An Investigation of Inclusion Complexes of Cyclodextrins with Phenylurea Herbicides by Photochemically-Induced Fluorescence. Analytical Applications

The effect of -cyclodextrin (-CD) and hydroxypropyl--cyclodextrin (HP--CD) upon the photochemically-induced fluorescence (PIF) properties of four phenylurea herbicides, including linuron, diuron, isoproturon and neburon has been studied. Photochemical conversion of these nonfluorescent herbicides into strongly fluorescent photoproducts was shown to occur in -CD and HP--CD aqueous media. The influence of pH, UV irradiation time and photoproduct stability on the fluorescence intensity was also investigated. In addition, the stoichiometry and formation constants of the complexes formed between herbicides and -cyclodextrin (-CD) or 2-hydroxypropyl--cyclodextrin (HP--CD) were determined. The formation constant values, ranging from 184 ± 40 to 1498 ± 245 M^-1, were calculated by applying the iterative nonlinear regression (NLR) approach to the PIF data. Linear calibrations graphs were established in the interval 1–12 g/mL, for diuron, linuron and neburon. The IUPAC limits of detection ranged between 580 and 700 ng/mL, according to the compound. Application to the analysis of phenylurea herbicides in spiked river water was also described.     

The inclusion complex of piromidic acid with dimethyl-β-cyclodextrin in aqueous solution and in the solid state

Inclusion complex formation of piromidic acid (PA) with dimethyl--cyclodextrin (DM--CD) in aqueous solution and in the solid state was confirmed by the solubility method, differential scanning calorimetry (DSC) and proton nuclear magnetic resonance (¹H-NMR) spectroscopy. The apparent stability constant,K _c , of the complex was estimated to be 244 M^–1. The stoichiometry of the complex was given as the ratio 1:2 of PA to DM--CD. The dissolution rate of the PA/DM--CD complex was much greater than that of intact PA.Presented at the Fourth International Symposium on Inclusion Phenomena and the Third International Symposium on Cyclodextrins, Lancaster, U.K., 20–25 July 1986.     

Adrenaline recognition in water

Host molecule 1 displays a high affinity in water towards catecholamines and especially related structures such as beta-blockers with extended aromatic pi-faces (up to 7x10(3) M(-1) for each single complexation step or 5x10(7) M(-2) for both steps). The amphiphilic structural design leads to an extensive self-association of host molecules through their aromatic flanks. Above a cmc (critical micelle concentration) of 3x10(-4) M, host 1 forms micelles that produce a favorable microenvironment for hydrophobic interactions with the included guest molecules. Electrostatic attraction of the ammonium alcohol by the phosphonate anions is thus combined with hydrophobic contributions between the aromatic moieties. Ionic hydrogen bonds with polar OH or NH groups of the guest enforce the non-covalent interactions, and finally lead to increased specificity. Both its affinity and its selectivity towards adrenergic receptor substrates are greatly enhanced if the receptor molecule 1 is transferred from water into a lipid monolayer. Catecholamines and beta-blockers lead to drastically different effects at concentrations approaching the micromolar regime. Especially beta-blockers with minute structural changes can be easily distinguished from each other. In both cases, extensive hydrophobic interactions with a self-associated and/or self-organized microenvironment are largely responsible for the observed high efficiency and specificity.     

A High Sensitivity Fluorescent Chemo-sensory System Based on β-Cyclodextrin Dimer Modified with Dansyl Moieties

