Improving cyclodextrin complexation of a new antihepatitis drug with glacial acetic acid

The purpose of this study was to develop and evaluate a solid nonaqueous oral dosage form for a new hepatitis C drug, PG301029, which is insoluble and unstable in water. Hydroxypropyl-β-cyclodextrin (HPβCD) and PG301029 were dissolved in glacial acetic acid. The acetic acid was removed by rotoevaporation such that the drug exists primarily in the complexed form. The stability of formulated PG301029 was determined upon dry storage and after reconstitution in simulated intestinal fluid (SIF), simulated gastric fluid (SGF), and water. Formulated PG301029 was found to be stable upon storage and can be reconstituted with water to a concentration 200 times that of the intrinsic solubility. Once reconstituted, the powder dissolves rapidly and PG301029 remains stable for 21 hours in SGF, SIF, and water. The unique use of acetic acid and HPβCD results in a solid dosage form of PG301029 that is both soluble and stable in water. Published: February 24, 2006     

A study on natural and synthetic humic acids and their complexing ability towards cadmium

The natural and synthetic humic acids were characterised by potentiometric titrations, viscosity and surface tension measurements, as well as visible spectometry The results have been correlated with coiling-decoiling behaviour and aliphatic–aromatic balance of these acids. The stability constant of complexes formed by these humic acids with Cd²⁺ ions in aqueous phase was evaluated by the ion-exchange method. Results tend to suggest that humic phenolic –OH group was involved in the formation of Cd²⁺–humic complex, leading to it the given stability in a manner as for the analogous metal–oxine complexation. The hydrophobic moiety of the synthetic humic acid may also provide a cage-type conformation around Cd²⁺ ion, imparting to the Cd²⁺–humic complex the desired stability.     

Transition metal complexes of a cyclic pseudo hexapeptide: synthesis,complex formation and catalytic activities

To contribute to a better understanding of metalloenzymes, we studied ion selectivity, complex formation tendencies and catalytic activities of linear and cyclic pseudopeptides. In this contribution, a linear and cyclic pseudo hexapeptide is described. The complex with transition metal ions and the sequence were designed using the programme COSMOS. Different routes of solid‐phase synthesis were performed and compared using anchoring by C‐terminus or a His side chain, using preformed pseudodipeptide building units or formation of N‐functionalized peptide bond during stepwise assembly. The different strategies were compared regarding cyclization tendency, yield and purity. Side‐chain anchoring to solid support favours the cyclization but leads to the formation of difficult to separate dioxopiperazine. Both routes require preformed building units. Complex‐formation tendencies and selectivity for certain bivalent transition metal ions were experimentally estimated and compared to ones predicted theoretically. CD measurements indicate conformational changes by complex formation with different metal ions. Catalytic activities on oxidation of catechol and hydrolysis of bis‐phosphate esters by some metal complexes of linear and cyclic peptide show only low catalytic activities compared to other model peptides and related metalloenzymes. The preference of the cyclic peptide for complexation of Ni²⁺ corresponds well to the predictions of COSMOS‐NMR force field calculations. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd.     

Insights into the structural dynamics of Liver kinase B1 (LKB1) by the binding of STe20 Related Adapterα (STRADα) and Mouse protein 25α (MO25α) co-activators

LKB1, the tumour suppressor, is found mutated in Peutz-Jeghers syndrome (PJS). The LKB1 is a serine-threonine kinase protein that is allosterically activated by the binding of STRADα and MO25α without phosphorylating the Thr212 present at activation loop. The present study aims to highlight the structural dynamics and complexation mechanism during the allosteric activation of LKB1 by these co-activators using molecular dynamics simulations. The all atom simulations performed on the complexes of LKB1 with ATP, STRADα, and MO25α for a period of 30 ns reveal that binding of STRADα and MO25α significantly stabilizes the highly flexible regions of LKB1 such as ATP binding region (β1-β2 loop), catalytic & activation loop segments and αG helix. Also, binding of STRADα and MO25α to LKB1 promotes coordinated motion between N- and C-lobes along with the catalytic & activation loops by forming H-bonds between LKB1 and co-activators, which further facilitate to establish the conserved attributes of active LKB1 such as (i) formation of salt bridge between Lys78 and Glu98, (ii) formation of stable hydrophobic R- and C-spines, and (iii) interaction between both catalytic and activation loops. Especially, the residues of LKB1 interacting with STRADα (Arg74, Glu342) and MO25α (Glu165, Pro203 and Phe204) are observed to play a significant role in stabilizing the (LKB1-ATP)-(STRADα-ATP)-MO25α complex. Overall, the present work highlighting the structural dynamics of LKB1 by the binding of allosteric co-activators is expected to provide a basic understanding on drug design specific to PJS syndrome.     

Chromium mobilization and plant availability — the impact of organic complexing ligands

Pot experiments were conducted to investigate the effect of various organic acids (carboxylic and amino acids) on the uptake and translocation of root-absorbed trivalent chromium by tomato ( Lycopersicum esculentum) plants grown in sand and soil culture. Statistically significant increases in chromium accumulation from Cr(III) treated plants in the presence of increasing concentrations of organic acid suggest the existence of Cr(III) — organic acid interactions in the soil-plant system. However, the amino acids have been less effective in the mobilization of chromium compared to carboxylic acids. The results are discussed on the basis of the potential of organic acids to form complexes with Cr(III). This revised version was published online in June 2006 with corrections to the Cover Date.     

