Fluorescence and Molecular Mechanics of 1-Methyl Naphthalenecarboxylate/Cyclodextrin Complexes in Aqueous Medium

Steady-state, time-resolved fluorescence and Molecular Mechanics techniques have been used to study the complexation of 1-methyl naphthalenecarboxylate with three naturally occurring cyclodextrins (CDs). Emission spectra of 1MN show two overlapping electronic bands. The stoichiometry, the formation constants of the complexes and the thermodynamics parameters upon inclusion were obtained from the change of intensity ratios R of the maxima of both bands and 〈τ〉 with [CD] and temperature. As with the 2-methyl naphthalenecarboxylate (2MN) guest, 1:1 stoichiometries were obtained for all complexes. The formation constants, however, were relatively low compared to those obtained for 2MN. Geometry of the complexes from Molecular Mechanics in the presence of water agrees with the experimental stoichiometry of the complexes and the signs of enthalpy and entropy changes. Quenching, R at [CD]→∞ and fluorescence depolarization measurements also support the proposed structures. As with 2MN the inclusion is mostly dominated by van der Waals interactions.     

Inclusion complexes of cyclodextrins with 4-amino-1,8-naphthalimides (part 2)

Fluorescence spectroscopy was used to characterize inclusion compounds between 4-amino-1,8-naphthalimides (ANI) derivatives and different cyclodextrins (CDs). The ANI derivatives employed were N-(12-aminododecyl)-4-amino-1,8-naphthalimide (mono-C₁₂ANI) and N,N′-(1,12-dodecanediyl)bis-4-amino-1,8-naphthalimide (bis-C₁₂ANI). The CDs used here were α-CD, β-CD, γ-CD, HP-α-CD, HP-β-CD and HP-γ-CD. The presence of CDs resulted in pronounced blue-shifts in the emission spectra of the ANI derivatives, with increases in emission intensity. This behavior was parallel to that observed for the dyes in apolar solvents, indicating that inclusion complexes were formed between the ANI and the CDs. Mono-C₁₂ANI formed inclusion complexes of 1:1 stoichiometry with all the CDs studied. Complexes with the larger CDs (HP-β-CD, HP-γ-CD and γ-CD) were formed by inclusion of the chromophoric ANI ring system, whereas the smaller CDs (α-CD, HP-α-CD and β-CD) formed complexes with mono-C₁₂ANI by inclusion of the dodecyl chain. Bis-C₁₂ANI formed inclusion complexes of 1:2 stoichiometry with HP-β-CD, HP-γ-CD and γ-CD, but did not form inclusion complexes with α-CD, HP-α-CD and β-CD. The data were treated in the case of the large CDs using a Benesi-Hildebrand like equation, giving the following equilibrium constants: mono-C₁₂ANI:HP-β-CD (K ₁₁ = 50 M^?1), mono-C₁₂ANI:HP-γ-CD (K ₁₁ = 180 M^?1), bis-C₁₂ANI:HP-β-CD (K ₁₂ = 146 M^?2), bis-C₁₂ANI:HP-γ-CD (K ₁₂ = 280 M^?2).     

Assessment of the complexation degree of camptothecin derivatives and cyclodextrins using spectroscopic and separative methodologies

The complexation of camptothecin and homocamptothecin derivatives, topoisomerase I inhibitors, with two cyclodextrins (CDs) of pharmaceutical interest (native and hydroxypropylated β-CD) was studied at pH 3.5 and 6. In a first step, the affinity order of the six compounds studied for the β-CD and HP-β-CD was evaluated in HPLC using immobilized stationary phases [Cyclobond I 2000 (β-CD) and Cyclobond I 2000 RSP (HP-β-CD)]. In a second step, the apparent binding constants of the 12 complexes studied were determined at both pH by HPLC using Scott’s method with CD as a chiral additive. The 1:1 stoichiometry of the complex formed between HP-β-CD and the homocamptothecin derivative elomotecan (R)-6 was established by fluorescence spectroscopy using the continuous variation method developed by Job and ESI-MS. Complementary investigations were achieved for topotecan (S)-3 and elomotecan (R)-6 using CE. Further studies provided similar conclusions concerning affinity of all the derivatives studied for both CDs: that is, a slightly larger affinity was observed for HP-β-CD with respect to β-CD, except for (S)-3. For (S)-3, this affinity increase with pH, in the range studied.     

