Complexation of the Non-steroidal Anti-inflammatory Drug Loxoprofen with Modified and Unmodified β-Cyclodextrins

The inclusion complex of the anti-inflammatory drug, loxoprofen, with -cyclodextrin-(CD), sulfated -CD, and glycerol ether -CD was studied by UV-VIS absorption and ¹H-NMR spectroscopy in solution. The inclusion complex of loxoprofen with -CDs was prepared by freeze-drying, and then characterized in the solid state by thermal analysis, X-ray diffraction, FT-IR and FT-Raman spectroscopy, and scanning electron microscopy (SEM). Furthermore, a physical mixture of loxoprofen/-CD (1/1, mol-%) in the solid state was also characterized. The solubility of the loxoprofen increased on addition of -CDs. The solubility enhancement of the loxoprofen with -CDs is in the following order: glycerol ether -CD > sulfated -CD > -CD.     

Inclusion of Ring A of Cholesterol Inside the β-Cyclodextrin Cavity: Evidence from Oxidation Reactions and Structural Studies

The disposition of cholesterol inside the -cyclodextrin cavity(-CD) was deduced from oxidation of cholesterol secondary alcoholgroups by Ca(OCl)₂ and H₂O₂ in thepyridine–acetic acid system. The amount of cholest-4-ene-3-one formedwas found to be proportional to the concentration of -cyclodextrin,resulting in 56.1% of ketone. The oxidation rate was enhanced by-cyclodextrin and its methyl, polymer and 1 : 1copper(II)–-cyclodextrin derivatives. Detailed investigationsinvolving UV-visible, ¹³C- and ¹H-NMR(T₁, 1D NOE and ROESY) spectroscopic studies were carried out.A binding constant value of 15,385 ± 1500 M^-2 wasobtained for the 2 : 1heptakis-2,6-di-O-methyl--cyclodextrin(DM-CD) : cholesterolcomplex in chloroform from UV studies. Proton and solid state¹³C-CP MAS spectra of the -CD–cholesterol mixtureshowed large magnitude shifts for the protons from the wider end of the-CD cavity as well as those of ring A and ring B of cholesterol. Both1D NOE and ROESY measurements indicated the proximity between ring A andring B protons of cholesterol and the wider end protons of -CD andDM-CD. Besides, analysis of _c,_i and tau;_m from T₁measurements showed not only a lowering of rotational motions but a value of 0.016–0.048 for some of the cholesterol protons, typical of aweak complex. Based on these studies, a probable structure for the 2 : 1complex involving two molecules of -CD/DM-CD was proposed withportions of ring A and ring B being present inside the wider end of the-CD/DM-CD cavity and ring D and the side chain attached atposition 17, projecting into the wider end of the secondCD/DM-CD molecule.     

Improvement of Solubility and Dissolution of 19-Norprogesterone via Inclusion Complexation

In an effort to modify the solubility and dissolution rate of the contraceptive steroid, 19-norprogesterone in order to improve its bioavailability, the cyclodextrin complexation approach was chosen. In solution, the complex formation with -cyclodextrin (-CD), hydroxyethyl -cyclodextrin (HE--CD) and hydroxypropyl -cyclodextrin (HP--CD) was confirmed by using solubility, UV, IR and ¹H-NMR spectrophotometric techniques. The phase solubility diagrams were categorized as A_L-type. The complexing affinity of the CDs investigated were ranked as follows: -CD > HP--CD > HE--CD. The complexation thermodynamic parameters were obtained from the temperature dependence of the dissociation constants. In the solid state, differential scanning calorimetery (DSC) and optical microscopy methods were utilized to characterize the complexes. Dissolution studies showed that such molecularly encapsulated forms offered a marked improvement in the dissolution rate compared to the parent drug.     

