A novel chalcone derivative which acts as a microtubule depolymerising agent and an inhibitor of P-gp and BCRP in in-vitro and in-vivo glioblastoma models

<p>Abstract</p> <p>Background</p> <p>Over the past decades, in spite of intensive search, no significant increase in the survival of patients with glioblastoma has been obtained. The role of the blood-brain barrier (BBB) and especially the activity of efflux pumps belonging to the ATP Binding Cassette (ABC) family may, in part, explain this defect.</p> <p>Methods</p> <p>The <it>in-vitro </it>activities of JAI-51 on cell proliferation were assessed by various experimental approaches in four human and a murine glioblastoma cell lines. Using drug exclusion assays and flow-cytometry, potential inhibitory effects of JAI-51 on P-gp and BCRP were evaluated in sensitive or resistant cell lines. JAI-51 activity on <it>in-vitro </it>microtubule polymerization was assessed by tubulin polymerization assay and direct binding measurements by analytical ultracentrifugation. Finally, a model of C57BL/6 mice bearing subcutaneous GL26 glioblastoma xenografts was used to assess the activity of the title compound <it>in vivo</it>. An HPLC method was designed to detect JAI-51 in the brain and other target organs of the treated animals, as well as in the tumours.</p> <p>Results</p> <p>In the four human and the murine glioblastoma cell lines tested, 10 μM JAI-51 inhibited proliferation and blocked cells in the M phase of the cell cycle, via its activity as a microtubule depolymerising agent. This ligand binds to tubulin with an association constant of 2 × 10⁵M^-1, overlapping the colchicine binding site. JAI-51 also inhibited the activity of P-gp and BCRP, without being a substrate of these efflux pumps. These <it>in vitro </it>studies were reinforced by our <it>in vivo </it>investigations of C57BL/6 mice bearing GL26 glioblastoma xenografts, in which JAI-51 induced a delay in tumour onset and a tumour growth inhibition, following intraperitoneal administration of 96 mg/kg once a week. In accordance with these results, JAI-51 was detected by HPLC in the tumours of the treated animals. Moreover, JAI-51 was detected in the brain, showing that the molecule is also able to cross the BBB.</p> <p>Conclusion</p> <p>These <it>in vitro </it>and <it>in vivo </it>data suggest that JAI-51 could be a good candidate for a new treatment of tumours of the CNS. Further investigations are in progress to associate the title compound chemotherapy to radiotherapy in a rat model.</p

The crystal and molecular structures of the nickel(II) complexes of malonamide-derived unsubstituted 14-and 13-membered tetraazamacrocycles and NMR study of the complexes in aqueous solution

The crystal structures of the nickel(II) complexes of the 14- and 13-membered malonamide-derived macrocycles [NiL1]. 6H(2)O and [NiL2]. 5H(2)O (H2L1 = 1,4,8,11-tetraazacyclotetradecane-5,7-dione, H2L2=1,4,7,10-tetraazacyclotridecane- 11,13-dione) have been determined. Two deprotonated amide and two amine donors form the approximately square planar environment of the metal in both complexes. The averaged Ni-N-amide and Ni-N-amine bonds are longer in the complex of the 14-membered macrocycle as compared to the 13-membered one (1.889 vs. 1.839 Angstrom and 1.941 vs. 1.889 Angstrom for [NiL1] and [NiL2] respectively). Water molecules do not co-ordinate but form an extended network of hydrogen bonds in the crystal lattices. The ligand in [NiL1]. 6H(2)O has the N-meso and in [NiL2]. 5H(2)O the N-rac configuration of the secondary amino groups. The analysis of H-1 NMR spectra reveals that the solid state conformation of both the 14- and 13-membered co-ordinated ligands is retained in aqueous solution though a substantial amount of the N-meso isomer is also detected for the latter.</p

Cyclic voltammetry study of the electrocatalysis of carbon dioxide reduction by bis(polyazamacrocyclic) nickel complexes

