Synthesis of β-cyclodextrin dimers as carrier systems for photodynamic therapy of cancer

The aim of our investigation was the development of carrier systems for an application of inert drugs in polyphasic photodynamic tumor therapy. As carrier systems, -cyclodextrin dimers linked at their primary and secondary faces by spacers of varying lengths were synthesized. Cyclodextrins are known to form stable inclusion complexes with porphyrinoïd photosensitizers. The influence of spacer length on the -cyclodextrin dimer inclusion complexes with porphyrinoïd photosensitizers was studied.     

Spectrometric and 2D NMR Studies on the Complexation of Chlorophenols with Cyclodextrins

The formation and structure of inclusion complexes of - and-cyclodextrins with 2-chlorophenol (2CP), 3-chlorophenol (3CP),4-chlorophenol (4CP), 2,4-dichlorophenol (24DCP), 2,6-dichlorophenol(26DCP) and 3,4-dichlorophenol (34DCP) have been studied by UV-VIS and¹H NMR spectroscopy. Both cyclodextrins were found to form 1:1inclusion complexes. Bindingconstants estimated from titration studies revealed that the stability of the complexes was highly dependent on the structure and polarity of the chlorophenol and on the cyclodextrin used. In general, weaker binding constants were observed for a given chlorophenol with -cyclodextrin than with-cyclodextrin. The weakest binding constants (K_{b < 200} M^-1) were obtained for the ortho-substituted chlorophenols (2CP and 26DCP) and the largest binding constants were obtained between para-chlorophenols (4CP, 24DCP and 34DCP) and-cyclodextrin. 2D-TROESY studies of chlorophenol-cyclodextrincomplexes in D₂O provided insight into the structure of the complexes.     

1H NMR study on the inclusion of bicyclo[3.3.1]nonanes in cyclodextrins

- and -cyclodextrins were found to form 1:1 inclusion complexes with 2,6- and 2,9-substituted bicyclo[3.3.1]nonanes. The binding constants and the structure of the complexes were estimated from titration studies and 2D ROESY experiments.     

Interaction of urea and urea derivatives with cyclohexamylose in aqueous solutions at 25°C

The interaction in water of urea, monomethylurea, monoethylurea, monopropylurea, and monobutylurea with -cyclodextrin(hexacycloamylose) was studied calorimetrically at 25°C. The results show that the last three substances form inclusion complexes with -cyclodextrin. The enthalpy and the association constants relative to the inclusion process were determined. The association constant values are low, indicating weak complexing that increases with increasing length of the alkyl chain. Urea and monomethylurea, on the other hand, do not form inclusion complexes. For these systems the calorimetric data were treated in terms of excess enthalpies, and the McMillan-Mayer approach was used to get an insight into the weak, non-bonding molecular interactions occurring in these solutions.Presented at the sixth Italian meeting on Calorimetry and Thermal Analysis (AICAT) held in Naples, December 4–7, 1984.     

A study of salt effects on the complexation between β-cyclodextrins and bile salts based on the Hofmeister series

The Hofmeister series is the ranking of ions according to their ability to strengthen (kosmotropic ions) or weaken (chaotropic ions) hydrophobic interactions. Such ions are therefore expected to affect the strength of cyclodextrin (CD) inclusion complexes and may thereby affect the release of CD bound drug molecules. The influence of Hofmeister ions on the binding constants of complexes between CDs (β-CD and hydroxypropylated β-CD) and bile salts (glycocholate and glycochenodeoxycholate) were examined by isothermal titration calorimetry. The chaotropic anions tended to weaken these inclusion complexes. Conversely, kosmotropic ions increased the binding strength and this effect scaled with the buried hydrophobic surface area. Both effects are relatively weak at physiological ion concentrations and may be neglected for most pharmaceutical purposes.     

1H NMR spectroscopic study of the interaction between cyclodextrins and bicyclo[3.3.1]nonanes

The formation and structure of inclusion complexes of 2,6- and 2,9-substituted bicyclo[3.3.1]nonanes with- and-cyclodextrin (CD) has been investigated by high-resolution¹H NMR spectroscopy.- and-CD were found to form 1:1 inclusion complexes and the binding constants were estimated from titration studies. 2D ROESY experiments provided insight into the structure of the complexes.Presented in part at the 8th International Cyclodextrin Symposium, Budapest, March 30–April 2, 1996.     

Study of the Inclusion Complexes of β-Cyclodextrin with the Sodium Salt of Trisulfonated Triphenylphosphine

The formation of inclusion complexesbetween the sodium salt of trisulfonatedtriphenylphosphine and -cyclodextrin has beeninvestigated at two temperatures by high field nuclearmagnetic resonance, electrospray mass and UV-visspectroscopies. At 268 K, titration experiments andJob's method suggest that the major species insolution is a 1 : 1 inclusion complex. The moleculargeometry of this inclusion complex was studied usingthe ROESY NMR technique complemented by molecularmodelling. All these methods converged towards thestructure attained by inserting one aromatic ring intothe hydrophobic cavity of the host from the side ofthe secondary hydroxyls. At 298 K, a higher proportionof 2 : 1 and 3 : 1 complexes induces strong alterations ofthe NMR signals, preventing an easy and reliabledetermination of association constants. Nevertheless,an apparent association constant can be determinedfrom UV-vis data by assuming a 1 : 1 equilibrium. Thegeometry of the 2 : 1 and 3 : 1 complexes is also brieflydiscussed from ROESY NMR experiments.     

