Quantitative structure activity relationships (QSAR) of substituded (S)-phenylpiperidines as preferential dopamine autoreceptor antagonists

A QSAR analysis for substituted (S)-phenylpiperidines as dopamine (DA) antagonists is described. The studied derivatives differ at the nitrogen substitutent (R) and at the substitutents (X) of the phenyl-ring. The analysis was done using the C-QSAR suite program (Biobyte) through the Internet. Clog P, CMR, M_Vol, B₁ and L (the Verloop's sterimol parameters for the substitutents) were used as parameters. In all the three studied cases clog P plays a significant part in the QSAR of DA antagonists, followed by the steric factors. In one case the electronic effect contributes significantly.     

New insights into the chemical and isotopic composition of human-body biominerals. I: Cholesterol gallstones from England and Greece

We have analyzed gallstones from four patients of Europe and particularly from England (including samples from a mother and a daughter) and Greece. According to the XRD, FTIR, NMR and laser micro-Raman results the studied materials correspond to typical cholesterol monohydrate (ChM). The micro-morphology of cholesterol microcrystals was investigated by means of SEM–EDS. The XRF results revealed that Ca is the dominant non-organic metal in all gallstones (up to ～1.95 wt.%) together with Fe, Cu, Pb and Ni (up to ～19 ppm for each metal). Gallstones from England contain additional Mn (up to ～87 ppm) and Zn (up to ～6 ppm) while the sample of the mother contains negligible Zn and Mn, compared to that of her daughter, but significant As (～4.5 ppm). All cholesterol gallstones examined are well enriched in potentially toxic metals (Pb, as well as Ni in one case) and metalloids (As also in one case) as compared to the global average. The position of Zn, which is a characteristic biometal, in the structure of cholesterol, was investigated by molecular simulation using the Accelrys Materials Studio^® software. On the basis of IRMS results, all gallstones examined exhibit a very light δ¹³C signature (average δ¹³C ～?24‰ PDB). Gamma-ray spectrometry measurements indicate the presence of ²¹⁴Pb and ²¹⁴Bi natural radionuclides due to the ²³⁸U series as well as an additional amount of ⁴⁰K.     

Synthesis, crystal structures and spectroscopy of meclofenamic acid and its metal complexes with manganese(II), copper(II), zinc(II) and cadmium(II). Antiproliferative and superoxide dismutase activity

Some new complexes of meclofenamic acid (N-(2,6-dichloro-m-tolyl)anthranilic acid), Hmeclo (1), with potentially interesting biological activities are described. Complexes [Mn(meclo)₂] (2), [Cu(meclo)₂(H₂O)₂] (3), [Zn(meclo)₂(H₂O)₂] (4) and [Cd(meclo)₂(H₂O)₂] (5) were prepared and structurally characterized by means of vibrational, electronic and ¹H and ¹³C NMR spectroscopies. The crystal structure of complexes [Cu₄(meclo)₆(OH)₂(DMSO)₂]2DMSO (3a) and [Cd(meclo)₂(DMSO)₃] (5a) have been determined by X-ray crystallography. Complex (3a) is a centrosymmetric tetramer built up around the planar cyclic Cu₂(OH)₂ unit. Complex 5a is mononuclear seven-coordinated complex with the meclofenamato ligand behaving as a bidentate deprotonated chelating ligand. Intra and intermolecular hydrogen bonds stabilize these two structures, while the crystal packing is determined by π-π and C−H−-π interactions. Meclofenamic acid and its metal complexes have been evaluated for antiproliferative activity in vitro against the cells of three human cancer cell lines, MCF-7 (breast cancer cell line), T24 (bladder cancer cell line), and A-549 (non-small cell lung carcinoma), and a mouse fibroblast L-929 cell line. Complex 5 exhibits the highest selectivity against MCF-7 and 4 shows the highest selectivity against T-24. Complexes 2-5 were found to be more potent cytotoxic agents against T-24 and complex 5 against MCF-7 cancer cell lines than the prevalent benchmark metallodrug, cis-platin. The superoxide dismutase activity was measured by the Fridovich test which showed that complex [Cu(meclo)₂(H₂O)₂] is a good superoxide scavenger.     

The triphenyltin(VI) complexes of NSAIDs and derivatives. Synthesis, crystal structure and antiproliferative activity. Potent anticancer agents