Understanding the interactions between artemisinin and cyclodextrins: spectroscopic studies and molecular modeling

Artemisinin extracted from Artemisia annua L. proved to be currently, with its derivatives, the most effective drugs against simple and severe malaria, and is also effective on the chloroquine-resistant forms. The advantageous effect of some cyclodextrins (CDs) on artemisinin solubilization was demonstrated by different authors. The present work aims to confirm the effect of several CDs on artemisinin solubilization and to analyse the complexes formed between these CDs and artemisinin in order to understand their solubilization capacities. In this context, solubility studies, liquid-state NMR spectroscopy (¹H NMR studies and ROESY experiments) as well as theoretical studies (molecular modeling) have been performed. Randomly methylated-βCD, Crysmeb^? and hydroxypropylated-γCD were also found to improve the aqueous solubilization of artemisinin as well as βCD, γCD and hydroxypropylated-βCD whose effects were already demonstrated. The best solubilization ability was found with Crysmeb^?. The spectroscopic studies showed a lot of interactions between artemisinin and all the CDs studied, but mainly outside the cavity. Molecular modeling confirmed that artemisinin and CDs formed non-inclusion complexes.     

A comparative study of inclusion complexes of flunarizine with alpha (α-CD) and beta-cyclodextrin (β-CD)

A detailed NMR (¹H, COSY, and ROESY) spectroscopic study of complexation of Flunarazine (FL) with α- and β-CD was carried out. ¹H NMR titration studies confirmed the formation of FL/α-CD and FL/β-CD complexes as evidenced by chemical shift variations of the proton resonances of both the CDs and FL. The stoichiometry of the complexes was determined to be 1:2 (FL/α-CD) and 1:1 (FL/β-CD) and overall binding constants were also calculated. It was confirmed with the help of ROESY spectral data that only one of the F-substituted aromatic ring and phenyl ring penetrate the α-CD cavity while both F-substituted aromatic rings as well as phenyl ring penetrates the β-CD cavity during complexation. The binding modes of FL/CD cavity interactions derived from ROESY experimental data show that the resulting complex of FL with β-CD possesses better induced fit interaction as compared to α-CD, which is responsible for the enhanced molecular stability with β-CD in comparison to α-CD. The mode of penetration of guest into the CD cavity and structures of the complexes has been established.     

Thermodynamic study of inclusion complexes of zaleplon with natural and modified cyclodextrins

The thermodynamics and stoichiometry of zaleplon (ZAL) complexation with different cyclodextrin derivatives [β-CD, hydroxypropyl-β-cyclodextrin (HP-β-CD), randomly methylated-β-cyclodextrin (RAMEB), sulphobutylether-β-cyclodextrin (SBE-β-CD)] in aqueous solution was studied by spectrofluorimetry and ¹H NMR spectroscopy in order to obtain a more general understanding of the driving forces behind the inclusion phenomena. Job’s plot derived from the NMR spectral data and statistical analysis of spectrofluorimetric titration data confirmed the formation of equimolar complexes in all systems tested, excluding the possibility of higher order complex formation. Furthermore, thermodynamic parameters obtained by both techniques gave similar and negative values of ΔG° for all complexes, indicating spontaneous inclusion of drug into CDs. From a thermodynamic point of view, two types of inclusions were determined. One is enthalpy driven ZAL complexation with β-CD, HP-β-CD and RAMEB, while the other is entropy driven complexation observed in the case of SBE-β-CD. The mechanisms behind each type of inclusion were discussed in detail.     