Potentiometric studies on mixed-ligand complexes of cobalt(II) and nickel(II) with amino acids as primary ligands and imidazole as secondary ligand

Summary The formation constants of mixed-ligand complexes of cobalt(II) and nickel(II) with glycine, DL--alanine and DL-valine as primary ligands and imidazole as secondary ligand have been determined potentiometrically under physiological-like conditions (T=37°C and I=0.15 M KNO₃). The proton association constants of the free ligands and the stability constants for binary systems involving the amino acids and imidazole were also determined under identical conditions, and the experimental pH-titration data were analysed using the computer SUPERQUAD program. The relative stability of the ternary complex as compared to that of the corresponding binary complexes has been quantitatively expressed in terms of log K and log X values.     

Ternary β-Cyclodextrin Complexes as Models of Allosteric Effects

Two guests reacting with cyclodextrins (CDs) may form ternary complexes, in addition to the common competition of 1:1 complexes. One of the guests can really be included into the cavity of the CD, while the second guest molecule is either inserted close to the first one or attached to the outer surface of the supramolecule by H-bonding. There is a further possibility when the included guest bears a substituent outside the cavity and the second guest can interact with it. The properties of the ternary species formed are highly influenced by the solely (or primarily) included guest. The changes are attributed to the altered properties of the hydrophilic domain of the CD. The phenomena can be proved by NMR data obtained for some binary systems of -CD inclusion complexes and acetic acid and by the stability constants of the ternary complexes formed. Allosteric effects as well as coenzyme/apoenzyme/substrate interactions could be well modelled by these types of CD complexes.     

Synthesis and inclusion properties study of some mono 6-amino ??-cyclodextrin dimers bridged by N,N-succinyldiamide linkers

Methylated and partially methylated cyclodextrin homo- and heterodimers linked by diamidosuccinic bridges were synthesised and their inclusion properties were evaluated using NMR and isothermic microcalorimetric measurements ITC. The selective binding of ligands, such as bisadamantyl derivatives, to the cavities of unprotected cyclodextrin dimers showed the equimolar formation of bidendate inclusion complexes (2:2, two ligand guest to two cavities host).     

Electrochemical studies of cationic drug inclusion complexes with α- andβ-cyclodextrins

Drug membrane selective electrodes have been constructed for the cationic drug propranolol hydrochloride, diphenhydramine hydrochloride, diphenylpyraline hydrochloride and also chlorcyclizine hydrochloride. The characteristics of these drug selective electrodes have been evaluated and the electrodes used to measure equilibrium constants of the inclusion compounds involving the drugs with both - and-cyclodextrins. The enthalpies and entropies associated with the formation of the inclusion complexes have also been estimated from the temperature dependence of the equilibrium constants.     

Spectral Studies on the Cyclodextrin Inclusion Complexes of Toluidine Blue O and Meldola's Blue in Aqueous Solution

The absorption and emission spectral properties of toluidine blue O (TBO) and Meldola's blue (MDB) in the presence of cyclodextrins (CDs) were studied. Formation of 1 : 1 and 1 : 2 (CD-Dye) inclusion complexes were observed with -CD and -CD, respectively. An increase in the emission intensity was noticed in the presence of -CD due to the formation of 1 : 1 (CD-Dye) inclusion complexes. However, a decrease in the emission intensity was observed in the presence of -CD due to the formation of 1 : 2 (CD-Dye) inclusion complexes. Dimerization of dye molecules in the presence of -CD lead to a decrease in the emission intensity. The formation constants for the 1 : 1 and 1 : 2 (CD-Dye) inclusion complexes were calculated.     

Complexation and (templated) synthesis of rhenium complexes with cyclodextrins and cyclodextrin dimers in water

Several small, lipophilic rhenium complexes form inclusion complexes with native beta-cyclodextrin (beta-CD) and beta-CD dimers. Association constants larger than 10(9)M(-1) were obtained using dimers. The use of beta-CD also enabled the synthesis of these rhenium complexes in water, in excellent yields, through complexation of the otherwise insoluble corresponding ligands. The influence of the reaction time and temperature on the configuration of the reaction products has been investigated in depth for one of these complexes. Using a beta-CD dimer, it proved possible to specifically template the formation of one configuration. The strength of the complexes of the rhenium complexes in cyclodextrin dimers may allow radiolabeling of biomolecules.     