Optically active crown ether‐based fluorescent sensor molecules: A mini‐review

This mini‐review focuses on fluorescent optically active crown ethers (polymeric derivatives are not included) reported in the literature (according to our knowledge), of which enantiomeric recognition ability, and in some cases, also inorganic cation complexation properties, were investigated by the sensitive and versatile fluorescence spectroscopy. These crown ether‐based chemosensors contain various fluorophore signaling units such as binaphthyl, anthracene, pyrene, tryptophan, benzimidazole, terpyridine, acridine, phenazine, acridone, BODIPY, and another conjugated aromatic one.     

Influence of hydrophilic polymers on celecoxib complexation with hydroxypropyl β-cyclodextrin

Complexation of celecoxib with hydroxypropyl β-cyclodextrin (HPβCD) in the presence and absence of 3 hydrophilic polymers—polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), and polyethylene glycol (PEG)—was investigated with an objective of evaluating the effect of hydrophilic polymers on the complexation and solubilizing efficiencies of HPβCD and on the dissolution rate of celecoxib from the HPβCD complexes. The phase solubility studies indicated the formation of celecoxib-HPβCD inclusion complexes at a 1∶1M ratio in solution in both the presence and the absence of hydrophilic polymers. The complexes formed were quite stable. Addition of hydrophilic polymers markedly enhanced the complexation and solubilizing efficiencies of HPβCD. Solid inclusion complexes of celecoxib-HPβCD were prepared in 1∶1 and 1∶2 ratios by the kneading method, with and without the addition of hydrophilic polymers. The solubility and dissolution rate of celecoxib were significantly improved by complexation with HPβCD. The celecoxib-HPβCD (1∶2) inclusion complex yielded a 36.57-fold increase in the dissolution rate of celecoxib. The addition of hydrophilic polymers also markedly enhanced the dissolution rate of celecoxib from HPβCD complexes: a 72.60-, 61.25-, and 39.15-fold increase was observed with PVP, HPMC, and PEG, respectively. Differential scanning calorimetry and X-ray diffractometry indicated stronger drug amorphization and entrapment in HPβCD because of the combined action of HPβCD and the hydrophilic polymers. Published: September 29, 2006     

基于同步辐射技术研究土壤铁氧化物固定重金属分子机制的进展

铁氧化物在土壤中广泛赋存,因其比表面积大,对重金属具有很强的吸附固定能力,深刻影响着土壤重金属的形态转化过程.因此,研究土壤铁氧化物对重金属的固定机制,对于深入理解重金属在土壤系统中的环境化学行为以及评估污染土壤重金属生物有效性具有重要意义.然而,采用传统的吸附模型和化学提取法研究土壤铁氧化物固定重金属的机制具有明显的局限性,无法从分子水平上阐明其固定机制.同步辐射技术在环境土壤学的应用显著推进了在分子水平上认识土壤铁氧化物吸附重金属及其受典型环境因子影响的分子机制.本文主要从同步辐射技术的发展历程、模拟系统和实际土壤系统中铁氧化物在多种因素影响下对重金属固定的分子机制等方面进行了综述,同时对同步辐射技术的未来发展趋势及其在该研究领域的应用进行了展望.     

Formation of insoluble and colloidally dispersed tannic acid complexes in the midgut fluid of Manduca sexta (Lepidoptera: Sphingidae): An explanation for the failure of tannic acid to cross the peritrophic envelopes of lepidopteran larvae

Magnesium and calcium ions, in concentrations comparable to those reported in the midgut fluids of lepidopteran larvae, bring about the precipitation of most of the tannic acid present in simple solutions buffered at pH 8.0 and 10.0, but not at pH 6.5. In contrast, when tannic acid is added to Manduca sexta midgut fluid, less than 31% of the tannic acid added to the gut fluid is converted to a form that can be centrifuged into a pellet. The rest remains in the supernatant solution in the form of a colloidal suspension. Very little of the tannic acid, if any, remains in true solution. We suggest that the tannic acid-containing phase that is produced when tannic acid is added to midgut fluid is a complex multi-molecular aggregate of indefinite chemical composition, incorporating varying amounts of tannic acid, surface-active phospholipids, proteins, and polyvalent metal ions. On the basis of this study, we further suggest that the failure of tannins to diffuse across the peritrophic envelopes of lepidopteran larvae is a result of the capacity of the peritrophic envelope to act as a physical barrier to insoluble and colloidally dispersed particles, not the presence of substances in the matrix that strongly adsorb polyphenols or the presence of an extensive network of fixed anionic sites in the matrix that acts as an electrostatic barrier to the passage of polyphenolate anions. Arch. Insect Biochem. Physiol. 39:109–117, 1998.© 1998 Wiley-Liss, Inc.     

Bile acid derivatives as enantiodifferentiating host molecules in inclusion processes

A review on the use of bile acids as hosts for molecular recognition and enantioresolution is presented. The optical resolution of different classes of organic derivatives, i.e., lactones, aliphatic alcohols, sulfoxides, epoxides, ketones, cyclic amides, cyclic carbonates, and sulfites, may be obtained by host-guest enantioselective inclusion complexation. The salient aspects of the enclathration process, including X-ray diffraction results, are discussed.