Bis-β-diketones as lonophores for Mg2+ in solvent polymeric membranes

Lipophilic bis--diketones have been prepared by covalently linking two-diketone subunits. Potentiometric studies on liquid membrane electrode cell assemblies showed no improvement of the ion selectivities induced by the bridged systems in comparison to unbridged-diketones. The dissociation constants of the enol functions in the bis--diketones indicate that under the conditions of the EMF measurement probably only one-diketone unit is deprotonated in the liquid membrane phase. The complexation of these-diketones with Mg²⁺ and Ca²⁺ was studied by¹³C NMR-monitored titrations in a homogeneous organic phase.On leave from the Chemistry Department, University of Warsaw, Warsaw, Poland     

Triterpene glycosides of the holothurian Eupentacta pseudoquinquisemita

The holothurianEupentacta pseudoquinquisemita Deichmann collected in Kraternaya Bay, Ushishir Islands has yielded two triterpene pentaosides — the previously known cucumarioside C₂, and cucumarioside H, which is a new glycoside. With the aid of¹³C NMR spectroscopy and solvolytic desulfation its structure has been determined as 6-acetoxy-3-([3-O-methyl--D-xylopyranosyl-(1 3)--D-glucopyranosyl-(1 4)] [-D-xylopyranosyl-(1 4)] [-D-xylopyranosyl-(1 2)]--D-quinovopy-ranosyl-(1 2)-(4-O-sulfato--D-xylopyranosyloxy)holosta-7,22,24(trans)-triene. Cucumarioside H was also identified inEupentacta (=Cucumaria)fraudatrix from Posyet Bay, Sea of Japan.Pacific Ocean Institute of Bioorganic Chemistry, Far Eastern Branch, USSR Academy of Sciences, Vladivostok. Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 221–225, March–April, 1988.     

Nitrosation of mefenorex in the presence of cyclodextrins

- and -Cyclodextrin (CD) and heptakis-2,6-di-O-methyl--cyclodextrin (DIMEB) form soluble inclusion compounds with mefenorex (MEF); with -CD a partial inclusion occurs. No solid inclusion compound could be obtained with the four CDs. -, -CD and DIMEB, but not -CD, enhance the nitrosation rate of MEF if the nitrosation assay procedure (NAP test) is applied. During this reaction with - and -CD, solid inclusion compounds of the CDs and nitrosomefenorex (NMEF) precipitate.Part of the Ph.D. thesis of V. Wedelich, Freie Universität Berlin, 1985.     

Crystal and molecular structure of β-piperidinopropioamidoxime monochloroacetate and hydrochlorides of its O-benzoylation products

The structures of -piperidinopropioamidoxime monochloroacetate and O-benzoyl- and O-para-toluyl--piperidinopropioamidoxime hydrochlorides have been determined. The geometry of these compounds is analyzed. The N-O bond is in the syn-planar position in -piperidinopropioamidoxime monochloroacetate, but adopts an anti-orientation relative to the C(2)-C(3) bond of the propioamidoxime fragment in the other two compounds. In -piperidinopropioamidoxime monochloroacetate crystals, the cation-anion pairs are joined by intermolecular hydrogen bonds into chains; the latter are linked by van der Waals contacts. The crystals of the O-benzoyl- and O-para-toluyl--piperidinopropioamidoxime hydrochlorides are characterized by the same system of hydrogen bonds; the cations and anions are linked by hydrogen bonds into layers, and the latter make van der Waals contacts in the structure.Original Russian Text Copyright © 2004 by K. M. Beketov, J. T. Welch, P. Toskano, L. A. Kayukova, A. L. Akhelova, and K. D. PralievTranslated from Zhurnal Strukturnoi Khimii, Vol. 45, No. 3, pp. 535–543, May–June 2004.     

Complexation of 6-Deoxy-6-(aminoethyl)amino-β-cyclodextrin with Sodium Cholate and Sodium Deoxycholate

In order to study its guest binding and the inclusion phenomena, 6-deoxy-6-(aminoethyl)amino--cyclodextrin (CDN) was synthesised and its binding properties examined. The complexation phenomena of sodium cholate (NaC) and sodium deoxycholate (NaDC) with CDN has been monitored by the NMR method using ¹³C chemical shift data. The method of continuous variation Job's method has been used to determine the stoichiometry of these supramolecular complexes. The Job's plot confirms the 1 : 1 supramolecular complex for NaC: CDN and the 1 : 2 supramolecular complex for NaDC: CDN. The interaction of NaC and NaDC with CDN has been obtained through two-dimensional Rotational Nuclear Overhauser Effect Spectroscopy (ROESY) NMR. Equilibrium constants were also obtained from ¹³C chemical shift data (C-1, C-3 & C-4) at different pH values (7, 9, & 11).     