Molecular Mechanics Study of the Complexes of β-Cyclodextrin with 4-(dimethylamino)benzonitrile and Benzonitrile

Molecular Mechanics calculations with the Tripos Force Field were employed to study the complexation of 4-(dimethylamino)benzonitrile (DMABN) and/or benzonitrile (BN) with -cyclodextrin (CD). The systems studied have 1 : 1 (DMABN : CD and BN : CD), 2 : 2 (DMABN : CD) and 1 : 1 : 2 (DMABN : BN : CD) stoichiometries. Evidence for the formation of such complexes, binding constants and other thermodynamic parameters were extracted from the analysis of the steady state fluorescence measurements performed in a previous work. The Molecular Mechanics study, based on the energy changes upon guest-host approaching, was performed in vacuo and in the presence of water as a solvent. Results show that the driving forces for 1 : 1 complexation are mainly dominated by non-bonded van der Waals host : guest interactions. However, the driving forces for association between 1 : 1 complexes to give 2 : 2 homo- or 1 : 1 : 2 heterodimers are dominated by non-bonded electrostatic interactions. Head-to-head electrostatic interactions between CDs, which are presumably due to the hydrogen bonding formation between secondary hydroxyl groups of CDs, are responsible for most of the stability of the dimers.     

Preparation and characterization of the inclusion complexes of equol with sulfobutylether-β-cyclodextrin: their antioxidant activity and dissolution evaluation

The formation of inclusion complexes between S-(?)-equol (SEq) and cyclodextrins (CDs) was investigated. The binding constant (K_c) of the SEq/sulfobutylether-β-cyclodextrin (SBE-β-CD) inclusion complex was determined to be 1600 L/mol based on UV data. The phenyl ring of the SEq molecule was found to be inserted from the secondary hydroxyl face of the SBE-β-CD as evidenced from ¹H–¹H rotating frame nuclear Overhauser effect spectroscopy (ROESY) NMR. The thermal properties of the solid SEq/SBE-β-CD inclusion complexes prepared by physical mixing, kneading and freeze-drying methods were studied by differential scanning calorimetry. For the solid complex obtained by the freeze-drying method, the endothermic peak corresponding to the melting point of SEq disappeared. The solid SEq/SBE-β-CD complexes exhibited a high score in antioxidant activity evaluation tests compared to SEq alone. Dissolution test revealed that the solid complex obtained by freeze-drying method had improved dissolution of SEq.     

Determination of Association Constants of Cyclodextrin-Nonionic Surfactant Inclusion Complexes by a Partition Coefficient Method

The partition behavior of isotopic labeled nonionic surfactants between carbon tetrachloride and an aqueous solution containing -cyclodextrin (-CD) was studied with a liquid scintillation counting technique. The association constants of the inclusion complexes were determined at different temperatures. It was found that the nonionic surfactants form 1 : 1 inclusion complexes with -CD. The results demonstrated that the smaller the HLB values of the nonionic surfactants, the greater the association constants with -CD, and that for the same surfactant the association constant is higher at lower temperatures.     

Equilibrium and hydrolysis of α-amino acid esters in mixed-ligand complexes with diethylenetriaminepalladium(II)

Summary The mixed-ligand complexes of palladium(II) containing diethylenetriamine as a primary ligand and -amino acid esters as secondary ligands were studied using potentiometric and conductometric techniques. The equilibrium and/or stability constants of the binary and mixed-ligand complexes formed were determined. The kinetics of base hydrolysis of the above esters in the presence and absence of Pd^II-dien complexes were studied at 30°C. The rate and catalysis constants were determined.     

Inclusion Behavior of α-Cyclodextrin with 2-Methylnaphthalene in Aqueous Solutions

By means of absorption and fluorescence spectroscopy, 2-methylnaphthalene (2MN) was found to be incorporated into the cavity of -cyclodextrin (-CD) to form a 1 : 1 inclusion complex. The 1 : 1 inclusion complex further associated with another -CD molecule, resulting in the formation of a 2 : 1 -CD-2MN inclusion complex. The equilibrium constants for the formation of the 1 : 1 and 2 : 1 inclusion complexes were estimated to be 44.6 and 376 mol-1 dm3, respectively, on the basis of a simulation of the observed 2MN fluorescence intensities. The induced circular dichroism spectra suggested that 2MN, buried within the -CD inclusion complexes, resided in a different orientation relative to the CD symmetry axis, as compared to 2MN within a -CD inclusion complex.     

Circular dichroism spectra of the inclusion complexes of phlorizin in cyclodextrins

Two aromatic rings of a phlorizin molecule form inclusion complexes with -CD and -CD. Induced circular dichroism spectra of these complexes have been measured to estimate the orientation of the two aromatic rings in the hydrophobic space of CDs. Apparent complex formation constants have been also estimated for each complex. It is concluded that phlorizin forms a stronger inclusion complex with -CD than with -CD.     

Stabilization of dyes against hydrolytic decomposition by the formation of inclusion compounds

The decomposition reactions of the dyes phenol blue and murexide were measured spectroscopically in acidic solution at different temperatures. From these reaction rates and their temperature dependence in the absence and presence of various hosts, the stability constants and the reaction enthalpies of the dye complexes with noncyclic dextrins, cyclodextrins and cucurbituril were calculated.-Cyclodextrin enhances the stability of phenol blue in acidic solution. This effect is even more pronounced with cucurbituril. Due to the molecular structure of murexide this dye cannot form inclusion complexes with hosts containing hydrophobic cavities.