Novel diaroylhydrazine ligands as iron chelators: coordination chemistry and biological activity

The search for orally effective drugs for the treatment of iron overload disorders is an important goal in improving the health of patients suffering diseases such as beta-thalassemia major. Herein, we report the syntheses and characterization of some new members of a series of N-aroyl-N'-picolinoyl hydrazine chelators (the H2IPH analogs). Both 1:1 and 1:2 Fe-III:L complexes were isolated and the crystal structures of Fe(HPPH)Cl-2, Fe(4BBPH)Cl-2, Fe(HAPH)(APH) and Fe(H3BBPH)(3BBPH) were determined (H2PPH=N,N'-bis-picolinoyl hydrazine; H(2)APH=N-4-aminobenzoyl-N'-picolinoyl hydrazine, H(2)3BBPH=N-3-bromobenzoyl-N'-picolinoylhydrazine and H(2)4BBPH=N-(4-bromobenzoyl)-N'-(picolinoyl)hydrazine). In each case, a tridentate N,N,O coordination mode of each chelator with Fe was observed. The Fe-III complexes of these ligands have been synthesized and their structural, spectroscopic and electrochemical characterization are reported. Five of these new chelators, namely H2BPH (N-(benzoyl)-N'-(picolinoyl)hydrazine), H2TPH (N-(2-thienyl)-N'-(picolinoyl)-hydrazine), H2PPH, H(2)3BBPH and H(2)4BBPH, showed high efficacy at mobilizing Fe-59 from cells and inhibiting Fe-59 uptake from the serum Fe transport protein, transferrin (Tf). Indeed, their activity was much greater than that found for the chelator in current clinical use, desferrioxamine (DFO), and similar to that observed for the orally active chelator, pyridoxal isonicotinoyl hydrazone (H2PIH). The ability of the chelators to inhibit Fe-59 uptake could not be accounted for by direct chelation of Fe-59-Tf. The most effective chelators also showed low antiproliferative activity which was similar to or less than that observed with DFO, which is important in terms of their potential use as agents to treat Fe-overload disease.

Edge-to-edge matching and its applications - Part I. Application to the simple HCP/BCC system

The edge-to-edge matching crystallographic model has been used to predict all the orientation relationships (OR) between crystals that have simple hexagonal close packed (HCP) and body-centered cubic (BCC) structures. Using the critical values for the interatomic spacing misfit along the matching directions and the cl-value mismatch between matching planes, the model predicted all the four common ORs, namely the Burgers OR, the Potter OR, the Pitsch-Schrader OR and the Rong Dunlop OR, together with the corresponding habit planes. Taking the c(H)/a(H) and a(H)/a(B) ratios as variables, where H and B denote the HCP and BCC structures respectively, the model also predicted the relationship between these variables and the four ORs. These predictions are perfectly consistent with the published experimental results. As was the case in the FCC/BCC system, the edge-to-edge matching model has been shown to be a powerful tool for predicting the crystallographic features of diffusion-controlled phase transformations. (C) 2004 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Edge-to-edge matching and its applications - Part II. Application to Mg-Al, Mg-Y and Mg-Mn alloys

A model for the crystallography and morphology of diffusion-controlled phase transformations - edge-to-edge matching - has been used to predict the orientation relationships (OR) and habit planes of precipitates Mg17Al12 in Mg-Al alloy, Mg24Y5 in Mg-Y alloy and alpha-Mn in Mg-Mn alloy. Based on the crystal structures and lattice parameters only, the model predicts that the possible ORs between Mg17Al12 and Mg matrix are the near Burgers OR, the Potter OR, the Gjonnes-Ostmoe OR and the Crawley OR. In the Mg-Y alloy, the OR between Mg24Y5 precipitates and the Mg matrix is predicted to be the Burgers OR only. The model also predicts that there are no reproducible ORs between alpha-Mn and Mg in the Mg-Mn alloy. Combining the edge-to-edge matching model and W. Zhang's Deltag approach, the habit plane and side facets of the precipitate for each OR can be determined. All the predicted ORs and the corresponding habit planes in Mg-Al and Mg-Y alloys agree very well with the experimental results. (C) 2004 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Novel natriuretic peptides from the venom of the inland taipan (Oxyuranus microlepidotus): isolation, chemical and biological characterisation