-Cyclodextrin dimer linked with ethylenediamine at the upper rim of the cyclodextrin has been synthesized and then modified with two dansyl moieties inthe presence of N,N'-dicyclohexylcarbodiimide. The sensing ability and bindingproperty of the title compound were investigated for steroids and terpenoids. Thefluorescence intensity of this dimer was decreased when a host–guest complex was formed. The value I/I⁰, where I⁰ and I are fluorescence intensitiesin the absence and presence of a guest and I is I⁰- I, was used as a parameter of sensitivity. This host exhibited a much higher sensitivity and selective molecular recognition ability for bile acids such as ursodeoxycholic acid andchenodeoxycholic acid and terpenoids such as (-)-borneol than the dansyl-modifiedcyclodextrins reported previously including -cyclodextrin dimer. The behaviors of the appended moieties of the host during the formation of host–guest complexes were studied using induced circular dichroism (ICD) and fluorescence spectra. The ICD intensityof this dimer was decreased on accommodation of a guest and this spectral pattern of the title dimer was opposite to that of bis dansyl-modified -cyclodextrin monomer. Theguest-induced variations in the fluorescence and ICD intensities suggest that this dimer formed a 1 : 1 host–guest complex and the appended moieties act as a hydrophobic cap.     

Highly conformationally constrained halogenated 6-spiroepoxypenicillins as probes for the bioactive side-chain conformation of benzylpenicillin

Summary The halogenated 6-spiroepoxypenicillins are a series of novel semisynthetic-lactam compounds with highly conformationally restricted side chains incorporating an epoxide. Their biological activity profiles depend crucially on the configuration at position C-3 of that epoxide. In derivatives with aromatic-containing side chains, e.g., anilide, the 3R-compounds possess notable Gram-positive antibacterial activity and potent-lactamase inhibitory properties. The comparable 3S-compounds are antibacterially inactive, but retain-lactamase inhibitory activity.Using the molecular simulation programs COSMIC and ASTRAL, we attempted to map a putative, lipophilic accessory binding site on the PBPs that must interact with the side-chain aromatic residue. Comparative computer-assisted modelling of the 3R, and 3S-anilides, along with benzylpenicillin, indicated that the available conformational space at room temperature for the side chains of the 3R and the 3S-anilides was mutually exclusive. The conformational space for the more flexible benzylpenicillin could accommodate the side chains ofboth the constrained penicillin derivatives. By a combination of van der Waals surface calculations and a pharmacophoric distance approach, closely coincident conformers of the 3R-anilide and benzylpenicillin were identified. These conformers must be related to the antibacterial, bioactive conformer for the classical-lactam antibiotics. From these proposed bioactive conformations, a model for the binding of benzylpenicillin to the PBPs relating the three-dimensional arrangement of a putative lipophilic S₂-subsite, specific for the side-chain aromatic moiety, and the 3-carboxylate functionality is presented.This work has been reported in preliminary form at the 4th Royal Society of Chemistry International Symposium on Recent Advances in the Chemistry of-lactam Antibiotics, Churchill College, Cambridge, U.K., 3–6 July 1988.     

Solubility Enhancement of Low Soluble Biologically Active Compounds by β-Cyclodextrin and Dimethyl-β-cyclodextrin

The solubility enhancement of triflumizole by complexation with -cyclodextrin and with dimethyl--cyclodextrin is compared with respect to the different physico-chemical properties of the host molecules. Although the inclusion reaction constants are rather similar for both complexation reactions, a completely different temperature dependence of the host-guest interaction is observed, which indicates a change of the reaction mechanisms. Moreover, the influence of ethanol as cosolvent is studied.     

Reactions of 1,2,4-Triazines with Nucleophiles. 6. Use of SNH Methodology for the Direct Introduction of Cyclic Diketone Residue into the 1,2,4-Triazine Ring FORENAME = D. N.

3-R-6-Phenyl-1,2,4-triazine 4-oxides react with cyclic -diketones (dimethylbarbituric acid, dimedone, and indan) in both acidic (substrate activation) and basic conditions (nucleophile activation) with formation of ^H-adducts, intermediates in the nucleophilic substitution of hydrogen (S_N ^H) in 3-R-5-Nu-4-hydroxy-6-phenyl-4,5-dihydro-1,2,4-triazines. Oxidative aromatisation of these intermediates or auto-aromatisation of acylated (benzoyl chloride) at the NOH -adducts with elimination of benzoic acid gave the corresponding substituted 1,2,4-triazine 4-oxides or 1,2,4-triazines.     

