Pyrene-azacrown ether hybrid: cation-π interaction

A pyrene-modified lariat ether was synthesized in order to observe the cation-π interaction in solution.     

Oxygenolysis of flavonoid compounds: DFT description of the mechanism for quercetin.

Flavonoids are naturally occurring phenol derivatives present in substantial amounts in a large variety of plants, fruits and vegetables daily eaten by humans. Most of these compounds exhibit several interesting biological activities, such as antiradical and antioxidant actions. Indeed, by complexation with specific enzymes, flavonoids are notably liable to metabolize molecular dioxygen. On the basis of experimental results describing oxygenolysis of the flavonoid quercetin, activated by the enzyme quercetin 2,3-dioxygenase (2,3-QD),ur attention has focused on the role of metal center in the activation of the substrate quercetin. Thus, in the present study, by means of DFT calculations at the B3LYP/ 6-31(+)G* level on model molecular systems, we describe different mechanisms for dioxygen metabolization by quercetin. Stationary points are described, and energetic and structural analyses along the reaction paths are reported. Our calculations show that the copper cation must act as an oxidant towards the substrate and that the reaction proceeds through a 1,3-cycloaddition.     

Gamma-ray polymerization of phospholipids having diene or triene groups as liposomes

Small unilamellar liposomes were prepared in an aqueous medium by the sonication of phospholipids containing diene or triene groups in their hydrocarbon acyl chains. These liposomes were polymerized by gamma-ray irradiation. Conversion of polymerization was successively followed by UV spectrometry. Diene-type lipid liposomes were revealed for which a gamma-ray dose of 0.8 Mrad was required for complete polymerization and which were polymerized more easily than triene-type lipid liposomes. Triene-type lipids required 2.3 Mrad gamma ray to polymerize them completely. Contrary to UV-irradiation polymerization, there was no concentration dependence on the polymerization. Structure of the polymerized liposomes were confirmed by electron microscopy as small unilamellar liposomes. Study on the leakage of fluorescein from inner aqueous phase of the polymerized liposomes revealed that polymerized triene-type liposomes were relatively more stable than the polymerized diene-type liposomes.     

Synthesis of 3-substituted 4H-1-benzothiopyran-4-ones

3-Substituted 2-phenyl-4H-1-benzothiopyran-4-ones (thioflavones) were prepared to test antimicrobial activity. It was found that 3-(phenyl)thiochromone derivatives (isothioflavones) were prepared by the Meerwein reaction of thiochromone with p-nitrobenzenediazonium ion. 3-(Formyl)thioflavone exhibits weak antimicrobial activity against Trichophytons and Candida.     

Trace analysis of rapamycin in human blood by micellar electrokinetic chromatography

A capillary electrophoretic method with UV detection at 278 nm has been developed for analysis of the immunosuppressant rapamycin (sirolimus) in human blood at low microgram per liter levels. Separation has been achieved in an acidic carrier electrolyte containing sodium dodecylsulfate and 30% (v/v) acetonitrile. For sample clean-up and preconcentration, an off-line solid-phase extraction step using a silica-based reversed-phase material and an on-capillary focussing technique were employed. The latter allows the injection of increased sample volumes without excessive band broadening. Although this new method is less sensitive than existing liquid chromatographic procedures combined with mass spectrometry, it is fully suited to routine analysis of rapamycin in blood from patients treated with this drug. Last but not least the low costs make it an attractive alternative to established methods.     

Photochromism of viologens included in crown ether cavity

The effect of a pi-electron-donating macrocyclic molecule on the photochromic behavior of viologen derivatives was investigated in a thin polymer film. The intermolecular interactions between the viologens and the macrocyclic molecule were investigated in a solution before photoirradiation. In acetone, benzylviologens, N,N'-dibenzyl-4,4'-bipyridinium hexafluorophosphate (1) and N,N'-dibenzyl-trans-1,2-bis(4-pyridinium)ethylene hexafluorophosphate (2) each derived from 4,4'-bipiyridine and trans-1,2-bis(4-pyridyl)ethylene, respectively, form an inclusion complex with p-benzocrown ether (3) with binding constants of ca 200 M-1, which was driven by a charge transfer interaction. The peak wavelength of the charge transfer absorption band was at 453 and 421 nm for the inclusion complexes of 1 and 2 with 3, respectively. Upon photoirradiation to the polymer film containing 1, the film changed color from colorless to blue, associated with the reduction of 1 from the dication to the radical cation. The original dication was recovered after 120 min. The addition of 3 into the film containing 1 caused not only the color change from colorless to yellow, associated with the charge transfer interaction between 1 and 3 before photoirradiation, but also an acceleration in the bleaching rate of the photoreduced 1. When p-dimethoxybenzene (4) was used as an acyclic analog of 3, a negligible change in the photochromic behavior of 1 was observed. Similar effect of 3 on the photochromic behavior of 2 was observed. These results imply that the pi-electron-donating macrocyclic molecule causes a faster bleaching of photoreduced viologens by forming the inclusion complex.     

Free energy perturbation approach to the critical assessment of selective cyclooxygenase-2 inhibitors

The discovery of selective cyclooxygenase-2 (COX-2) inhibitors represents a major achievement of the efforts over the past few decades to develop therapeutic treatments for inflammation. To gain insights into designing new COX-2-selective inhibitors, we address the energetic and structural basis for the selective inhibition of COX isozymes by means of a combined computational protocol involving docking experiment, force field design for the heme prothetic group, and free energy perturbation (FEP) simulation. We consider both COX-2- and COX-1-selective inhibitors taking the V523I mutant of COX-2 to be a relevant structural model for COX-1 as confirmed by a variety of experimental and theoretical evidences. For all COX-2-selective inhibitors under consideration, we find that free energies of binding become less favorable as the receptor changes from COX-2 to COX-1, due to the weakening and/or loss of hydrogen bond and hydrophobic interactions that stabilize the inhibitors in the COX-2 active site. On the other hand, COX-1-selective oxicam inhibitors gain extra stabilization energy with the change of residue 523 from valine to isoleucine because of the formations of new hydrogen bonds in the enzyme-inhibitor complexes. The utility of the combined computational approach, as a valuable tool for in silico screening of COX-2-selective inhibitors, is further exemplified by identifying the physicochemical origins of the enantiospecific selective inhibition of COX-2 by -substituted indomethacin ethanolamide inhibitors.     

Condensed thienopyrimidines. II. Synthesis and gastric antisecretory activity of thiazole and polymethylene condensed thienopyrimidine derivatives

Thiazolo[3,2-a]thieno[3,2-d]-, [3,4-d]- and [2,3-d]pyrimidin-5-one derivatives (6, 11 and 16), and polymethylene condensed thieno[3,2-d]-, [3,4-d]- and [2,3-d]pyrimidin-5-one derivatives (19-21), in which the oxygen atom of the oxazolidine moiety in 3 was replaced by a sulfur atom or methylene groups, were synthesized and evaluated for gastric antisecretory activity in pylorus-ligated rats. The structure-activity relationships of these compounds are discussed.