The novel triphenyltin(IV) esters of flufenamic acid (1), Hflu, [Ph₃Sn(flu)] (2), and of [2-(2,3-dichlorophenylamino)benzoic acid] (3), Hdcpa, [Ph₃Sn(dcpa)] (4) have been structurally characterized by means of vibrational and ¹H, ¹³C NMR spectroscopic studies. The crystal and molecular structures of [SnPh₃(dcpa)(DMSO)] 4a are described. The molecular structure of 4a reveals that the Sn atom has a distorted trigonal bipyramidal coordination geometry with equatorial phenyl groups and the carboxylate and dimethylsulfoxide oxygen atoms occupying axial positions. The crystal structure of 4a is self-assembled by C-H---π and π-π stacking interactions. The in vitro cytotoxic activity of 1-4 and of the related non-steroidal anti-inflammatory drugs, NSAIDs, [2-(2,6-dimethylphenylamino)benzoic acid], Hdmpa (5), [Ph₃Sn(dmpa)] (6), [2-(2,3-dimethylphenylamino)benzoic acid], mefenamic acid, Hmef (7) and [Ph₃Sn(mef)] (8) has been evaluated against the cancer cell lines MCF-7, T-24, A-549 and L-929. The ligands exhibited very poor cytotoxic activity against the four cancer cell lines. Complex 6 exhibits the highest activity and selectivity against A-549 and MCF-7 cancer cell lines and complex 8 the highest activity and selectivity against T-24 cancer cell line. The cytotoxic results indicate that coupling of Hdmpa and Hmef with R₃Sn(IV) metal center results in complexes with important biological properties and remarkable cytotoxic activity, since they display IC₅₀ values in a μΜ range better to that of the antitumor drug cis-platin. Complexes 6 and 8 are considered as excellent antitumor compounds and the results of this study represent the discovery of triphenyltin(IV)esters as a potential novel class of anticancer agents.     

Cytochrome P450 6M2 from the malaria vector Anopheles gambiae metabolizes pyrethroids: Sequential metabolism of deltamethrin revealed

Resistance to pyrethroid insecticides in the malaria vector Anopheles gambiae is a major threat to malaria control programmes. Cytochome P450-mediated detoxification is an important resistance mechanism. CYP6M2 is over-expressed in wild populations of permethrin resistant A. gambiae but its role in detoxification is not clear. CYP6M2 was expressed in Escherichia coli and a structural model was produced to examine its role in pyrethroid metabolism. Both permethrin and deltamethrin were metabolized. Rates were enhanced by A. gambiae cytochrome b₅ with kinetic parameters of K_M = 11 ± 1 ??M and k_cat = 6.1 ± 0.4 per min for permethrin (1:1 cis-trans) and K_M = 2.0 ± 0.3 ??M and k_cat = 1.2 ± 0.1 per min for deltamethrin. Mass spectrometry and NMR analysis identified 4′-hydroxy deltamethrin and hydroxymethyl deltamethrin as major and minor deltamethrin metabolites respectively. Secondary breakdown products included cyano(3-hydroxyphenyl)methyl deltamethrate and deltamethric acid. CYP6M2 was most highly transcribed in the midgut and Malpighian tubules of adult A. gambiae, consistent with a role in detoxification. Our data indicates that CYP6M2 plays an important role in metabolic resistance to pyrethroids and thus an important target for the design of new tools to combat malaria.     

Synthesis and In vivo anti-inflammatory activity of long-chain 2-amino-alcohols

The synthesis of optically pure long-chain 2-amino-alcohols and 1-O-dodecyl-2-deoxy-2-amino-sn-glycerol was carried out starting from L- or D-Boc-Ser(OBn)-ol by oxidation and consecutive Wittig reaction or etherification reaction. 2-Amino-oleyl alcohol was synthesized by reduction of the corresponding 2-amino-oleic acid. All the long chain amino-alcohols presented interesting inhibition of carrageenin-induced paw edema in rats (ED(50) from 0.017 to 0.010 mmol/kg).     

Biocompatible photolithographic process for the patterning of biomolecules

A new approach for the patterning of biomolecule layers is introduced based on the design of a new photoresist material with biocompatible lithographic processing requirements. The photoresist is based on poly(t-butyl acrylate), which allows positive imaging with very dilute basic solutions, tolerable by selected biomolecules used in immunoanalysis. Sensitivity at lambda>300 nm is obtained using a suitable sulfonium salt photoacid generator. Thermal steps also take place under conditions tolerable by biomolecules. Lithographic results on Si wafer substrates show resolution capabilities for equal lines/spaces, down to the range of 5-10 microm under biocompatible conditions. The process is also used on substrates of different geometries, including inner capillary surfaces. The patterning of the inner surface of a polystyrene capillary with mouse IgG is reported to demonstrate the principles of the above approach.     

Commercial video frame rates can produce reliable results for both normal and CP spastic gait's spatiotemporal, angular, and linear displacement variables

To investigate what sampling frequency is adequate for gait, the correlation of spatiotemporal parameters and the kinematic differences, between normal and CP spastic gait, for three sampling frequencies (100 Hz, 50 Hz, 25 Hz) were assessed. Spatiotemporal, angular, and linear displacement variables in the sagittal plane along with their 1st and 2nd derivatives were analyzed. Spatiotemporal stride parameters were highly correlated among the three sampling frequencies. The statistical model (2 × 3 ANOVA) gave no interactions between the factors group and frequency, indicating that group differences were invariant of sampling frequency. Lower frequencies led to smoother curves for all the variables, with a loss of information though, especially for the 2nd derivatives, having a homologous effect as the one of oversmoothing. It is proposed that in the circumstance that only spatiotemporal stride parameters, as well as angular and linear displacements are to be used, in gait reports, then commercial video camera speeds (25/30 Hz, 50/60 Hz when deinterlaced) can be considered as a low-cost solution to produce acceptable results.