Two series of binuclear macrocyclic nickel(II) complexes with varying lengths of the chain linking the two macrocyclic rings were characterised by cyclic voltammetry under argon and CO2. The first series consisted of binuclear complexes [Ni2L2-6](4+) containing pentaaza macrocycles with (CH2)(n) bridges (n = 2, 3, 4, 6) or a p-xylyl linkage (L-6). In general, the two nickel sites in the binuclear complexes behave independently with the currents corresponding to the simultaneous transfer of two electrons. The redox potentials are remarkably constant along this series, but the peak separations increase, reflecting slower electron transfer due to more effective adsorption on the electrode. Electrochemical data for the electrocatalytic reduction of CO2 in MeCN/10% H2O revealed catalytic waves for CO2 reduction with EF, close to - 1.7 V and catalytic currents (i(p)(c)) which are about half those of the mononuclear complex, proposed to be due to steric constraints allowing strong interaction of only one nickel centre of the binuclear one on the surface. The catalytic currents increased slightly as the linking chain length increased as the stereochemical constrains were relaxed somewhat. There was also a splitting in the catalytic peaks of the bismacrocyclic complexes which could reflect two types of adsorbed catalyst sites. In the more sterically crowded series of complex, [Ni2L7](4+) along with the series of linked heptaaza macrocyclic complexes [Ni2L9-11](4+) much more positive redox potentials were observed due to both alkylation of the coordinated nitrogen atoms, which decreases the ligand field, and the introduction of steric barriers to axial coordination. These steric barriers prevented strong electrode interaction and led to a lower catalytic activity. Indeed, the complex [Ni2L7](4+) did not even show any interaction with CO2 in dry acetonitrile. The complexes showed well separated peaks due to solution and surface catalytic activity, and the surface catalytic currents were now comparable to mononuclear complexes at the same effective concentration. We proposed that the less effective absorption on the electrode arising from ligand steric interactions places far fewer stereochemical constraints on the adsorption of both nickel centres to the same extent as the binuclear complex, and hence the catalytic currents for binuclear complex and mononuclear complex are comparable. (C) 2000 Elsevier Science Ltd. All rights reserved.</p

Restorative benefits of the natural environment : enhancing restoration of directed attention & stress reduction through raising levels of cognitive awareness & physical encounter

Interaction with the natural environment has a vital role in human well-being - physical, social, spiritual and psychological - and yet in the twenty-first century many people lead a way of life totally separated from natural environments. Built environments and the increasing complexity of technological tasks necessitate increased demands for attention and a constant processing of information. Adaptation to such demands can result in depletion of psychological resources leading to stress and mental fatigue. Psychological resources must then be “restored” as they are critical for effective functioning. A review of restorative environments literature suggests there is further scope for enhancing restorative opportunities. A hypothetical model of enhanced restoration is proposed. It posits that an individual assuming a more active role, through raised cognitive awareness and physical encounter in the person-natural environment interaction will experience enhanced restoration in terms of restoration of directed attention and reduction of stress. The research hypotheses are tested using a quantitative field-based pretest-posttest experimental design with a sample of 100 volunteers. Data is collected through computerised objective and subjective measurement scales of attention and affect. Data is analysed through ANOVA. The major finding is that posttest scores improved compared to pretest scores in all 3 attention tests, 2 subjective attention scores and both affect measures, averaged over all 4 intervention groups. This means that the participants’ directed attention improved and they considered themselves to be less stressed regardless of the allocated experimental intervention group. Therefore, the most effective intervention in improving directed attention fatigue and reducing stress was raising an individual’s level of physical encounter with the natural environment. Further research is warranted, into the contribution that an individual can make to enhance the restorative process, and the need for education to raise awareness of the importance of the natural environment as a valuable (health-care) resource

Dilemma game in a cellular automaton model with a non-signalized intersection

We numerically study traffic flow, energy dissipation and social payoff in the Nagel-Schreckenberg model with a non-signalized intersection. In terms of game theory, we analyze dilemma game observed in some traffic states. There are four traffic phases: free-flow phase, phase-segregated 1, phase-segregated 2 and jammed phase in the case of vmax > 1. In phase-segregated 1, maximum traffic flow corresponds to minimal energy dissipation. Dilemma game is observed at the phase-segregated 1 in the case of vmax > 1, and phase segregation state when vmax = 1. Theoretical analyses give an agreement with numerical results