Synthesis and Heterocyclization of β-Aroyl-α-diphenylphosphorylpropionic Acids

It has been established that diphenylphosphine oxide reacts smoothly with -aroylacrylic acids with the formation of -aroyl--diphenylphosphorylpropionic acids, which were cyclized under the action of hydroxylamine, hydrazine hydrate, and phenylhydrazine hydrochloride into phospho derivatives of dihydrooxazinone and tetrahydropyridazinone respectively. It was shown that imidazole may serve as nucleophilic protection for the synthesis of dihydropyridazinone derivatives from -aroylacrylic acids.     

Substituierte 3-Amino-thiophene und 3-Amino-selenophene aus β-Chlor-α-cyan-zimtsäurenitril

Summary -Chloro--cyano-cinnamonitrile (1) reacts in one step with -oxo-thioles3 or successively with sodium sulphide and -chlorocarbonyl compounds4 to form the 5-substituted 4-amino-2-phenyl-thiophene-3-carbonitriles5. Analogously, the successive reactions of -chloro cinnamonitrile1 with sodium selenide — produced in situ from selene and sodium boronhydride — and -chlorocarbonyl compounds4 yields the 5-substituted 4-amino-2-phenyl-selenophene-3-carbonitriles6.

     

Sodium Dithionite Reduction of 2S,5R-(-)-menthone and R-(+)-pulegone in the Presence of β-Cyclodextrin and Hydroxypropyl-β-cyclodextrin

Menthone on reduction with sodium dithionite,showed a good amount of mentholformation in the water/DMF system, withincreasing -cyclodextrin (-CD)concentration from 47.0% for 0.1 equivalent of-CD to 93.5% for 1 equivalentof -CD. Increasing hydroxypropyl--cyclodextrin(HP-CD) gave higher menthol/neomenthol (M/N) ratiosfrom 2.8 to 3.5. In the case of pulegone,increasing -CD showed an increase in the formationof menthols in thewater/DMF system from 13.3% for 0.1 equivalent of-CD to 78.1% for 1equivalent of -CD with greater proportions ofneomenthol and neoisomenthol.However, HP-CD which showed only marginalenhancement in the formationof menthol from menthone (32.1–41%), exhibiteda greater proportion of mentholformation in the case of pulegone (55.1%).However, the phase-transfer capabilityof HP-CD was not found to be significant.     

The role of intra- and intermolecular hydrogen bonds in the formation of β-cyclodextrin head-to-head and head-to-tail dimers. The results of ab initio and semiempirical quantum-chemical calculations

The conformation of a free -cyclodextrin molecule optimized by the MNDO/PM3 quantum-chemical calculations has C₇ symmetry. The right orientation of the interglucose hydrogen bonds in -cyclodextrin, in which the 2-OH groups act as the proton donors and the O atoms of the nearby 3"-OH groups function as the proton acceptors, is advantageous for thermodynamic reasons. The ring of seven H bonds thus formed stabilizes the symmetrical form of -cyclodextrin. The -cyclodextrin head-to-head dimer has D ₇ symmetry and consists of molecules whose 2-OH groups partcipate as proton donors in the formation of fourteen complementary intermolecular hydrogen bonds. The energy of H bonds in the -cyclodextrin monomer and dimer was estimated to be 1.0--1.4 kcal mol^–1. Of the two possible -cyclodextrin dimers, the head-to-tail dimer is more thermodynamically stable. The thermodynamic preference of the right orientation of the inter-glucose H bonds in -cyclodextrin was confirmed by the MP2/6-31G(d,p)//6-31G(d,p) ab initio calculations for maltose (-glucodioside). The maltose molecule with inter-glucose H bonds of the type 2-OHO(3")-H is more stable than the structure with the H-(2)OH-O(3") orientation of H bonds with a difference of 2.7 kcal mol^–1. According to the MNDO/PM3 method, the maltose structure with the right H bond orientation is more stable by 3.1 kcal mol^–1.     

