Antiinflammation Derived Suzuki-Coupled Fenbufens as COX-2 Inhibitors: Minilibrary Construction and Bioassay

A small fenbufen library comprising 18 compounds was prepared via Suzuki Miyara coupling. The five-step preparations deliver 9–17% biphenyl compounds in total yield. These fenbufen analogs exert insignificant activity against the IL-1 release as well as inhibiting cyclooxygenase 2 considerably. Both the para-amino and para-hydroxy mono substituents display the most substantial COX-2 inhibition, particularly the latter one showing a comparable activity as celecoxib. The most COX-2 selective and bioactive disubstituted compound encompasses one electron-withdrawing methyl and one electron-donating fluoro groups in one arene. COX-2 is selective but not COX-2 to bioactive compounds that contain both two electron-withdrawing groups; disubstituted analogs with both resonance-formable electron-donating dihydroxy groups display high COX-2 activity but inferior COX-2 selectivity. In silico simulation and modeling for three COX-2 active—p-fluoro, p-hydroxy and p-amino—fenbufens show a preferable docking to COX-2 than COX-1. The most stabilization by the p-hydroxy fenbufen with COX-2 predicted by theoretical simulation is consistent with its prominent COX-2 inhibition resulting from experiments.     

Comparative FTIR spectroscopy of HX adsorbed on solid water: Ragout-jet water clusters vs ice nanocrystal arrays

In addition to revealing the stretch-mode bands of the smallest mixed clusters of HCl and HBr (HX) with water, the ragout-jet FTIR spectra of dense mixed water-acid supersonic jets include bands that result from the interaction of HX with larger water clusters. It is argued here that low jet temperatures prevent the water-cluster-bound HX molecules from becoming sufficiently solvated to induce ionic dissociation. The molecular nature of the HX can be deduced directly from the observed influence of changing from HCl to HBr and from replacing H2O with D2O. Furthermore, the band positions of HX are roughly coincidental with bands assigned to molecular HCl and HBr adsorbed on ice nanocrystal surfaces at temperatures below 100 K. It is also interesting that the HX band positions and widths approximate those of HX bound to the surface of amorphous ice films at <60 K. Though computational results suggest the adsorbed HX molecules observed in the jet expansions are weakly distorted by single coordination with surface dangling-oxygen atoms, on-the-fly trajectories indicate that the cluster skeletons undergo large-amplitude low-frequency vibrations. Local HX solvation, the extent of proton sharing, and the HX vibrational spectra undergo serious modulation on a picosecond time scale.     

The beta-carboline analog Mana-Hox causes mitotic aberration by interacting with DNA

Mana-Hox, an analog of beta-carbolines with anticancer activity, induces aberrant mitosis and delays mitotic exit. However, the cellular target is not known. In this study, we visualized the intracellular localization of Mana-Hox. Mana-Hox rapidly penetrated into cells (within 1 min) and concentrated on disorganized metaphase chromosomes after 13 hr of exposure. We demonstrated that Mana-Hox is a noncovalent DNA binder that can interact with DNA through intercalation and/or through minor groove binding. Furthermore, Mana-Hox also inhibits topoisomerase II relaxation activity in vitro, suggesting that Mana-Hox could perturb mitotic chromosome decatenation. Overall, Mana-Hox binding to DNA plays a critical role in the induction of aberrant mitosis and contributes to its anticancer activity.     

The β-Carboline Analog Mana-Hox Causes Mitotic Aberration by Interacting with DNA

Mana-Hox, an analog of beta-carbolines with anticancer activity, induces aberrant mitosis and delays mitotic exit. However, the cellular target is not known. In this study, we visualized the intracellular localization of Mana-Hox. Mana-Hox rapidly penetrated into cells (within 1 min) and concentrated on disorganized metaphase chromosomes after 13 hr of exposure. We demonstrated that Mana-Hox is a noncovalent DNA binder that can interact with DNA through intercalation and/or through minor groove binding. Furthermore, Mana-Hox also inhibits topoisomerase II relaxation activity in vitro, suggesting that Mana-Hox could perturb mitotic chromosome decatenation. Overall, Mana-Hox binding to DNA plays a critical role in the induction of aberrant mitosis and contributes to its anticancer activity.     

The Use of Bovine Serum Albumin as a Ligand in Affinity Chromatographic Clean-up of Non-Steroidal Anti-Inflammatory Drugs from Bovine Plasma

The European Union regulates the use of non-steroidal anti-inflammatory drugs (NSAID) in animal production and official national analytical monitoring programmes have been set up in each member state to detect residues of the drugs in bovine plasma. In this work, we describe the development and application of affinity chromatography for molecular recognition of NSAID in bovine plasma. Bovine serum albumin (BSA), the plasma protein which binds such drugs, was covalently bound to a polymeric support via its glycosyl moieties. Loading capacities and specificity were tested both on standard solutions and on spiked bovine plasma for nine drugs—ketoprofen, naproxen, phenylbutazone, oxyphenylbutazone, acetylsalicylic acid, salicylic acid, tolfenamic acid, diclofenac, and nimesulide—chosen as being the most representative of the different chemical sub-classes of NSAID. The BSA columns could bind up to 150 × 10^–6 g total of a mixture of these nine NSAID, with mean recoveries ranging from 74.0% (tolfenamic acid) to 96.0% (nimesulide). HPLC separation on an RP C₁₈ column with a linear gradient enabled resolution of the drugs; identification was achieved by coupling with photodiode array detection (DAD) operated at 240 and 280 nm. Results showed that all the compounds except acetylsalicylic acid were bound effectively by the BSA affinity columns. When plasma samples were spiked at 2.5 g mL^–1 with a mixture of the NSAID the chromatographic profile and UV spectra recorded (in the range 220–350 nm) indicated the procedure was sufficiently selective for identification of the drugs at the concentrations expected according to their pharmacokinetics. No memory effects and matrix interferences were observed.Revised: 18 December 2003 and 16 April 2004     

Kadsuphilactones A and B, two new triterpene dilactones from kadsuraphilippinensis

[structure: see text]. Two novel triterpene dilactones, kadsuphilactones A (1) and B (2), were isolated from the Taiwanese medicinal plant Kadsura philippinensis. The structures of 1 and 2 were elucidated on the basis of extensive spectroscopic methods, including two-dimensional NMR techniques, and confirmed by X-ray crystallographic analysis. Kadsuphilactone B (2) exhibited in vitro anti-HBV activity with IC(50) values of 6 microg/mL by HBsAg enzyme immunoassay.     

Preparation of analogues of efaroxan and KU14R as potential imidazoline receptor subtype 3 ligands

The preparation and characterization of new analogues of the imidazoline insulin secretagogue efaroxan 1 are described. These include 1,2,4‐triazole, 1,3,4‐oxadiazole, pyrimidine, 1,4,5,6‐tetrahydropyrimidine and 1,2‐dihydro‐1,2,4,5‐tetrazine analogues. Bromination of 2,3‐dihydro‐2‐ethylbenzo[b]furan‐2‐carbonitrile 19 gives the 3,3‐dibromo analogue 28 , which is readily hydrolysed to the corresponding ketone 29 . Reduction of this ketone gives the alcohol 31 as a mixture of diastereoisomers that is converted to the fluoride 32 using diethylaminosulfur trifluoride.