Effects of Cyclodextrin Derivatives on the Catalytic Activity of Tyrosine Phenol-Lyase

The impact of permethylated α-, β-, γ-cyclodextrin (TMα-CD, TMβ-CD, TMγ–CD, respectively) on TPL-catalysed decomposition of L-tyrosine was investigated by means of spectrophotometric measurements. The inhibitory effects of TM-CDs on the catalytic activity of the enzyme were shown. This phenomenon is supposed to be connected with the host–guest complex formation. CDs were found to have impact on maximal velocity and on Michaelis constant of described catalysis.     

The Role of Temperature in Enantioseparation of Norgestrel with Native Cyclodextrins: A Combined LC and NMR Study

Temperature dependence (10–50 °C) of the chiral LC separation of norgestrel was studied using native CDs added to a methanol–water 1:1 eluent. α- or β-CDs gave no enantiodiscrimination, while baseline LC separation was achieved with γ-CD. ¹H NMR titrations of the racemate with α-CD showed only weak complexation, while β- or γ-CDs caused enantiomeric splitting of the steroid signals. Both the chiral selectivity values and their insignificant temperature dependence measured in the γ-CD-modified LC system were successfully reproduced by NMR titrations. This agreement corroborates the intuitive view for a wider temperature range that the stability difference of the diastereomeric γ-CD/steroid complexes governs this LC enantioseparation.     

Complexation of triptolide and its succinate derivative with cyclodextrins: affinity capillary electrophoresis, isothermal titration calorimetry and 1H NMR studies

The complexation of the triptolide PG490 and its succinate derivative PG490-88Na with various cyclodextrins was studied using three complementary techniques: affinity capillary electrophoresis (ACE), isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR). The apparent binding constants of the complexes formed between the drugs and 8 CDs (α-CD, β-CD, γ-CD, HP-α-CD, HP-β-CD, HP-γ-CD, CM-β-CD and amino-β-CD) were determined by ACE through linear Scott's plots. The apparent and averaged binding constants of the complexes formed between PG490-88 and β-CD, γ-CD, HP-α-CD, HP-β-CD or HP-γ-CD are contained in the narrow range 135-167 M(-1). For the anionic CM-β-CD and cationic amino-β-CD, these constants are 38 and 278 M(-1), respectively, which is in accordance with electrostatic repulsions or attractions with the succinate moiety. ITC and NMR investigations for the binding constants determinations were performed for 2 CDs allowing high complexation: HP-β-CD and amino-β-CD. The three techniques provided similar results. ITC and NMR, in contrast to ACE, allowed to study the complexes formed between the neutral compound PG490 and neutral cyclodextrins. A more advanced characterization of the PG 490-88Na/amino-β-CD complex, which displays the highest apparent binding constant, was undertaken using NMR spectroscopy. The 1:1 stoichiometry of the complex was established by (1)H NMR 1D and selective 1D TOCSY experiments using the continuous variation method. Moreover, the 1D and 2D ROESY experiments revealed the inclusion of the isopropyl moiety of the triptolide derivative in the hydrophobic CD cavity. Altogether, the data provide strong evidences that the two triptolide compounds can be efficiently complexed with CD.     

Analogs of ecdysteroids with a tetrasubstituted Δ<Superscript>8,14</Superscript>-bond

By hydrogenation of (20R,22R)-6α,14α,25-trihydroxy-and (20R,22R)-6β,14α,25-trihydroxy-2,3:20,22-bis(isopropylidenedioxy)-5α-cholest-7-enes on a catalyst (Raney nickel) the corresponding (5α,6α)-and (5β,6β)-epimers of previously unknown Δ^8,14-6-hydroxy derivatives of ecdysteroids were synthesized.     