Three natriuretic-like peptides (TNP-a, TNP-b, and TNP-c) were isolated from the venom of Oxyuranus microlepidotus (inland taipan) and were also present in the venoms of Oxyuranus scutellatus canni (New Guinea taipan) and Oxyuranus scutellatus scutellatus (coastal taipan). They were isolated by HPLC, characterised by mass spectrometry and Edman analysis, and consist of 35-39 amino acid residues. These molecules differ from ANP/BNP through replacement of invariant residues within the 17-membered ring structure and by inclusion of proline residues in the C-terminal tail. TNP-c was equipotent to ANP in specific GC-A assays or aortic ring assays whereas TNP-a and TNP-b were either inactive (GC-A over-expressing cells and endothelium-denuded aortic rings) or weakly active (endothelium-in tact aortic rings). TNP-a and TNP-b were also unable to competitively inhibit the binding of TNP-c in endothelium-denuded aortae (GC-A) or endothelium-in tact aortae (NPR-C). Thus, these naturally occurring isoforms provide a new platform for further investigation of structure-function relationships of natriuretic peptides. (C) 2004 Elsevier Inc. All rights reserved.

Biological monitoring and Biological Limit Values (BLV): The strategy of the European Union

Occupational standards concerning allowable concentrations of chemical compounds in the ambient air of workplaces have been established in several countries worldwide. With the integration of the European Union (EU), there has been a need of establishing harmonised Occupational Exposure Limits (OEL). The European Commission Directive 95/320/EC of 12 July 1995 has given the tasks to a Scientific Committee for Occupational Exposure Limits (SCOEL) to propose, based on scientific data and where appropriate, occupational limit values which may include the 8-h time-weighted average (TWA), short-term limits/excursion limits (STEL) and Biological Limit Values (BLVs). In 2000, the European Union issued a list of 62 chemical substances with Occupational Exposure Limits. Of these, 25 substances received a skin notation, indicating that toxicologically significant amounts may be taken up via the skin. For such substances, monitoring of concentrations in ambient air may not be sufficient, and biological monitoring strategies appear of potential importance in the medical surveillance of exposed workers. Recent progress has been made with respect to formulation of a strategy related to health-based BLVs. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

Proteins in the saliva of the Ixodida (ticks): Pharmacological features and biological significance

The saliva of ticks (Suborder Ixodida) is critical to their survival as parasites. A tick bite should result in strong responses from the host defence systems (haemostatic, immune and inflammatory) but tick saliva appears to have evolved to counter these responses. We review current knowledge of tick saliva components, with emphasis on those molecules confirmed to be present in the secreted saliva but including some that have only been confirmed to be present in salivary glands. About 50 tick saliva proteins that are well described in the literature are discussed. These saliva components include enzymes, enzyme inhibitors, amine-binding proteins and cytokine homologues that act as anti-haemostatic, anti-inflammatory or immuno-modulatory agents. Sequence comparisons are illustrated. The importance of tick saliva and the significance of the findings to date are also discussed. (C) 2006 Elsevier Ltd. All rights reserved.

Cinderella and the wicked stepmother: How do we perceive step and biological families?

Undergraduate psycholog)' students from stepfamilies (always one step and one biological parent) and biologically intact families (always both biological parents) participated in this study. The goal was to assess perceptions of stepfamilies (N = 106, Nstepfamilies = 44, Nbiological = 62, age range = 17.17 to 28.92 years, M = 19.46 years). One theoretical perspective, the social stigma h)'pothesis, argues that there is a stigma attached to stepfamilies, or that stepfamilies are consistentiy associated with negative stereotypes. In the current study, participants were assessed on a number of variables, including a semantic differential scale, a perceived conflict scale and a perceived general satisfaction scale. It was found that a consistently negative view of stepfamilies was prevalent. Furthermore, the negative stereotypes existed, irrespective of participant family type. Results support the theoretical view that stepfamilies are stereotypically viewed as negative, when compared to biological families.