Investigation on the Interaction of Bendazac with β-, Hydroxypropyl-β-, and γ-, yclodextrins

The interactions of Bendazac, a topical non-steroidal anti-inflammatory drug, with-cyclodextrin, hydroxypropyl--cyclodextrin and -cyclodextrinwere investigated to evaluate possibilities to improve the drug's poor water solubilityand eventually to enhance the topical delivery of Bendazac. Phase solubility studiesdemonstrated the ability of the selected cyclodextrins to complex with Bendazac andincrease drug solubility. The amount of solubilized Bendazac increased linearly withthe addition of each cyclodextrin according toA_L type plots. ¹³C-NMR studiesshowed that the Bendazac A-ring was included in the cavity of the three cyclodextrins.The -cyclodextrin was also able to include the B-ring of Bendazac, forminga complex where one drug molecule fitted into two cyclodextrin molecules. Equimolarsolid systems of the drug with each cyclodextrin carrier were prepared using varioustechniques (physical mixing, spray-drying and freeze-drying). The results of differential scanning calorimetry and Fourier transform infrared analysis, performed on the solid systems, demonstrated that freeze-dried and spray-dried products had a high degree of amorphization and agreed with the hypothesis of the existence of drug–cyclodextrin interaction in the solid state. The cyclodextrins tested were able to improve the dissolution of Bendazac. The dissolution profile of the drug was also affected by the physico-chemical properties of each solid system, the freeze-dried products being the most rapidly dissolving forms.     

Chiral separation of β-amino alcohols by capillary electrophoresis using cyclodextrins as buffer additives. I. Effect of varying operating parameters

Summary Capillary electrophoresis has been used for the chiral analysis of two -amino alcohol pharmaceutical compounds. Capillary zone electrophoresis conditions were used with -cyclodextrin as a chiral mobile phase additive. The effects of variation of -cyclodextrin concentration, temperature, pH, background electrolyte composition and concentration have been investigated. Optimum separations were achieved for clenbuterol using -cyclodextrin at its solubility limit (16mM), the lowest practicable temperature (19°C), pH 4.0 and an electrolyte solution with a high ionic strength prepared from 0.1 M citric acid and 0.3 M Na₂HPO₄. For the development compound picumeterol and its (S)-enationmer, the optimum pH 4.0 buffer was prepared from 0.1 M citric acid and 0.2 M sodium acetate. Baseline separation with resolution greater than 2 was achieved for both compounds.This work was presented in part at the 2nd International Symposium on Chiral Discrimination, Rome, May 27–31, 1991.     

Simultaneous determination of tetrahydro-β-carbolines and β-carbolines

Summary Reversed-phase ion-pair HPLC with fluorimetric detectors connected in series was studied for the simultaneous determination of two tetrahydro--carbolines and two -carbolines. After additon of internal standards the samples were reacted with fluorescamine, and then subjected to serial extractions to remove their precursor (tryptamine) from the analytical system. This treatment not only suppressed the artefactual formation of tetrahydro--carbolines and -carbolines during analysis, but also effectively purified them. Under optimum conditions, using trifluoroacetic acid as counter ion, all analytes were separated within 14 min and without major interfering peaks. The quantitative ranges were 0.25–80.0 ng mL^–1 for both tetrahydro--carbolines and 0.1–30.0 ng mL^–1 for both -carbolines. Replicate spiking experiments showed that recovery from most of the samples tested was over 90% and the relative standard deviation ranged from 0.7 to 10.4% within and between assays. The proposed method was applicable to various materials such as soy sauce, vinegar, ketchup, tabasco, beer, wine, sake, whisky, brandy, cows' milk, coffee, cocoa, cheese, cigarette smoke and urine.