Cyclodextrins as Surfactants for Solubilization and Purification of Carbon Nanohorn Aggregates

Nano‐ to micrometer‐scale surface roughness contributes to the hydrophobicity of materials as discussed often in terms of superhydrophobicity. We report here that as little as 1 wt% of α, β, and γ‐cyclodextrins (CDs) can disperse carbon nanohorn aggregates (CNHa) as surfactants in water by binding on their pointed tips. The binding mode was visually demonstrated using single‐molecule atomic resolution real‐time electron microscopy (SMART‐EM). The SMART‐EM data provided an estimation of the equilibrium constant of the CD binding to be close to that of adamantane ammonium chloride to β‐CD. A qualitative study on the rate of decomplexation of α, β, and γ‐CDs from CNHa suggests a substantial mechanistic difference in their binding mode to the CNH tips. A sequence of α‐CD complexation and decomplexation allows us to purify CNHa by selectively removing graphitic ball‐shaped impurity (GB). Upon treatment with NaNH₂, the purified CNHa produce GB‐free amino‐CNHa where the tips are functionalized with NH₂ groups.     

Characterization of the complexation of tauro- and glyco-conjugated bile salts with γ-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin using affinity capillary electrophoresis

The complexation of seven bile salts, present in the small intestine of rat, dog and man, (taurocholate, tauro-β-muricholate, taurodeoxycholate, taurochenodeoxycholate, glycocholate, glycodeoxycholate and glycochenodeoxycholate) with γ-cyclodextrin and the chemically modified 2-hydroxypropyl-γ-cyclodextrin, was studied using affinity capillary electrophoresis (ACE). The cyclodextrins (CDs) were investigated due to their use in drug formulation as excipients for solubilisation of poorly soluble drugs and drug candidates. Using mobility shift ACE, the bile salt cyclodextrin interactions were characterized demonstrating 1:1 binding stoichiometry with stability constants ranging from 2 × 10³ to 8 × 10⁴ M^?1. The binding constants showed a systematic dependence on the number and position of hydroxyl groups on the steroid skeleton and the stability constants were in general higher for complexation with the native cyclodextrin than with the modified cyclodextrin. Based upon the size of the complexation constants, it was suggested that the interaction between the CDs and the bile salts takes place at the C and D ring of the steroid skeleton. The complexation of bile salts with the γ-cyclodextrins may compete with drug-γ-cyclodextrin complex formation and, thus, potentially affect drug absorption and efficacy.     

Structures of three polymorphs of the complex oxide K5Yb(MoO4)4

Polymorphous modifications (γ-, β- and α-) of the double potassium ytterbium molybdenum oxide K₅Yb(MoO₄)₄ were synthesized by the solid-state method and their structures were studied by X-ray powder diffraction, electron diffraction and high-resolution electron microscopy. DSC analysis shows that the γ→β↔α phase transitions are not accompanied with a significant reconstruction of the palmierite-type structure. All modifications of K₅Yb(MoO₄)₄ are related to the mineral palmierite—K₂Pb(SO₄)₂. The palmierite-type structure is made up of isolated AO₄ tetrahedra, which connect the MO_n polyhedra into a 3-D framework via common vertices. Cations occupy two crystallographic positions M1 and M2. The γ-phase crystallizes in a monoclinic system (space group C2/c) with unit-cell parameters: a=14.8236(1) Å, b=12.1293(1) Å, c=10.5151(1) Å, β=114.559(1)°, Z=4. The α-phase has space group with unit-cell parameters: a=6.0372(1) Å, c=20.4045(2) Å. The structures of the γ- and α-modification were refined by the Rietveld method (R_wp=6.25%, R_I=2.16% and R_wp=9.09%, R_I=5.80% for γ- and α-, respectively). In K₅Yb(MoO₄)₄ ytterbium cations occupy M1 while K⁺ cations occupy M2 and M1 positions of the palmierite-type structure. In the high-temperature (α-) modification the Yb³⁺ and K⁺ occupy the M1 site in a statistical manner (M1=0.5Yb³⁺+0.5K⁺) while in the low-temperature (γ-) modification these cations occupy this site in an ordered way. The intermediate β-phase shows an incommensurate modulated structure.     