Effect of 2-Hydroxypropyl-β-cyclodextrin on Release Rate of Metoprolol from Ternary Metoprolol/2-hydroxypropyl-β-cyclodextrin/Ethylcellulose Tablets

The effect of 2-hydroxypropyl--cyclodextrin (HP--CyD) on the release of a water-soluble ₁-selective adrenoreceptor antagonist, metoprolol (Met), from ternary Met/HP--CyD/ethylcellulose (EC) tablets was investigated. The release rate of Met from the ternary tablets was dependent on amounts of HP--CyD in the tablets, i.e., the rate decreased when small amounts of HP--CyD were added, while large amounts of HP--CyD accelerated the rate. The slowest rate was observed for the tablet consisted of a 30/10/60 weight ratio of Met/HP--CyD/EC. The analyses of the release rates by the Korsmeyer equation and their temperature dependence suggested that Met is released from the EC matrix containing HP--CyD according to the diffusion-controlled mechanism. The water penetration studies and the micro- and macroscopic observations suggested that the retarding effect of HP--CyD is attributable to a viscous gel formation in small pores on the surface of the tablets, where HP--CyD gels may work as a barrier for the water penetration into the tablets and the release of the drug from the tablets. The in-vitro release property of the ternary tablets was reflected in the in-vivo absorption profile in dogs. The results indicated that a combination of HP--CyD and EC is useful for the release control of water-soluble drugs such as Met.     

Structural Studies on Host + Guest Recognition Sensory Systems

Rhodamine B-ethylenediamine--cyclodextrins (RhB--CDen) and rhodamine B--cyclodextrins (RhB--CD) can form inclusive complexes with many guest molecules, a reaction which can be used as a nucleic acid probe. In this paper, the most stable conformations of RhB--CDen and RhB--CD have been determined by fluorescence experiments and analyzed by molecular modeling simulation. The interaction between RhB--CDen and two guest molecules, 1-borneol and cyclohexanol, has also been investigated. The results showed that RhB--CDen has a stronger interaction with 1-borneol than with cyclohexanol. Borneol could push the three aromatic-rings of rhodamine B out of the CD cavity, while the cyclohexanol could not. The interactive sites of host and guest are also presented.     

Recent progress in tartaric acid‐modified Raney nickel system for enantio‐differentiating hydrogenation

Tartaric acidmodified Raney nickel (TAMRNi) is an enantiodifferentiating catalyst for hydrogenation of ketones. The stereochemical models explaining the enantiodifferentiation of ketoester and 2alkanone were unified as an extended stereochemical model by the experimental supports. Based on this new model, a working hypothesis to improve the enantiomeric excess (ee) of the ketoester/TAMRNi system was developed, and the ee was improved to 96%. By further fine tuning of this system, almost perfect enantiodifferentiation resulting in over 98% ee was achieved.     

Electrostatic and structural similarity of classical and non-classical lactam compounds

Various electrostatic and structural parameters for a series of classical and non-classical -lactams were determined and compared in order to ascertain whether some specific -lactams possess antibacterial or -lactamase inhibitory properties. The electrostatic parameters obtained, based on the Distributed Multipole Analysis (DMA) of high-quality wavefunctions for the studied structures, suggest that some non-classical -lactams effectively inhibit the action of -lactamases. As shown in this work, such electrostatic parameters provide much more reliable information about the antibacterial and inhibitory properties of -lactams than do structural parameters.     

