for chloride is impressively

Supramolecular FRET photocyclodimerization of anthracenecarboxylate with naphthalene-capped γ-cyclodextrin

• Qian Wang,
• Cheng Yang,
• Gaku Fukuhara,
• Tadashi Mori,
• Yu Liu and
• Yoshihisa Inoue

Beilstein J. Org. Chem. 2011, 7, 290–297, doi:10.3762/bjoc.7.38

• = 182 M−1 and K2 = 56700 M−1) [12], the first binding constant was enhanced by a factor of 3.5–5.8 by introducing the naphthalene moiety, whilst the second binding constant was reduced by a factor of 2.5–3.0, thus making the overall binding constant (K1K2) approximately twice as high. It is known that

Fluorometric recognition of both dihydrogen phosphate and iodide by a new flexible anthracene linked benzimidazolium-based receptor

• Kumaresh Ghosh and
• Debasis Kar

Beilstein J. Org. Chem. 2011, 7, 254–264, doi:10.3762/bjoc.7.34

• showed 1:1 binding (Supporting Information File 1). However, the selectivity of 1 towards the anions studied was established by determining the binding constant values from fluorescence titration data (Table 1) [39]. As can be seen from Table 1, the receptor 1 shows a marginal selectivity for H2PO4−. The

• the polar C+–H bond of benzimidazolium motif and reduces the possibility of host–guest interactions [46]. This is clearly reflected in the binding constant values in Table 1. Due to the presence of a minimum amount of CH3CN in CHCl3 the binding constant values for the selected anions are greater in

• of the study due to insolubility in the NMR concentration range and this was one reason for not determining the binding constant values by the NMR method. However, both the amide and benzimidazolium protons (0.51 ppm) were found to move downfield and thereby supported our binding proposition as

Anthracene appended pyridinium amide–urea conjugate in selective fluorometric sensing of L-N-acetylvaline salt

• Kumaresh Ghosh,
• Tanmay Sarkar and
• Asoke P. Chattopadhyay

Beilstein J. Org. Chem. 2010, 6, 1211–1218, doi:10.3762/bjoc.6.139

• and guest used at which the titration experiments are monitored. Analysis of the emission data provided the association constants (Ka), reported in Table 2 [33]. For determining binding constant values for L-N-acetylvaline and L-N-acetylalanine salts, we considered the emission data up to the addition

• of 13 equivalents of the guests added, since in the presence of large excess of such guests complex stoichiometries were noted. From Table 2 it can be seen that receptor 1 exhibits higher binding constant values for L-N-acetylvaline in the series. At this moment, we believe that it is due to

• structural aspects as well as to the hydrogen bonding capacity of the valine salt. Furthermore, to establish the hydrogen bonding influence of the acylamino and hydroxy groups of the amino and hydroxy acids respectively, we determined the binding constant for the acetate anion. This was found to be slightly