Electrospray ionization mass spectrometric study of encapsulation of amino acids by cyclodextrins

Electrospray ionization (ESI) mass spectrometry has been used to study inclusion (host-guest) complexes of cyclodextrins (CDs) with amino acids. Host-guest complexes formed in solution are stable for characterization by ESI mass spectrometry: The relative abundances and the stoichiometry of the complexes formed in solution can, thus, be determined in the gas phase. The studies verified that β- and γ-cyclodextrin better accommodate protonated amino acids than α-cyclodextrin, and that chemically modified cyclodextrins such as heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) may show profound improvement in complexation. The preferential formation of DM-β-CD-aromatic amino acid over DM-β-CD-aliphatic amino acid complexes is confirmed by the experiments, and the relative gas-phase stabilities determined by repeller-collimator collision-induced dissociation show an identical trend to the complexation in solution. Although molecular mechanics studies also may predict the encapsulation preference of protonated amino acids by cyclodextrins, only small differences in the total complexation energies are obtained because of the inability of the calculations to consider hydrophobic interactions. An experimental approach based on ESI mass spectrometry is, therefore, more reliable in predicting host-guest interactions that involve cyclodextrins and amino acids than the theoretical calculations that employ molecular mechanics models.     

Macromolecular Recognition: Interaction of Cyclodextrins with an Alternating Copolymer of Sodium Maleate and Dodecyl Vinyl Ether

Interaction of cyclodextrins (CDs) with an alternating copolymer of sodium maleate and dodecyl vinyl ether (pC₁₂MA), which forms micelle‐like aggregates in aqueous media, is investigated by several NMR techniques to explore the competition of the complexation of CDs with the dodecyl (C₁₂) groups and the self‐association of the C₁₂ groups. ¹H NMR and two‐dimensional nuclear Overhauser effect spectroscopy data demonstrate that α‐CD interacts significantly with the C₁₂ groups in pC₁₂MA but β‐ or γ‐CD does not, which indicates that the competition with self‐association of the C₁₂ groups enhances the selectivity towards α‐CD. Furthermore, the binding isotherm prepared using ¹H NMR data exhibits a sigmoidal curve, which is indicative of cooperative complexation of α‐CD with pC₁₂MA.

     

Preparation of 616X,6Y-Tris-O-(tert-butyldimethyl-silyl)-β-cyclodextrins,and Isolation and Regiochemical Determination of Five Positional Isomers

Abstract

Five positional isomers of 6¹,6^X,6^Y-tris-O-(tert-butyldimethylsilyl)-cyclomaltoheptaose (β-cyclodextrin, βCD) were prepared by reaction of β CD with tert-butyldimethylsilyl chloride in pyridine, and were isolated by HPLC and characterized by ¹³C NMR spectroscopy. The regiochemical determination of those positional isomers was carried out by the extended Körner's method, that is, by comparison with compounds obtained by additional monosilylation of 6¹, 6^X-bis-O-(tert-butyldimethylsilyl)-βCDs, and by conversion to the known compounds, 6¹,6^X,6^Y-tri-O-(toluene-sulfonyl)-βCDs.     

Study on Inclusion Complexes of Cyclodextrin with Sodium Dodecyl Polyoxyethylenated Sulfonate Using Microcalorimetry and 1H NMR

The association of α‐, β‐ and γ‐cyclodextrin (α‐CD, β‐CD and γ‐CD) with sodium dodecyl polyoxyethylenated sulfonate (C₁₂E_nS n=1, 3) was studied by means of isothermal titration calorimetry and ¹H NMR measurements in aqueous solution at T=298.15 K. The results indicate that the binding processes of β‐CD with the surfactants are characterized by both enthalpy favorable and entropy favorable, while those of α‐CD or γ‐CD with the surfactants are mainly entropy driven. The stoichiometry of β‐CD binding with the surfactants is different with different numbers of oxyethyl groups in surfactant molecules, while that of α‐CD or γ‐CD binding with the surfactants makes no difference. The ¹H NMR spectra reveal that chemical shift data of all protons in α‐CD, β‐CD and γ‐CD molecules move to high field in the presence of C₁₂E_nS, which can be regarded as a microscopic evidence of the occurrence of inclusion interaction.     