Complex formation between polyethylene oxide-containing nonionic surfactants and α- and β-cyclodextrins

The inclusion complexes based on polyethylene oxide (PEO)-containing nonionic surfactants and ()-cyclodextrins (CD) were synthesized. Their composition and crystal structure were studied. The inclusion complexes of the surfactants with -CD form a crystal structure similar to that of the -CD—PEO complex. The inclusion complexes of the nonionic surfactants with -CD form a structure similar to that of the -CD—PEO complex. The structural models of the crystalline complexes were proposed. The micelle-forming abilities of the surfactants in dilute solutions in the presence of CD were studied. The CD binding to a surfactant molecule in aqueous solutions begins from the PEO fragment. Possible reasons for the formation of inclusion complexes between noncomplementary surfactant and -CD molecules were discussed. The thermal stability was studied, and the possibility of thermal dissociation of the pseudo-complementary -CD—surfactant complexes was shown.     

Molecular Interactions and Inclusion Phenomena in Substituted β-Cyclodextrins. Simple Inclusion Probes: H2O, C, CH4, C6H6, NH4 +, HCOO−

Using a simple molecular mechanics approach interaction energy profiles of simple probes (C, CH₄, C₆H₆, H₂O, NH₄ ⁺, and HCOO^-) passing through the center of the -CD ring cavity along the main molecular symmetry axis were first evaluated. Molecular Electrostatic Potential (MEP) values along the same path were also evaluated. The effect of the flexibility of the host -CD molecule together with solute-solvent (H₂O) interactions have been represented by averaging structures of MD calculations for -CD alone and -CD surrounded by 133 H₂O molecules. The effect of various substitutions of -CD has also been evaluated. Small symmetric hydrophobic probes (such as C, CH₄, C₆H₆) are predicted to form stable inclusion complexes with non-substituted and substituted -CDs, the probe position typically being near the cavity center. The stability of the inclusion complexes will increase with increasing size and aliphatic character of the probe. Small polar and charged probes (such as H₂O, NH₄ ⁺, HCOO^-) are predicted to prefer the interaction with the solvent (water) in the bulk phase rather than the formation of inclusion complexes with non-substituted and substituted -CDs. Guest–host interactions in the stable inclusion complexes with hydrophobic probes are almost entirely dominated by dispersion interactions. The MEP reaches magnitudes close to zero in the center of the non-substituted -CD ring cavity and in most of the studied substituted -CDs and shows maximum positive or negative values outside of the cavity, near the ring faces. Substitution of -CD by neutral substituents leads to enhanced binding of hydrophobic probes and significant changes in the MEP profile along the -CD symmetry axis.     

NMR Spectral Assignment of Per-substituted Key-Intermediates of β-Cyclodextrin and Implications in the Structures of the Derivatives

The compounds, 6-per-O-(t-butyldimethylsilyl)--cyclodextrin(1), 2,3-per-O-benzyl-6-per-O-(t-butyldimethylsilyl)--cyclodextrin(2), 2,3-per-O-benzyl--cyclodextrin (3),2,3,6-per-O-benzyl--cyclodextrin (4),2,3,6-per-O-benzoyl--cyclodextrin (5), are used as keyintermediates in the synthesis of selectively substituted -CD derivatives. Simple and assignable ¹H and ¹³C NMR spectra (chemical shifts and coupling constants) were obtained for compounds1–4 indicating C₇ symmetry, ⁴C₁ glucose conformation and major arrangement of H6, H6' atoms at the primary side. The derivative 5, however, gave very broad peaksat room temperature. The peaks could partially be assigned at 270 K, but the broadening was still present at 220 K. This implies that there exist several conformers of similar energyand C₁ symmetry that continuously interchange, since there is not a single type of stabilizing interaction thatpredominates. We attributed this phenomenon to the presence of the carbonyl group, which probablydisfavors - stacking and induces random arrangements of the aromatic rings.     

Triterpene Glycosides from Plants of the Astragalus Genus. Structure of Cyclounifolioside A from Astragalus unifoliolatus

The known compound oleanolic acid (1) and a new cycloartane glycoside cyclounifolioside A (2), which has the structure 6,16-di-O-acetyl-24R-cycloartan-6,16,24,25-pentaol 3-O--D-glucopyranoside, were isolated from Astragalus unifoliolatus Bunge. The structures of the isolated compounds were established using chemical transformations and two-dimensional spectra (TOCSY, ROESY, HMBC, HSQC, COSY).