Cyclodextrin as a Macrocyclic Monomer: Cationic Ring‐Opening Polymerization of O‐Permethylcyclodextrins

It has been disclosed for the first time that a cyclodextrin (CD) derivative is able to act as a macrocyclic monomer for ring‐opening polymerization to produce linear polyglucan. O‐Permethylated α‐, β‐, and γ‐CDs were found to be polymerizable with the aid of a cationic initiator, e.g., Et₃O⁺PF₆^– in dichloromethane. Interestingly, the more strained monomer (α‐ > β‐ > γ‐CD) was less reactive, which is ascribable to the characteristic shape of the CD molecule.     

Divalent transition metal phosphonates with new structure containing hydrogen-bonded layers of phosphonate anions

A series of divalent transition metal phosphonates containing hydrogen-bonded layers of phosphonate anions, namely [M(phen)₃]·C₆H₅PO₃·11H₂O [M=Co(1), Ni(2), Cu(3)] and [Cd(phen)₃]·C₆H₅PO₃H·Cl·7H₂O (4) have been synthesized, structurally characterized by single-crystal X-ray diffraction method. These compounds all crystallize in the triclinic system, space group P-1. The lattice parameters are a=12.1646(5), b=12.4155(6), c=15.4117(10) Å, α=78.216(2), β=79.735(3), γ=77.8380(3)°, V=2205.1(2) Å³, Z=2 for 1; a=12.097(2), b=12.606(3), c=15.742(3) Å, α=76.66(3), β=80.04(3), γ=77.75(3)°, V=2263.4(8) Å³, Z=2 for 2; a=12.058(2), b=12.518(3), c=15.781(3) Å, α=77.77(3), β=80.02(3), γ=77.91(3)°, V=2255.5(8) Å³, Z=2 for 3 and a=12.47680(10), b=12.6693(2), c=16.1504(3) Å, α=82.600(1), β=71.122(1), γ=77.355(1)°, V=2352.37(6) Å³, Z=2 for 4. All structures are refined by full-matrix least-squares methods [for 1, R1=0.0602 using 6458 independent reflections with I>2σ(I); for 2, R1=0.0632 using 4657 independent reflections with I>2σ(I); for 3, R1=0.0634 using 6221 independent reflections with I>2σ(I); for 4, R1=0.0400 using 7930 independent reflections with I>2σ(I)]. In the crystal structures, the phenylphosphonate anions and water molecules are hydrogen-bonded to form layers, and there exist the cationic species [M(phen)₃]²⁺ between the adjacent layers of anions and water. Luminescence, thermal analysis as well as IR spectroscopic studies are also presented.     

An efficient synthetic method for Z-fluoroalkene dipeptide isosteres: Application to the synthesis of the dipeptide isostere of Sta-Ala

Reaction of γ,γ-difluoro-α,β-enoates having a δ-hydroxyl group with trialkylaluminum (R₃Al) was found to be promoted by CuI·2LiCl and to proceed in SN2′ manner giving rise to the α-alkylated (Z)-γ-fluoro-β,γ-enoates, while reductive defluorination of γ,γ-difluoro-α,β-enoates with Me₂CuLi followed by reaction with alkyl halides provided the corresponding (Z)-α-alkylated products in high yields. The latter reaction was applied to the preparation of the dipeptide (Z)-fluoroalkene isostere of Sta-Ala, which is the central dipeptide unit in Pepstatin, a natural inhibitor of aspartate proteases.